TW202515614A - Methods and compositions for treating non-small cell lung cancer - Google Patents

Abstract

The present invention relates to the treatment of non-small cell lung cancer (NSCLC). More specifically, the invention relates to the treatment of patients having an NSCLC by administering a treatment regimen that includes an anti-TIGIT antagonist antibody (e.g., tiragolumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) following surgical resection and adjuvant chemotherapy or by administering a treatment regimen that includes an adjuvant chemotherapy, an anti-TIGIT antagonist antibody (e.g., tiragolumab), and a PD-1 axis binding antagonist (e.g., atezolizumab) following surgical resection.

Description

Translated fromChinese

治療非小細胞肺癌之方法及組成物Methods and compositions for treating non-small cell lung cancer

本發明涉及非小細胞肺癌 (NSCLC) 之治療。更具體而言，本發明涉及藉由在手術切除及輔助化學療法後投予包括抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 的治療方案或者藉由在手術切除後投予包括輔助化學療法、抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 的治療方案來治療患有 NSCLC 之患者。The present invention relates to the treatment of non-small cell lung cancer (NSCLC). More specifically, the present invention relates to treating patients with NSCLC by administering a treatment regimen comprising an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) after surgical resection and adjuvant chemotherapy or by administering a treatment regimen comprising adjuvant chemotherapy, an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) after surgical resection.

肺癌仍然係全球癌症死亡之主要原因，且係男性及女性兩者最常見的癌症之一。據估計，在 2023 年，美國有 238,340 例新發肺癌病例及 127,070 例肺癌死亡病例。來自歐洲的資料估計，2023 年將有 159,057 例肺癌死亡。Lung cancer remains the leading cause of cancer death worldwide and is one of the most common cancers in both men and women. It is estimated that in 2023, there will be 238,340 new cases of lung cancer and 127,070 lung cancer deaths in the United States. Data from Europe estimate that there will be 159,057 lung cancer deaths in 2023.

非小細胞肺癌 (NSCLC) 為肺癌之主要亞型，佔所有病例之約 80%-85%。NSCLC 可分為兩種主要的組織學類型：腺癌及鱗狀細胞癌。腺癌組織學佔所有 NSCLC 之約 40%-50%，而鱗狀細胞組織學佔 NSCLC 之約 20%-30%。其餘的 NSCLC 病例以大細胞癌、神經內分泌腫瘤、及肉瘤樣癌為代表，並且組織學分化差。Non-small cell lung cancer (NSCLC) is the major subtype of lung cancer, accounting for approximately 80%-85% of all cases. NSCLC can be divided into two major histological types: adenocarcinoma and squamous cell carcinoma. Adenocarcinoma histology accounts for approximately 40%-50% of all NSCLCs, while squamous cell histology accounts for approximately 20%-30% of NSCLCs. The remaining NSCLC cases are represented by large cell carcinomas, neuroendocrine tumors, and sarcomatoid carcinomas, and are poorly differentiated histologically.

在美國，每 100,000 例中 I、II、IIIA、IIIB 及 IV 期 NSCLC 之年發生率 (2017) 分別為 13.2、3.8、5.9、2.5 及 19.6。此外，在美國，診斷時患有局限性疾病 (I-II 期) 的患者之 5 年存活為 59.0%，患有區域性疾病 (III 期) 的患者之 5 年存活降至 31.7%，且患有轉移性疾病 (IV 期) 的患者之 5 年存活為 5.8%。In the United States, the annual incidence rates (2017) for stage I, II, IIIA, IIIB, and IV NSCLC are 13.2, 3.8, 5.9, 2.5, and 19.6 per 100,000 cases, respectively. Additionally, in the United States, the 5-year survival for patients with localized disease (stages I-II) at diagnosis is 59.0%, which decreases to 31.7% for patients with regional disease (stage III), and 5.8% for patients with metastatic disease (stage IV).

在其早期階段，NSCLC 的手術治療具有治愈目的。然而，接受切除的患者中有 30% 至 70% 由於疾病進展而導致復發並死亡。不再建議手術後放射療法作為 I 期及 II 期 NSCLC 患者的輔助治療選擇，因為它已被證明對長期存活產生有害影響。In its early stages, surgical treatment of NSCLC has curative intent. However, 30% to 70% of patients who undergo resection will have their cancer relapse and die due to progressive disease. Postoperative radiation therapy is no longer recommended as an adjuvant treatment option for patients with stage I and II NSCLC because it has been shown to have a deleterious effect on long-term survival.

因此，對於患有 NSCLC 之患者，迫切需要新的、有效的輔助療法。Therefore, new and effective adjuvant therapies are urgently needed for patients with NSCLC.

在一個態樣中，本發明提供了一種治療患有非小細胞肺癌 (NSCLC) 之個體的方法，該方法包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且個體已接受輔助化學療法。In one aspect, the invention provides a method of treating an individual having non-small cell lung cancer (NSCLC), the method comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received adjuvant chemotherapy.

在某些態樣中，該個體已接受介於一個給藥週期與四個給藥週期之間之輔助化學療法 (例如，已接受四個給藥週期之輔助化學療法)。In some aspects, the subject has received between one dosing cycle and four dosing cycles of adjuvant chemotherapy (e.g., has received four dosing cycles of adjuvant chemotherapy).

在另一態樣中，本發明提供了一種治療患有非小細胞肺癌 (NSCLC) 之個體的方法，該方法包含向該個體投予輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除。In another aspect, the invention provides a method of treating an individual having non-small cell lung cancer (NSCLC), the method comprising administering to the individual adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected.

在一些態樣中，該方法包含向個體投予介於一個給藥週期與四個給藥週期之間之輔助化學療法 (例如，包含向個體投予四個給藥週期之輔助化學療法)。In some aspects, the method comprises administering to the subject between one dosing cycle and four dosing cycles of adjuvant chemotherapy (e.g., comprises administering to the subject four dosing cycles of adjuvant chemotherapy).

在一些態樣中，在最後投予的一劑該輔助化學療法之後十週內開始該一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗之投予。In some aspects, administration of the one or more dosing cycles of tislelizumab and atezolizumab is initiated within ten weeks after the last dose of the adjuvant chemotherapy.

在一些態樣中，該方法包含每四週以約 1680 mg 之固定劑量向個體投予阿替利珠單抗。In some aspects, the method comprises administering to the subject atezolizumab at a fixed dose of about 1680 mg every four weeks.

在一些態樣中，該方法包含每四週以約 840 mg 之固定劑量向個體投予替瑞利尤單抗。In some aspects, the method comprises administering to the subject tisleliumab at a fixed dose of about 840 mg every four weeks.

在一些態樣中，替瑞利尤單抗及阿替利珠單抗之一個或多個給藥週期中之各者的長度為 28 天。在一些態樣中，該方法包含在各 28 天給藥週期之約第 1 天向個體投予阿替利珠單抗及/或替瑞利尤單抗。In some aspects, each of one or more dosing cycles of tisleliumab and atezolizumab is 28 days in length. In some aspects, the method comprises administering atezolizumab and/or tisleliumab to the individual on about day 1 of each 28-day dosing cycle.

在一些態樣中，該方法包含向個體共同投予阿替利珠單抗及替瑞利尤單抗。在一些態樣中，該方法包含藉由靜脈內共同輸注向個體共同投予阿替利珠單抗及替瑞利尤單抗。在一些態樣中，將阿替利珠單抗及替瑞利尤單抗調配在一起並作為固定劑量組合 (FDC) 靜脈內投予。In some aspects, the method comprises co-administering atezolizumab and tisleliumab to a subject. In some aspects, the method comprises co-administering atezolizumab and tisleliumab to a subject by co-infusion intravenously. In some aspects, atezolizumab and tisleliumab are formulated together and administered intravenously as a fixed dose combination (FDC).

在其他態樣中，該方法包含 (i) 在替瑞利尤單抗之前向個體投予 (例如，靜脈內投予) 阿替利珠單抗或 (ii) 在阿替利珠單抗之前向個體投予 (例如，靜脈內投予) 替瑞利尤單抗。In other aspects, the method comprises (i) administering (e.g., intravenously) atezolizumab to the individual prior to tislelizumab or (ii) administering (e.g., intravenously) tislelizumab to the individual prior to atezolizumab.

在一些態樣中，向個體投予至多 13 個給藥週期之替瑞利尤單抗及阿替利珠單抗。In some aspects, up to 13 dosing cycles of tisleliumab and atezolizumab are administered to a subject.

在一些態樣中，向個體投予若干給藥週期之替瑞利尤單抗及阿替利珠單抗，持續至多一年。In some aspects, the subject is administered dosing cycles of tisleliumab and atezolizumab for up to one year.

在另一態樣中，本發明提供了一種治療患有 NSCLC 之個體的方法，該方法包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且個體已接受介於一個週期與四個週期之間之鉑類輔助化學療法，其中該 NSCLC 為 (a) IIB 期 NSCLC；(b) IIIA 期 NSCLC；或 (c) T3N2 IIIB 期 NSCLC。In another aspect, the invention provides a method of treating an individual having NSCLC, the method comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received between one and four cycles of platinum-based adjuvant chemotherapy, wherein the NSCLC is (a) stage IIB NSCLC; (b) stage IIIA NSCLC; or (c) T3N2 stage IIIB NSCLC.

在另一態樣中，本發明提供了一種治療患有 NSCLC 之個體的方法，該方法包含向該個體投予介於一個週期與四個週期之間之鉑類輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除，其中該 NSCLC 為 (a) IIB 期 NSCLC；(b) IIIA 期 NSCLC；或 (c) T3N2 IIIB 期 NSCLC。In another aspect, the invention provides a method of treating an individual having NSCLC, the method comprising administering to the individual between one and four cycles of platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is (a) stage IIB NSCLC; (b) stage IIIA NSCLC; or (c) T3N2 stage IIIB NSCLC.

在另一態樣中，本發明提供了一種替瑞利尤單抗及/或阿替利珠單抗在藥物的製造中之用途，該藥物用於治療患有 NSCLC 之個體，該治療包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除，並且改個體已接受輔助化學療法。In another aspect, the present invention provides a use of tisleliumab and/or atezolizumab in the manufacture of a medicament for treating an individual suffering from NSCLC, the treatment comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received adjuvant chemotherapy.

在另一態樣中，本發明提供了一種替瑞利尤單抗及/或阿替利珠單抗在藥物的製造中之用途，該藥物用於治療患有 NSCLC 之個體，該治療包含向該個體投予輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除。In another aspect, the present invention provides a use of tisleliumab and/or atezolizumab in the manufacture of a medicament for treating an individual with NSCLC, the treatment comprising administering to the individual adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected.

在另一態樣中，本發明提供了替瑞利尤單抗及/或阿替利珠單抗，其使用於治療患有 NSCLC 之個體，該治療包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且個體已接受輔助化學療法。In another aspect, the present invention provides tisleliumab and/or atezolizumab for use in treating an individual with NSCLC, the treatment comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received adjuvant chemotherapy.

在另一態樣中，本發明提供了替瑞利尤單抗及/或阿替利珠單抗，其使用於治療患有 NSCLC 之個體，該治療包含向該個體投予輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除。In another aspect, the present invention provides tisleliumab and/or atezolizumab for use in treating an individual with NSCLC, the treatment comprising administering to the individual adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected.

在某些態樣中，該個體已接受介於一個給藥週期與四個給藥週期之間之輔助化學療法 (例如，已接受四個給藥週期之輔助化學療法)。In some aspects, the subject has received between one dosing cycle and four dosing cycles of adjuvant chemotherapy (e.g., has received four dosing cycles of adjuvant chemotherapy).

在一些態樣中，待向個體投予介於一個給藥週期與四個給藥週期之間之輔助化學療法 (例如，待向個體投予四個給藥週期之輔助化學療法)。In some aspects, between one dosing cycle and four dosing cycles of adjuvant chemotherapy are administered to the subject (e.g., four dosing cycles of adjuvant chemotherapy are administered to the subject).

在一些態樣中，待在最後投予的一劑輔助化學療法後十週內開始一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗之投予。In some aspects, administration of one or more dosing cycles of tislelizumab and atezolizumab is initiated within ten weeks after the last dose of adjuvant chemotherapy.

在一些態樣中，待每四週以約 1680 mg 之固定劑量投予阿替利珠單抗。在一些態樣中，待每四週以約 840 mg 之固定劑量投予替瑞利尤單抗。In some aspects, atezolizumab is administered at a fixed dose of about 1680 mg every four weeks. In some aspects, tisleliumab is administered at a fixed dose of about 840 mg every four weeks.

在一些態樣中，替瑞利尤單抗及阿替利珠單抗之一個或多個給藥週期中之各者的長度為 28 天。在一些態樣中，待在各 28 天給藥週期之約第 1 天向該個體投予阿替利珠單抗及/或替瑞利尤單抗。In some aspects, the length of each of one or more dosing cycles of tisleliumab and atezolizumab is 28 days. In some aspects, atezolizumab and/or tisleliumab are administered to the individual on about day 1 of each 28-day dosing cycle.

在一些態樣中，待向個體共同投予阿替利珠單抗及替瑞利尤單抗。在一些態樣中，待藉由靜脈內共同輸注向個體共同投予阿替利珠單抗及替瑞利尤單抗。在一些態樣中，待將阿替利珠單抗及替瑞利尤單抗調配在一起並作為固定劑量組合 (FDC) 靜脈內投予。在其他態樣中，(i) 待在替瑞利尤單抗之前向個體投予 (例如，靜脈內投予) 阿替利珠單抗或 (ii) 待在阿替利珠單抗之前向個體投予 (例如，靜脈內投予) 替瑞利尤單抗。In some aspects, atezolizumab and tisleliumab are co-administered to a subject. In some aspects, atezolizumab and tisleliumab are co-administered to a subject by co-infusion intravenously. In some aspects, atezolizumab and tisleliumab are formulated together and administered intravenously as a fixed dose combination (FDC). In other aspects, (i) atezolizumab is administered (e.g., intravenously) to a subject prior to tisleliumab or (ii) tisleliumab is administered (e.g., intravenously) to a subject prior to atezolizumab.

在一些態樣中，待向個體投予至多 13 個給藥週期之替瑞利尤單抗及阿替利珠單抗。在一些態樣中，待向個體投予若干給藥週期之替瑞利尤單抗及阿替利珠單抗，持續至多一年。In some aspects, up to 13 dosing cycles of tisleliumab and atezolizumab are administered to the subject. In some aspects, several dosing cycles of tisleliumab and atezolizumab are administered to the subject for up to one year.

在另一態樣中，本發明提供了一種替瑞利尤單抗及/或阿替利珠單抗在藥物的製造中之用途，該藥物用於治療患有 NSCLC 之個體，該治療包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且該個體已接受介於一個週期與四個週期之間之鉑類輔助化學療法，其中該 NSCLC 為 (a) IIB 期 NSCLC；(b) IIIA 期 NSCLC；或 (c) T3N2 IIIB 期 NSCLC。In another aspect, the present invention provides a use of tisleliumab and/or atezolizumab in the manufacture of a medicament for treating an individual with NSCLC, the treatment comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received between one and four cycles of platinum-based adjuvant chemotherapy, wherein the NSCLC is (a) stage IIB NSCLC; (b) stage IIIA NSCLC; or (c) T3N2 stage IIIB NSCLC.

在另一態樣中，本發明提供了一種替瑞利尤單抗及/或阿替利珠單抗在藥物的製造中之用途，該藥物用於治療患有 NSCLC 之個體，該治療包含向該個體投予介於一個週期與四個週期之間之鉑類輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除，其中該 NSCLC 為 (a) IIB 期 NSCLC；(b) IIIA 期 NSCLC；或 (c) T3N2 IIIB 期 NSCLC。In another aspect, the present invention provides a use of tisleliumab and/or atezolizumab in the manufacture of a medicament for treating an individual with NSCLC, the treatment comprising administering to the individual between one cycle and four cycles of platinum-based adjuvant chemotherapy, followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is (a) stage IIB NSCLC; (b) stage IIIA NSCLC; or (c) T3N2 stage IIIB NSCLC.

在另一態樣中，本發明提供了替瑞利尤單抗及/或阿替利珠單抗，其使用於治療患有 NSCLC 之個體，該治療包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且個體已接受介於一個週期與四個週期之間之鉑類輔助化學療法，其中該 NSCLC 為 (a) IIB 期 NSCLC；(b) IIIA 期 NSCLC；或 (c) T3N2 IIIB 期 NSCLC。In another aspect, the present invention provides tisleliumab and/or atezolizumab for use in treating an individual with NSCLC, the treatment comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received between one and four cycles of platinum-based adjuvant chemotherapy, wherein the NSCLC is (a) stage IIB NSCLC; (b) stage IIIA NSCLC; or (c) T3N2 stage IIIB NSCLC.

在另一態樣中，本發明提供了替瑞利尤單抗及/或阿替利珠單抗，其使用於治療患有 NSCLC 之個體，該治療包含向該個體投予介於一個週期與四個週期之間之鉑類輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除，其中該 NSCLC 為 (a) IIB 期 NSCLC；(b) IIIA 期 NSCLC；或 (c) T3N2 IIIB 期 NSCLC。In another aspect, the present invention provides tisleliumab and/or atezolizumab for use in treating an individual with NSCLC, the treatment comprising administering to the individual between one cycle and four cycles of platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is (a) stage IIB NSCLC; (b) stage IIIA NSCLC; or (c) T3N2 stage IIIB NSCLC.

在一些態樣中，完全切除為肺葉切除術、袖式肺葉切除術、雙肺葉切除術或肺切除術。在一些態樣中，完全切除係產生 (i) 無殘留腫瘤及 (ii) 所有手術切緣均呈侵襲性癌陰性之切除。In some aspects, a complete resection is a lobectomy, a sleeve lobectomy, a bilobectomy, or a pneumonectomy. In some aspects, a complete resection is a resection that results in (i) no residual tumor and (ii) all surgical margins being negative for invasive cancer.

在一些態樣中，輔助化學療法為鉑類輔助化學療法。在一些態樣中，鉑類輔助化學療法包含順鉑。在一些態樣中，鉑類輔助化學療法包含卡鉑。In some embodiments, the adjuvant chemotherapy is platinum-based adjuvant chemotherapy. In some embodiments, the platinum-based adjuvant chemotherapy comprises cis-platinum. In some embodiments, the platinum-based adjuvant chemotherapy comprises carboplatinum.

在一些態樣中，鉑類輔助化學療法進一步包含一種或多種另外的化學治療劑。在一些態樣中，一種或多種另外的化學治療劑包含長春花屬生物鹼 (vinca alkaloid) (例如，長春瑞濱)、紫杉烷 (例如，多西紫杉醇或紫杉醇)、抗代謝物 (例如，吉西他濱或培美曲塞)、拓樸異構酶 II 抑制劑 (例如，依托泊苷) 或其組合。In some embodiments, the platinum-adjuvant chemotherapy further comprises one or more additional chemotherapeutic agents. In some embodiments, the one or more additional chemotherapeutic agents comprise a vinca alkaloid (e.g., vinorelbine), a taxane (e.g., docetaxel or paclitaxel), an anti-metabolite (e.g., gemcitabine or pemetrexed), a topoisomerase II inhibitor (e.g., etoposide), or a combination thereof.

在一些態樣中，鉑類輔助化學療法為鉑類輔助雙效化學療法。在一些態樣中，鉑類輔助雙效化學療法包含 (i) 以一個或多個 21 天給藥週期投予之順鉑及培美曲塞，其中在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞；(ii) 以一個或多個 21 天給藥週期投予之順鉑及吉西他濱，其中在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且在各 21 天給藥週期之第 1 天及第 8 天以約 1250 mg/m²的劑量投予吉西他濱；(iii) 以一個或多個 21 天給藥週期投予之順鉑及多西他賽，其中在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量投予多西紫杉醇；(iv) 以一個或多個 28 天給藥週期投予之順鉑及長春瑞濱，其中在各 28 天給藥週期之第 1 天及第 8 天以約 50 mg/m²的劑量靜脈內投予順鉑，且在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 25 mg/m²的劑量投予長春瑞濱；(v) 以一個或多個 28 天給藥週期投予之順鉑及長春瑞濱，其中在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，且在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 30 mg/m²的劑量投予長春瑞濱；(vi) 以一個或多個 21 天給藥週期投予之順鉑及長春瑞濱，其中在各 21 天給藥週期之第 1 天及第 8 天以約 75 至 80 mg/m²的劑量靜脈內投予順鉑，且在各 21 天給藥週期之第 1 天及第 8 天以約 25 至 30 mg/m²的劑量投予長春瑞濱；(vii) 以一個或多個 28 天給藥週期投予之順鉑及依托泊苷，其中在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，且在各 28 天給藥週期之第 1 天至第 3 天以約 100 mg/m²的劑量投予依托泊苷；(viii) 以一個或多個 21 天給藥週期投予之卡鉑及紫杉醇，其中在各 21 天給藥週期之第 1 天以 AUC 6 靜脈內投予卡鉑，且在各 21 天給藥週期之第 1 天以約 200 mg/m²的劑量投予紫杉醇；(ix) 以一個或多個 21 天給藥週期投予之卡鉑及吉西他濱，其中在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，且在各 21 天給藥週期之第 1 天及第 8 天以約 1000 mg/m²的劑量投予吉西他濱；或者 (x) 以一個或多個 21 天給藥週期投予之卡鉑及吉西他濱，其中在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，且在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞。In some aspects, platinum-adjuvanted chemotherapy is platinum-adjuvanted double-acting chemotherapy. In some embodiments, the platinum-based adjuvant dual-acting chemotherapy comprises (i) c-platin and pemetrexed administered in one or more 21-day dosing cycles, wherein c-platin is administered intravenously at a dose of about 75 mg/m² on day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/m² on day 1 of each 21-day dosing cycle; (ii) c-platin and gemcitabine administered in one or more 21-day dosing cycles, wherein c-platin is administered intravenously at a dose of about 75 mg/m² on day 1 of each 21-day dosing cycle, and pemetrexed is administered intravenously on days 1 and 8 of each 21-day dosing cycle. (iii) cisplatin and docetaxel administered in one or more 21-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 75 mg/m² on Day 1 of each 21-day dosing cycle, and docetaxel is administered at a dose of about 75 mg/m² on Day 1 of each 21-day dosing cycle; (iv) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 50 mg/m² on Days 1 and 8 of each 28-day dosing cycle, and docetaxel is administered intravenously at a dose of about 75 mg/m² on Day 1 of each 28-day dosing cycle. (v) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle and vinorelbine is administered at a dose of about 30 mg/^m2 on days 1, 8, 15 and 22 of each 28-day dosing cycle; (vi) cisplatin and vinorelbine administered in one or more 21-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 75 to 80 mg/^m2 on days 1 and 8 of each 21-day dosing cycle.² and vinorelbine is administered on Day 1 and Day 8 of each 21-day dosing cycle at a dose of about 25 to 30 mg/^m2 ; (vii) cisplatin and etoposide administered on one or more 28-day dosing cycles, wherein cisplatin is administered on Day 1 of each 28-day dosing cycle at a dose of about 100 mg/^m2 and etoposide is administered on Days 1 to 3 of each 28-day dosing cycle; (viii) carboplatin and paclitaxel administered on one or more 21-day dosing cycles, wherein on Day 1 of each 21-day dosing cycle, the intravenous dose is about 100 mg/m2 and the intravenous dose is about 100 mg/^m2 . (ix) carboplatin and gemcitabine administered in one or more 21-day cycles, wherein carboplatin is administered intravenously at AUC 5 on Day 1 of each 21-day cycle, and paclitaxel is administered at a dose of about 200 mg/m² on Day 1 of each 21-day cycle; or (x) carboplatin and gemcitabine administered in one or more 21-day cycles, wherein carboplatin is administered intravenously at AUC 5 on Day 1 of each 21-day cycle, and gemcitabine is administered at a dose of about 1000 mg/m² on Days 1 and 8 of each 21-day cycle. Pemetrexed is administered at a dose of approximately 500 mg/m² on day 1 of a 4-day dosing cycle.

在一些態樣中，個體在完全切除後尚未經歷 NSCLC 之復發。In some aspects, the individual has not experienced recurrence of NSCLC following complete resection.

在一些態樣中，個體在輔助化學療法後尚未經歷 NSCLC 之復發。In some aspects, the individual has not experienced recurrence of NSCLC following adjuvant chemotherapy.

在一些態樣中，NSCLC 為 (a) IIB 期 NSCLC；(b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。在一些態樣中，NSCLC 分期係依照國際抗癌聯盟/美國癌症聯合委員會 (UICC/AJCC) 分期系統，第 8 版。In some aspects, the NSCLC is (a) stage IIB NSCLC; (b) stage IIIA NSCLC; or (c) T3N2 stage IIIB NSCLC. In some aspects, the NSCLC is staged according to the Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC)staging system, 8th edition.

在一些態樣中，NSCLC 為鱗狀 NSCLC。在其他態樣中，NSCLC 為非鱗狀 NSCLC。In some aspects, the NSCLC is squamous NSCLC. In other aspects, the NSCLC is non-squamous NSCLC.

在一些態樣中，從個體獲得的腫瘤樣品的 PD-L1 陽性腫瘤細胞分數已藉由免疫組織化學 (IHC) 測定法來判定。在一些態樣中，PD-L1 陽性腫瘤細胞分數藉由用抗 PD-L1 抗體進行陽性染色來判定，其中該抗 PD-L1 抗體為 SP263、22C3、SP142 或 28-8 (例如，使用 Ventana SP263 IHC 測定法、pharmDx 22C3 IHC 測定法、Ventana SP142 IHC 測定法或 pharmDx 28-8 IHC 測定法來判定)。In some aspects, the PD-L1 positive tumor cell fraction of a tumor sample obtained from an individual has been determined by an immunohistochemistry (IHC) assay. In some aspects, the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8 (e.g., determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay).

在一些態樣中，PD-L1 陽性腫瘤細胞分數已使用 Ventana SP263 IHC 測定法來判定。在一些態樣中，從個體獲得的腫瘤樣品已被判定具有等於或大於 1% 的任何膜染色高於背景的腫瘤細胞百分比 (TC)。在一些態樣中，從個體獲得的腫瘤樣品已被判定具有等於或大於 50% 的 TC。In some aspects, the PD-L1 positive tumor cell fraction has been determined using the Ventana SP263 IHC assay. In some aspects, a tumor sample obtained from an individual has been determined to have a tumor cell percentage (TC) equal to or greater than 1% with any membrane staining above background. In some aspects, a tumor sample obtained from an individual has been determined to have a TC equal to or greater than 50%.

在一些態樣中，個體不具有上皮生長因子受體 (EGFR) 或退行性淋巴瘤激酶 (ALK) 基因體腫瘤畸變。In some aspects, the individual does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration.

在一些態樣中，個體患有鱗狀 NSCLC 並且尚未針對 EGFR 或 ALK 基因體腫瘤畸變進行評定。In some aspects, the individual has squamous NSCLC and has not been evaluated for EGFR or ALK genomic tumor aberrations.

在一些態樣中，個體未接受過使用 CD137 促效劑或免疫查核點阻斷療法之先前治療。In some aspects, the individual has not received prior treatment with a CD137 agonist or immune checkpoint blockade therapy.

在一些態樣中，與參考 DFS 持續時間 (例如，已接受對照治療 (例如，阿替利珠單抗單一療法) 的個體群體的平均或中值 DFS 持續時間) 相比，治療使無疾病存活 (DFS) 持續時間增加。In some aspects, treatment increases disease-free survival (DFS) duration compared to a reference DFS duration (e.g., the mean or median DFS duration for a population of individuals who have received a control treatment (e.g., atezolizumab monotherapy)).

在一些態樣中，與參考 OS 持續時間 (例如，已接受對照治療 (例如，阿替利珠單抗單一療法) 的個體群體的平均或中值 OS 持續時間) 相比，治療使總存活 (OS) 持續時間增加。In some aspects, treatment increases overall survival (OS) duration compared to a reference OS duration (e.g., the mean or median OS duration in a population of individuals who have received a control treatment (e.g., atezolizumab monotherapy)).

在一些態樣中，與參考 DFS 率 (例如，已接受對照治療 (例如，阿替利珠單抗單一療法) 的個體群體的 DFS 率) 相比，治療使 DFS 率增加。在一些態樣中，DFS 率為 3 年 DFS 率、5 年 DFS 率或 7 年 DFS 率。In some aspects, treatment increases the DFS rate compared to a reference DFS rate, e.g., the DFS rate in a population of individuals who have received a control treatment (e.g., atezolizumab monotherapy). In some aspects, the DFS rate is a 3-year DFS rate, a 5-year DFS rate, or a 7-year DFS rate.

在一些態樣中，個體為人類。In some aspects, the individual is a human.

I.I.定義Definition

如本文所用，術語「約」係指本技術領域技術人員易於知曉的各個值的通常誤差範圍。在本文中，涉及「約」的值或參數包括 (並描述) 指向該值或參數本身之態樣。例如，涉及「約 X」的描述包括對「X」的描述。As used herein, the term "about" refers to the usual error range of various values that are readily known to those skilled in the art. In this article, reference to a value or parameter of "about" includes (and describes) the state of the value or parameter itself. For example, a description of "about X" includes a description of "X".

如本文所用，「鉑類輔助化學療法」或「輔助鉑類化學療法」係指包括鉑類化學治療劑的輔助化學療法方案。例如，輔助鉑類化學療法可包括鉑類化學治療劑 (例如，順鉑或卡鉑) 與一種或多種另外的化學治療劑 (例如，長春花屬生物鹼 (例如，長春瑞濱)、紫杉烷 (例如，多西紫杉醇)、抗代謝物 (例如，吉西他濱或培美曲塞) 或其組合) 的組合。 在一些態樣中，輔助鉑類化學療法是鉑類雙效化學療法，例如，包含鉑類化學治療劑 (例如，卡鉑或順鉑) 及另外的治療劑 (例如，培美曲塞、多西紫杉醇、吉西他濱、長春瑞濱、紫杉醇或 nab-紫杉醇) 的化學療法。「輔助化學療法」係在主要或初始療法之後向個體投予 (例如，在癌症手術切除之後投予) 的化學療法 (例如，化學療法方案)。As used herein, "platinum-adjuvant chemotherapy" or "adjuvant platinum chemotherapy" refers to an adjuvant chemotherapy regimen that includes a platinum-based chemotherapy agent. For example, adjuvant platinum-based chemotherapy may include a combination of a platinum-based chemotherapy agent (e.g., cisplatin or carboplatin) and one or more additional chemotherapy agents (e.g., a vinca alkaloid (e.g., vinorelbine), a taxane (e.g., docetaxel), an anti-metabolite (e.g., gemcitabine or pemetrexed), or a combination thereof). In some aspects, adjuvant platinum chemotherapy is a platinum doublet chemotherapy, e.g., chemotherapy comprising a platinum chemotherapy agent (e.g., carboplatin or cisplatin) and an additional therapeutic agent (e.g., pemetrexed, docetaxel, gemcitabine, vinorelbine, paclitaxel, or nab-paclitaxel). "Adjuvant chemotherapy" is chemotherapy (e.g., a chemotherapy regimen) that is administered to an individual after primary or initial therapy (e.g., administered after surgical resection of a cancer).

「化學治療劑」包括用於治療癌症的化學化合物。化學治療劑的實例包括厄洛替尼 (TARCEVA^®, Genentech/OSI Pharm.)、硼替佐米 (VELCADE^®, Millennium Pharm.)、二硫龍、表沒食子兒茶素沒食子酸酯、salinosporamide A、卡非佐米、17-AAG (格爾德黴素)、根赤殼菌素(radicicol)、乳酸脫氫酶 A (LDH-A)、氟維司群 (FASLODEX^®, AstraZeneca)、舒尼替尼 (SUTENT^®, Pfizer/Sugen)、利妥唑 (FEMARA^®, Novartis)、甲磺酸伊馬替尼 (GLEEVEC^®, Novartis)、finasunate (VATALANIB^®, Novartis)、奧沙利鉑 (ELOXATIN^®, Sanofi)、5-FU (5-氟尿嘧啶)、甲醯四氫葉酸、雷帕黴素 (Sirolimus, RAPAMUNE^®, Wyeth)、拉帕替尼 (TYKERB^®, GSK572016, Glaxo Smith Kline)、Lonafamib (SCH 66336)、索拉非尼 (NEXAVAR^®, Bayer Labs)、吉非替尼 (IRESSA^®, AstraZeneca)、AG1478、烷化劑諸如噻替派及 CYTOXAN^®環磷醯胺；磺酸烷基酯諸如白消安、英丙舒凡及哌泊舒凡；氮丙啶類諸如苯佐替派、卡波醌、美妥替派及烏瑞替派；乙撐亞胺類及甲基蜜胺類，包括六甲蜜胺、三乙撐蜜胺、三乙撐磷醯胺、三乙撐硫代磷醯胺及三羥甲蜜胺；acetogenin (特別是布拉他辛及布拉他辛酮)；喜樹鹼 (包括拓撲替康及伊立替康)；苔蘚蟲素；callystatin；CC-1065 (包括其阿多來新、卡折來新及比折來新合成類似物)；念珠藻素類 (特別是念珠藻素 1 及念珠藻素 8)；腎上腺皮質類固醇類 (包括潑尼松及潑尼松龍)；乙酸環丙孕酮；5α-還原酶 (包括非那雄胺及度他雄胺)；伏立諾他、羅米地辛、帕比司他、丙戊酸、mocetinostat 多拉司他汀、阿地白介素、滑石倍癌黴素 (talc duocarmycin) (包括合成類似物 KW-2189 及 CB1-TM1)；五加素 (eleutherobin)；水鬼蕉鹼；匍枝珊瑚醇 (sarcodictyin)；海綿抑素；氮芥子氣諸如氯芥苯丁酸、萘氮芥、膽磷醯胺 (chloro phosphamide)、雌莫司汀 (estramustine)、依弗醯胺 (ifosfamide)、甲基二(氯乙基)胺、甲基二(氯乙基)胺氧化鹽酸 (mechlorethamine oxide hydrochloride)、黴法蘭、新氮芥 (novembichin)、苯芥膽甾醇 (phenesterine)、潑尼莫司汀 (prednimustine)、曲磷胺 (trofosfamide)、尿嘧啶氮芥 (uracil mustard)；亞硝脲類 (nitrosoureas) 諸如雙氯乙基亞硝脲、氯脲黴素 (chlorozotocin)、福莫司汀 (fotemustine)、洛莫司汀 (lomustine)、尼莫司汀 (nimustine) 及雷莫司汀 (ranimnustine)；抗生素類諸如烯二炔抗生素 (例如，加利車黴素黴素，特別是加利車黴素 γ1I 及加利車黴素 ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186)；達內黴素 (dynemicin)，包括達內黴素 A (dynemicin A)；雙磷酸鹽類類諸如氯膦酸鹽 (clodronate)；埃斯培拉黴素 (esperamicin)；以及新製癌菌素發色團及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素類 (aclacinomysins)、放線菌素、胺茴黴素 (authramycin)、氮絲胺酸、博來黴素類、放線菌素 (cactinomycin)、卡拉比星 (carabicin)、洋紅黴素 (caminomycin)、嗜癌黴素 (carzinophilin)、色黴素 (chromomycinis)、放線菌素 D (dactinomycin)、道諾黴素、地托比星 (detorubicin)、6-重氮-5-側氧基-L-正白胺酸 (6-diazo-5-oxo-L-norleucine)、ADRIAMYCIN^®(多柔比星)、𠰌啉代多柔比星 (morpholino-doxorubicin)、氰基𠰌啉代多柔比星 (cyanomorpholino-doxorubicin)、2-吡咯代多柔比星 (2-pyrrolino-doxorubicin)及脫氧多柔比星 (deoxydoxorubicin)、表柔比星 (epirubicin)、依索比星 (esorubicin)、伊達比星 (idarubicin)、麻西羅黴素 (marcellomycin)、絲裂黴素類諸如絲裂黴素 C、霉酚酸、諾拉黴素 (nogalamycin)、橄欖黴素類、培洛黴素 (peplomycin)、波弗黴素、嘌呤黴素、三鐵多柔比星 (quelamycin)、羅多比星 (rodorubicin)、鏈黴黑素、鏈佐星 (streptozocin)、殺結核菌素 (tubercidin)、烏苯美司 (ubenimex)、淨司他丁 (zinostatin)、佐柔比星 (zorubicin)；抗代謝物類諸如胺甲喋呤及 5-氟尿嘧啶 (5-FU)；葉酸類似物諸如二甲葉酸 (denopterin)、胺甲喋呤、蝶羅呤 (pteropterin)、三甲曲沙 (trimetrexate)；嘌呤類似物諸如氟達濱 (fludarabine)、6-巰基嘌呤、硫脒嘌呤 (thiamiprine)、硫鳥嘌呤；嘧啶類似物諸如安西他濱 (ancitabine)、阿扎胞苷 (azacitidine)、6-硫唑脲嘧啶、卡莫氟 (carmofur)、阿糖胞苷 (cytarabine)、雙脫氧尿苷 (dideoxyuridine)、去氧氟尿苷、依諾他濱 (enocitabine)、脫氧氟尿苷 (floxuridine)；雄激素類諸如卡魯睪酮 (calusterone)、丙酸屈他雄酮 (dromostanolone propionate)、環硫雄醇 (epitiostanol)、美雄烷 (mepitiostane)、睪內酯 (testolactone)；抗腎上腺素類諸如胺麩精、米托坦 (mitotane)、曲洛司坦 (trilostane)；葉酸補充劑諸如活性葉酸；醋葡醛內酯 (aceglatone)；醛磷醯胺糖苷 (aldophosphamide glycoside)；胺基乙醯丙酸；恩尿嘧啶 (eniluracil)；安吖啶 (amsacrine)；阿莫司汀 (bestrabucil)；比生群 (bisantrene)；依達曲沙 (edatraxate)；地磷醯胺 (defofamine)；地美可辛 (demecolcine)；地吖醌 (diaziquone)；elfomithine；依利醋銨 (elliptinium acetate)；埃博黴素 (epothilone)；依托格魯 (etoglucid)；氮化鎵；羥基脲；蘑菇多糖；洛尼達明 (lonidainine)；美登木素生物鹼類 (maytansinoids) 諸如美登素 (maytansine) 及安絲菌素 (ansamitocins)；米托胍腙 (mitoguazone)；米托蒽醌 (mitoxantrone)；莫哌達醇 (mopidamnol)；二胺硝吖啶 (nitraerine)；噴司他丁 (pentostatin)；蛋胺氮芥 (phenamet)；吡柔比星 (pirarubicin)；洛索蒽醌 (losoxantrone)；鬼臼酸 (podophyllinic acid)；2-乙基醯肼 (2-ethylhydrazide)；丙卡巴肼 (procarbazine)；PSK^®多醣複合物 (JHS Natural Products, Eugene, Oreg.)；雷佐生 (razoxane)；根黴素 (rhizoxin)；西索菲蘭 (sizofuran)；螺旋鍺 (spirogermanium)；細交鏈孢菌酮酸 (tenuazonic acid)；三亞胺醌 (triaziquone)；2,2',2''-三氯三乙胺；新月毒素類 (特別是 T-2 毒素、疣孢菌素 A (verracurin A)、桿孢菌素 A (roridin A) 及蛇行菌素 (anguidine))；烏拉坦；長春地辛 (vindesine)；達卡巴嗪 (dacarbazine)；甘露醇氮芥 (mannomustine)；二溴甘露醇 (mitobronitol)；二溴衛矛醇 (mitolactol)；哌泊溴烷 (pipobroman)；噶薩托辛 (gacytosine)；阿拉伯糖苷 (arabinoside) (「Ara-C」)；環磷醯胺；噻替派(thiotepa)；紫杉烷 (紫杉烷類)，例如，TAXOL^®(卡培他濱、Bristol-Myers Squibb Oncology, Princeton, N.J.)、ABRAXANE^®(無克列莫佛的)、卡培他濱的白蛋白改造的奈米顆粒製劑 (例如，卡培他濱的白蛋白改造的奈米顆粒 (nab-紫杉醇)) (American Pharmaceutical Partners, Schaumberg, Ill.)，及 TAXOTERE^®(多西紫杉醇，doxetaxel；Sanofi-Aventis)；氯芥苯丁酸、GEMZAR^®(吉西他濱)；6-硫鳥嘌呤；巰基嘌呤；胺甲喋呤；鉑類似物諸如順鉑及卡鉑；長春鹼；依托泊苷 (etoposide) (VP-16)；依弗醯胺；米托蒽醌；長春新鹼；NAVELBINE^®(長春瑞濱)；米托蒽醌；替尼泊苷；依達曲沙；道諾黴素；胺基蝶呤；卡培他濱 (XELODA^®)；伊班膦酸鹽；CPT-11；拓撲異構酶抑制劑 RFS 2000；二氟甲基鳥胺酸 (DMFO)；類視黃醇諸如視黃酸；以及上述任一項的藥學上可接受的鹽、酸及衍生物。"Chemotherapeutic agents" include chemical compounds used to treat cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA^® , Genentech/OSI Pharm.), bortezomib (VELCADE^® , Millennium Pharm.), disulfiram, epigallocatechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldermycin), radicicol, lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX^® , AstraZeneca), sunitinib (SUTENT ® , Pfizer/Sugen), rituximab (FEMARA^® , Novartis), imatinib mesylate (GLEEVEC^® , Novartis), finasunate (VATALANIB^® , Novartis), oxaliplatin^{(ELOXATIN ®,} Sanofi), 5-FU (5-fluorouracil), folinic acid, rapamycin (Sirolimus, RAPAMUNE^® , Wyeth), lapatinib (TYKERB^® , GSK572016, Glaxo Smith Kline), lonafamib (SCH 66336), sorafenib (NEXAVAR^® , Bayer Labs), gefitinib (IRESSA^® , AstraZeneca), AG1478, alkylating agents such as thiotepa and CYTOXAN^® cyclophosphamides; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodepa, carboquinone, metodepa and uredepa; ethylimides and methylmelamines, including altretamine, triethylmelamine, triethylphosphatamide, triethylthiophosphatamide and trihydroxymethylmelamine; acetogenins (especially bratacin and bratacinone); camptothecins (including topotecan and irinotecan); lichenin; callystatin; CC-1065 (including its synthetic analogs adolesin, carzelesin and biszelesin); nostocs (especially nostoc 1 and moniliformin 8); adrenal cortical steroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase (including finasteride and dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dolastatin, aldesleukin, talc duocarmycin (including synthetic analogs KW-2189 and CB1-TM1); eleutherobin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, naphthalene nitrogen mustard, cholephosphamide (chloro phosphamide, estramustine, ifosfamide, methyldi(chloroethyl)amine, methyldi(chloroethyl)amine oxide hydrochloride, mycophenolate mofetil, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as dichloroethyl nitrosourea, chlorozotocin, fotemustine, lomustine, nimustine and ranimnustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1I); and calicheamicin ω1I (Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicins, including dynemicin A; bisphosphates such as clodronate; esperamicin; and neocarcinogens (chromophores and related chromoproteins (enediyne antibiotic chromophores), aclacinomysins, actinomycins, authramycins, azaserine, bleomycins, cactinomycins, carabicins, caminomycins, carzinophilins, chromomycinis, actinomycin D dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN^® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, cin), marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, oleocanthin, peplomycin, bofomycin, puromycin, quelamycin, rodorubicin, streptozocin, tubercidin, ubenimex ), zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-hydroxypurine, thiamiprine, thioguanine; pyrimidine analogs Such as ancitabine, azacitidine, 6-thiouracil, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, dromostanolone propionate, propionate, epitiostanol, mepitiostane, testolactone; antiadrenergics such as glutathione, mitotane, trilostane; folic acid supplements such as activated folic acid; aceglatone; aldophosphamide glycoside; aminoacetyl propionate; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitride; hydroxyurea; mushroom polysaccharides; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK^® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; crescent toxins (particularly T-2 toxin, verracurin A, roridin A) and anguidine); uracil; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes (taxanes), e.g., TAXOL^® (capecitabine, Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE^® (without cremophor), albumin-engineered nanoparticle formulations of capecitabine (e.g., albumin-engineered nanoparticles of capecitabine (nab-paclitaxel)) (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE^® (docetaxel; Sanofi-Aventis); chlorpheniramine, GEMZAR^® (gemcitabine); 6-thioguanine; nitropurine; methotrexate; platinum analogs such as cis-platinum and carboplatin; vinblastine; etoposide (VP-16); effulgamide; mitoxantrone; vincristine; NAVELBINE^® (vinorelbine); mitoxantrone; teniposide; edatrexate; daunorubicin; aminopterin; capecitabine (XELODA^® ); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the foregoing.

化學治療劑還包括 (i) 起調節或抑制激素對腫瘤作用的作用的抗激素劑，諸如抗雌激素及選擇性雌激素受體調節劑 (SERM)，包括例如，他莫昔芬 (包括 NOLVADEX^®；檸檬酸他莫昔芬)、雷洛昔芬、屈洛昔芬、iodoxyfene、4-羥基他莫昔芬、曲沃昔芬、那洛昔芬、LY117018、奧那司酮及 FARESTON^®(檸檬酸托瑞米芬)；(ii) 抑制在腎上腺中調節雌激素產生的芳香酶的芳香酶抑制劑，諸如例如，4(5)-咪唑、胺麩精、MEGASE^®(乙酸甲地孕酮)、AROMASIN^®(依西美坦；Pfizer)、福美坦、法倔唑、RIVISOR^®(伏羅唑)、FEMARA^®(利妥唑；Novartis) 及 ARIMIDEX^®(阿那曲唑，AstraZeneca)；(iii) 抗雄激素類，諸如氟他米特、尼魯米特、比卡米特、亮丙瑞林及戈捨瑞；布捨瑞林、曲普瑞林、乙酸甲羥孕酮、己烯雌酚、倍美力、氟甲睪酮、全反式視黃酸、芬維 A 胺，以及曲沙他濱 (1,3-二氧戊環核苷胞嘧啶類似物)；(iv) 蛋白質激酶抑制劑 (例如，退行性淋巴瘤激酶 (Alk) 抑制劑，諸如 AF-802 (也稱為 CH-5424802 或阿來替尼) )；(v) 脂質激酶抑制劑；(vi) 反義掛核苷酸，特別是抑制牽涉異常細胞增生的信號傳導途徑中的基因表現的反義寡核苷酸，諸如例如，PKC-α、Ralf 及 H-Ras；(vii) 核酶，諸如 VEGF 表現抑制劑 (例如，ANGIOZYME^®) 及 HER2 表現抑制劑；(viii) 疫苗，諸如基因療法疫苗，例如，ALLOVECTIN^®、LEUVECTIN^®及 VAXID^®；PROLEUKIN^®、rIL-2；拓撲異構酶 1 抑制劑，諸如 LURTOTECAN^®；ABARELIX^®rmRH；以及 (ix) 上述任一項的藥學上可接受的鹽、酸及衍生物。Chemotherapeutic agents also include (i) antihormonal agents that act to modulate or inhibit the effects of hormones on the tumor, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including^NOLVADEX® ; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, troxifene, naloxifene, LY117018, onapristone, and^FARESTON® (toremifene citrate); (ii) aromatase inhibitors that inhibit the aromatase enzyme that regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, fenvalerate,^MEGASE® (megestrol acetate),^AROMASIN® (exemestane; Pfizer), formestane, fadroxil,^RIVISOR® (vorozole), FEMARA^® (rituzole; Novartis), and ARIMIDEX^® (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicamamide, leuprolide, and gosseretide; buserelin, triptorelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, flumethyltestosterone, all-trans retinoic acid, fenretinide, and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors (e.g., anaplastic lymphoma kinase (Alk) inhibitors, such as AF-802 (also known as CH-5424802 or alectinib)); (v) lipid kinase inhibitors; (vi) Antisense oligonucleotides, in particular antisense oligonucleotides that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as, for example, PKC-α, Ralf and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (e.g.,^ANGIOZYME® ) and HER2 expression inhibitors; (viii) vaccines, such as gene therapy vaccines, for example,^ALLOVECTIN® ,^LEUVECTIN® and^VAXID® ;^PROLEUKIN® , rIL-2; topoisomerase 1 inhibitors, such as^LURTOTECAN® ;^ABARELIX® rmRH; and (ix) pharmaceutically acceptable salts, acids and derivatives of any of the above.

化學治療劑還包括「基於鉑」之化學治療劑，在本文中也稱為「鉑劑」，其包括含有鉑作為分子整體部分的有機化合物。通常，鉑類化學治療劑為鉑的配位複合物。鉑類化學治療劑在本領域中有時稱為「鉑類劑」。鉑類化學治療劑的實例包括但不限於順鉑、卡鉑、奧沙利鉑、奈達鉑 (nedaplatin)、四硝酸三鉑 (triplatin tetranitrate)、菲蒽鉑 (phenanthriplatin)、吡鉑 (picoplatin)、脂鉑 (lipoplatin) 及沙鉑 (satraplatin)。鉑類化學治療劑 (例如，順鉑或卡鉑) 可以與一種或多種另外的化學治療劑 (例如，核苷類似物 (例如，吉西他濱)、抗代謝物 (例如，培美曲塞或吉西他濱) 或紫杉烷 (例如，紫杉醇或 nab-紫杉醇)) 共同投予。Chemotherapeutic agents also include "platinum-based" chemotherapeutic agents, also referred to herein as "platinum agents," which include organic compounds containing platinum as an integral part of the molecule. Typically, platinum-based chemotherapeutic agents are coordination complexes of platinum. Platinum-based chemotherapeutic agents are sometimes referred to in the art as "platinum-based agents." Examples of platinum-based chemotherapeutic agents include, but are not limited to, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, lipoplatin, and satraplatin. Platinum-based chemotherapeutics (e.g., cisplatin or carboplatin) can be co-administered with one or more additional chemotherapeutics (e.g., nucleoside analogs (e.g., gemcitabine), anti-metabolites (e.g., pemetrexed or gemcitabine), or taxanes (e.g., paclitaxel or nab-paclitaxel)).

術語「有資格接受鉑類化學療法的治療」意指個體在主治醫生的判斷中或根據本領域已知的鉑類化學療法的資格標準而有資格接受鉑類化學療法的治療。The term "eligible for treatment with platinum-based chemotherapy" means that the individual is eligible for treatment with platinum-based chemotherapy in the judgment of the treating physician or according to the eligibility criteria for platinum-based chemotherapy known in the art.

化學治療劑還包括「非鉑類化學治療劑」，如本文所用，係指不是「基於鉑」之化學治療劑。如本文所用，術語「非鉑類化學治療劑」及「非鉑劑」可互換使用。例示性非鉑類化學治療劑包括抗代謝物 (例如，培美曲塞 (pemetrexed) 及吉西他濱 (gemcitabine))、拓撲異構酶 II 抑制劑 (例如，依托泊苷、替尼泊苷 (teniposide)、多柔比星 (doxorubicin)、道諾黴素、米托蒽醌、安吖啶、玫瑰樹鹼 (ellipticine)、金精三羧酸或 HU-331)、紫杉烷 (例如，紫杉醇 (例如，白蛋白改造的紫杉醇，也稱為奈米顆粒-結合白蛋白的紫杉醇 (nab-紫杉醇))、多西紫杉醇 (docetaxel)、拉洛他賽 (larotaxel)、卡巴他賽 (cabazitaxel)、米拉他賽 (milataxel)、替塞他賽 (tesetaxel) 及/或 orataxel)。例示性非鉑類化學治療劑還包括烷化劑 (例如，環磷醯胺)。Chemotherapeutic agents also include "non-platinum chemotherapeutic agents," which, as used herein, refer to chemotherapeutic agents that are not "platinum-based." As used herein, the terms "non-platinum chemotherapeutic agent" and "non-platinum agent" are used interchangeably. Exemplary non-platinum chemotherapeutic agents include anti-metabolites (e.g., pemetrexed and gemcitabine), topoisomerase II inhibitors (e.g., etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, ellipticine, aurintricarboxylic acid, or HU-331), taxanes (e.g., paclitaxel (e.g., albumin-modified paclitaxel, also known as nanoparticle-albumin-bound paclitaxel (nab-paclitaxel)), docetaxel, larotaxel, cabazitaxel, milataxel, tesetaxel, and/or orataxel). Exemplary non-platinum chemotherapeutic agents also include alkylating agents (e.g., cyclophosphamides).

如本文所用，「核苷類似物」係指包括核酸類似物及糖的核苷。核苷類似物可作為抗代謝物。例示性核苷類似物包括但不限於吉西他濱、阿糖胞苷 (cytarabine)、氟達拉濱 (fludarabine) 及克拉屈濱 (cladribine)。As used herein, "nucleoside analogs" refers to nucleosides including nucleic acid analogs and sugars. Nucleoside analogs can act as anti-metabolites. Exemplary nucleoside analogs include, but are not limited to, gemcitabine, cytarabine, fludarabine, and cladribine.

本文所用的「紫杉烷」是可以與微管蛋白結合，促進微管組裝及穩定及/或防止微管解聚的二萜。本文包括的紫杉烷包括紫杉類 10-脫乙醯漿果赤黴素 III 及/或其衍生物。示例性紫杉烷包括但不限於紫杉醇 (亦即，TAXOL^®，CAS # 33069-62-4)、多西紫杉醇 (亦即，TAXOTERE^®，CAS # 114977-28-5)、拉洛他賽、卡巴他賽、米拉他賽、替塞他賽及/或 orataxel。在一些態樣中，紫杉烷是白蛋白包被的奈米顆粒 (例如，nab-紫杉醇，即 ABRAXANE^®及/或 nab-多西紫杉醇，ABI-008)。在一些態樣中，紫杉烷是 nab-紫杉醇 (ABRAXANE^®)。在一些態樣中，紫杉烷以 CREMAPHOR^®(例如，TAXOL^®) 及/或在吐溫諸如聚山梨酯 80 (例如，TAXOTERE^®) 中配製。在一些態樣中，紫杉烷是脂質體包封的紫杉烷。在一些態樣中，紫杉烷是紫杉烷的前藥形式及/或共軛形式 (例如，與紫杉醇、聚谷胺酸紫杉醇 (paclitaxel poliglumex) 及/或亞油酸碳酸酯-紫杉醇共價共軛的 DHA)。在一些態樣中，紫杉醇基本上不與表面活性劑進行配製 (例如，在不存在 CREMAPHOR 及/或吐溫的情況下 - 諸如 TOCOSOL^®紫杉醇)。As used herein, "taxane" is a diterpene that can bind to tubulin, promote microtubule assembly and stabilization and/or prevent microtubule depolymerization. Taxanes included herein include taxanes 10-deacetyl berry erythromycin III and/or its derivatives. Exemplary taxanes include, but are not limited to, paclitaxel (i.e.,^TAXOL® , CAS # 33069-62-4), docetaxel (i.e.,^TAXOTERE® , CAS # 114977-28-5), larotaxel, cabazitaxel, milatataxel, tesetaxel and/or orataxel. In some aspects, the taxane is an albumin-coated nanoparticle (e.g., nab-paclitaxel, i.e.,^ABRAXANE® and/or nab-docetaxel, ABI-008). In some aspects, the taxane is nab-paclitaxel (^ABRAXANE® ). In some aspects, the taxane is formulated in^CREMAPHOR® (e.g.,^TAXOL® ) and/or in a Tween such as polysorbate 80 (e.g.,^TAXOTERE® ). In some aspects, the taxane is a liposomally encapsulated taxane. In some aspects, the taxane is a prodrug form and/or a conjugated form of the taxane (e.g., DHA covalently conjugated to paclitaxel, paclitaxel poliglumex, and/or linoleic acid carbonate-paclitaxel). In some aspects, the paclitaxel is formulated substantially without a surfactant (e.g., in the absence of CREMAPHOR® and/or Tween-such as^TOCOSOL® paclitaxel).

如本文所用，「抗代謝物」是一種干擾並抑制 (全部或部分) 細胞 (例如，癌細胞) 內的內源 (正常) 代謝過程的化學治療劑。抗代謝物包括吉西他濱、培美曲塞、卡培他濱、羥基脲、胺甲喋呤、氟尿嘧啶、克拉屈濱、巰嘌呤及普拉曲沙。As used herein, an "anti-metabolite" is a chemotherapeutic agent that interferes with and inhibits (in whole or in part) the endogenous (normal) metabolic process in a cell (e.g., a cancer cell). Anti-metabolites include gemcitabine, pemetrexed, capecitabine, hydroxyurea, methotrexate, fluorouracil, cladribine, valproate, and pralatrexate.

化學治療劑還包括地塞米松 (dexamethasone)、干擾素、秋水仙鹼、氯苯胺啶 (metoprine)、環孢素、兩性黴素、硝基甲嘧唑乙醇、阿侖單抗 (alemtuzumab)、阿利維 A 酸 (alitretinoin)、異嘌呤醇、胺磷汀 (amifostine)、三氧化二砷、天冬醯胺酸酶、活 BCG、貝伐珠單抗 (bevacizumab)、貝沙羅汀 (bexarotene)、克拉屈濱、氯法拉濱 (clofarabine)、阿法達貝泊汀 (darbepoetin alfa)、denileukin、右雷佐生 (epoetin alfa)、阿法依泊汀 (elotinib)、elotinib、非格司亭、乙酸組胺瑞林 (histrelin acetate)、替伊莫單抗、干擾素 α-2a、干擾素 α-2b、來那度胺 (lenalidomide)、左旋咪唑衍生物、美司鈉 (mesna)、甲氧沙林、諾龍 (nandrolone)、奈拉濱、nofetumomab、奧普瑞白介素 (oprelvekin)、帕利夫明 (palifermin)、帕米磷酸二鈉 (pamidronate)、培加酶 (pegademase)、培門冬酶 (pegaspargase)、培非格司亭、培美曲塞二鈉 (palifermin)、普卡黴素 (plicamycin)、卟吩姆鈉 (porfimer sodium)、奎納克林 (quinacrine)、拉布立酶 (rasburicase)、沙格司亭、替莫唑胺 (temozolomide)、VM-26、6-TG、托瑞米芬 (toremifene)、視網酸、ATRA、戊柔比星 (valrubicin)、唑來膦酸鹽 (zoledronate) 及唑來膦酸 (zoledronic acid) 及其醫藥上可接受之鹽類。Other chemotherapy agents include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, nitrazepam, alemtuzumab, alitretinoin, isopurinol, amifostine, arsenic trioxide, asparaginase, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, epoetin alfa, elotinib, elotinib, filgrastim, histrelin acetate, ibritumomab, interferon alpha-2a, interferon alpha-2b, lenalidomide, levamisole derivatives, mesna, methoxsalen, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim, palifermin, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim, temozolomide, VM-26, 6-TG, toremifene, retinoic acid, ATRA, valrubicin valrubicin, zoledronate and zoledronic acid and their pharmaceutically acceptable salts.

化學治療劑還包括氫化皮質酮、乙酸皮質醇、乙酸皮質酮、新戊酸替可的松 (tixocortol pivalate)、丙酮特安皮質醇、曲安奈德醇 (triamcinolone alcohol)、莫米松 (mometasone)、胺西尼德 (amcinonide)、布地奈德 (budesonide)、地鬆奈德 (desonide)、氟洛奈皮質醇、丙酮氟洛皮質醇、倍他米松 (betamethasone)、貝皮質醇磷酸鈉、迪皮質醇、磷酸鈉迪皮質醇、氟可龍 (fluocortolone)、17-丁酸氫化皮質酮、17-戊酸氫化皮質酮、氯米松酮二丙酸酯 (aclometasone dipropionate)、戊酸貝皮質醇、二丙酸貝皮質醇 (betamethasone dipropionate)、潑尼卡酯 (prednicarbate)、17-丁酸可洛貝他松、17-丙酸氯貝皮質醇、己酸氟可龍 (fluocortolone caproate)、新戊酸氟可龍 (fluocortolone pivalate) 及乙酸氟潑尼定 (fluprednidene acetate)；免疫選擇性抗炎肽 (ImSAID)，諸如苯丙胺酸-麩醯胺酸-甘胺酸 (FEG) 及其 D-異構體 (feG) (IMULAN BioTherapeutics, LLC)；抗風濕藥，諸如硫唑嘌呤、環孢素(ciclosporin) (環孢黴素 A)、D-青黴胺、金鹽、羥氯喹 (hydroxychloroquine)、Leflunomideminocycline、柳氮磺胺吡啶、腫瘤壞死因子 α (TNFα) 阻斷劑、例如，Etanercept (Enbrel)、英夫利西單抗 (Remicade)、阿達木單抗 (Humira)、賽妥珠單抗 (Cimzia)、戈利木單抗 (Simponi)、白細胞介素 1 (IL-1) 阻斷劑諸如阿那白滯素 (Kineret)、T 細胞共刺激阻斷劑諸如阿巴西普 (Orencia)、白介素 6 (IL-6) 阻斷劑諸如托珠單抗 (ACTEMERA®)；白細胞介素 13 (IL-13) 阻斷劑，諸如 lebrikizumab；干擾素 α (IFN) 阻斷劑，諸如 Rontalizumab；β7 整合素阻斷劑諸如 rhuMAb β7；IgE 通路阻斷劑，諸如 Anti-M1 prim；分泌同源三聚體 LTa3 及膜結合異三聚體 LTa1/β2 阻斷劑，諸如抗淋巴毒素 α (LTa)；放射性同位素 (例如，At211、I131、I125、Y90、Re186、Re188、Sm153、Bi212、P32、Pb212 及 Lu 的放射性同位素) ；其他研究藥物，諸如 thioplatin、PS-341、苯基丁酸鹽 (phenylbutyrate)、ET-18-OCH3 或法呢基轉移酶抑制劑 (L-739749、L-744832)；多酚，諸如槲皮素、白藜蘆醇、白皮杉醇、表沒食子兒茶素沒食子酸酯、茶黃素、黃烷醇、原花青素 (procyanidins)、樺木酸及其衍生物；自噬抑制劑，諸如氯喹；Δ-9-四氫大麻酚 (Dronabinol，MARINOL®)；β-拉帕醌 (beta-lapachone)；拉帕酚；秋水仙鹼；樺木酸；乙醯喜樹鹼、莨菪素 及 9-胺基喜樹鹼)；鬼臼毒素；替加氟(tegafur) (UFTORAL®)；貝沙羅汀 (TARGRETIN®)；雙膦酸鹽類，諸如氯膦酸鹽 (例如，BONEFOS® 或 OSTAC®)、依替膦酸鹽 (etidronate) (DIDROCAL®)、NE-58095、唑來膦酸 (zoledronic acid)/唑來膦酸鹽 (zoledronate) (ZOMETA®)、阿崙膦酸鹽 (alendronate) (FOSAMAX®)、帕米膦酸鹽 (pamidronate) (AREDIA®)、替魯膦酸鹽 (tiludronate) (SKELID®) 或利塞膦酸鹽 (risedronate) (ACTONEL®)；及上皮生長因子受體 (EGF-R)；疫苗，諸如 THERATOPE® 疫苗；哌立福辛 (perifosine)、COX-2 抑制劑 (例如，塞來昔布 (celecoxib) 或依托昔布 (etoricoxib))、蛋白體抑制劑 (例如，PS341)；CCI-779；替吡法尼 (tipifarnib) (R11577)；奧拉非尼 (orafenib) (ABT510)；Bcl-2 抑制劑，諸如奧利馬生鈉 (oblimersen sodium) (GENASENSE®)；吡咯烷酮 (pixantrone)；法呢基轉移酶抑制劑，諸如洛那法尼 (lonafarnib) (SCH 6636、SARASARTM)；以及上述任何一種之藥學上可接受的鹽類、酸或衍生物；以及上述兩種或多種的組合，諸如 CHOP (環磷醯胺、多柔比星、長春新鹼與潑尼松龍的聯合療法的縮寫) 及 FOLFOX (奧沙利鉑 (ELOXATINTM) 與 5-FU 及甲醯四氫葉酸的聯合治療方案的縮寫)。Chemotherapeutic agents also include hydrocorticosterone, corticol acetate, corticosterone acetate, tixocortol pivalate, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocortol, fluocortol acetonide, betamethasone, betamethasone sodium phosphate, decortin, decortin sodium phosphate, fluocortolone, 17-butyric acid hydrocorticosterone, 17-valerate hydrocorticosterone, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednisone prednicarbate, clobetasol 17-butyrate, clobetasol 17-propionate, fluocortolone caproate, fluocortolone pivalate, and fluprednidene acetate; Immunoselective anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamine-glycine (FEG) and its D-isomer (feG) (IMULAN BioTherapeutics, LLC); Antirheumatic drugs, such as azathioprine, ciclosporin (cyclosporin A), D-penicillin, gold salts, hydroxychloroquine, leflunomideminocycline, sulfasalazine, tumor necrosis factor α (TNFα) blockers, such as etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab (Cimzia), golimumab (Simponi), interleukin 1 (IL-1) blockers such as anakinra (Kineret), T cell costimulatory blockers such as abatacept (Orencia), interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN) blockers such as rontalizumab; beta 7 integrin blockers such as rhuMAb β7; IgE pathway blockers such as Anti-M1 prim; secretory homotrimer LTa3 and membrane-bound heterotrimer LTa1/β2 blockers such as antilymphotoxin α (LTa); radioisotopes (e.g., At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212, and radioisotopes of Lu); other investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH3, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavins, flavanols, procyanidins, bisabolol and its derivatives; autophagy inhibitors such as chloroquine; Δ-9-tetrahydrocannabinol (Dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; bisabolol; acetylcamptothenate, scopoletin and 9-aminocamptothenate); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines, such as THERATOPE®; perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); CCI-779; tipifarnib (R11577); orafenib (ABT510); Bcl-2 inhibitors, such as oblimersen sodium (GENASENSE®); pixantrone; farnesyl transferase inhibitors, such as lonafarnib (SCH 6636, SARASARTM); and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing; and combinations of two or more of the foregoing, such as CHOP (an abbreviation for the combination therapy of cyclophosphamide, doxorubicin, vincristine and prednisolone) and FOLFOX (oxaliplatin (ELOXATINTM) and abbreviation for combination therapy with 5-FU and leucovorin).

化學治療劑還包括具有鎮痛、退熱及抗發炎作用之非類固醇抗炎藥。NSAID 包括環氧化酶之非選擇性抑制劑。NSAID 的具體實例包括：阿斯匹林；丙酸衍生物，諸如伊布洛芬、非諾洛芬 (fenoprofen)、酮洛芬 (ketoprofen)、氟白普洛芬 (flurbiprofen)、奧沙普嗪 (oxaprozin) 及萘普生 (naproxen)；乙酸衍生物，諸如吲哚美洒辛、舒林酸、依托度酸 (etodolac)、雙氯芬酸 (diclofenac)；烯醇酸衍生物，諸如吡羅昔康 (piroxicam)、美洛昔康 (meloxicam)、替諾昔康 (tenoxicam)、屈昔康 (droxicam)、氯諾昔康 (lornoxicam)及伊索昔康 (isoxicam)；芬那酸 (fenamic acid) 衍生物，諸如甲芬那酸 (mefenamic acid)、甲氯芬那酸 (meclofenamic acid)、氟芬那酸 (flufenamic acid)、托芬那酸 (tolfenamic acid)；以及 COX-2 抑制劑，諸如塞來昔布 (celecoxib)、依托考昔 (etoricoxib)、羅美昔布 (lumiracoxib)、帕瑞昔布 (parecoxib)、羅非昔布 (rofecoxib) 及伐地昔布 (valdecoxib)。NSAID 適用於緩解症狀，諸如類風濕性關節炎、骨關節炎、發炎性關節炎、關節黏連性脊椎炎、牛皮癬性關節炎、Reiter 氏症候群、急性痛風、經痛、轉移性骨痛、頭痛及偏頭痛、術後疼痛、發炎症及組織損傷引起的輕度至中度疼痛、發熱、腸阻塞及腎絞痛。Chemotherapy also includes nonsteroidal anti-inflammatory drugs that have analgesic, antipyretic and anti-inflammatory properties. NSAIDs include non-selective inhibitors of cyclooxygenase. Specific examples of NSAIDs include: aspirin; propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprozin and naproxen; acetic acid derivatives such as indomethacin, sulindac, etodolac, diclofenac; enolic acid derivatives such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam; fenamic acid derivatives such as mefenamic acid, meclofenamic acid, flufenamic acid, NSAIDs are used to relieve symptoms of rheumatoid arthritis, osteoarthritis, inflammatory arthritis, ankylosing spondylitis, psoriasis, Reiter's syndrome, acute gout, menstrual pain, metastatic bone pain, headaches and migraines, postoperative pain, mild to moderate pain caused by inflammation and tissue damage, fever, intestinal obstruction, and angina.

化學治療劑還包括「EGFR 抑制劑」，其係指與 EGFR 結合或直接與 EGFR 交互作用並阻止或降低其信號傳導活性的化合物，並且可替代地稱為「EGFR 拮抗劑」。此等藥劑的實例包括與 EGFR 結合之小分子。EGFR 拮抗劑包括小分子，諸如以下美國專利號中描述的化合物：5,616,582、5,457,105、5,475,001、5,654,307、5,679,683、6,084,095、6,265,410、6,455,534、6,521,620、6,596,726、6,713,484、5,770,599、6,140,332、5,866,572、6,399,602、6,344,459、6,602,863、6,391,874、6,344,455、5,760,041、6,002,008 及 5,747,498，以及以下 PCT 出版物中描述之化合物：WO98/14451、WO98/50038、WO99/09016 及 WO99/24037。特定的小分子 EGFR 拮抗劑包括 OSI-774 (CP-358774，厄洛替尼，TARCEVA® Genentech/OSI Pharmaceuticals)；PD 183805 (CI 1033，2-丙烯醯胺，N-[4-[(3-氯-4-氟苯基)胺基]-7-[3-(4-𠰌啉基)丙氧基]-6-喹唑啉基]-二鹽酸鹽，Pfizer Inc.)；ZD1839，(吉非替尼(gefitinib ) (IRESSA^®)，4-(3'-氯-4'-氟苯胺基)-7-甲氧基-6-(3-𠰌啉丙氧基)喹唑啉，AstraZeneca)；ZM 105180 (6-胺基-4-(3-甲基苯基-胺基)-喹唑啉，Zeneca)；BIBX-1382 (N8-(3-氯-4-氟-苯基)-N2-(1-甲基-哌啶-4-基)-嘧啶[5,4-d]嘧啶-2,8-二胺，Boehringer Ingelheim)；PKI-166 ((R)-4-[4-[(1-苯乙基)胺基]-1H-吡咯並[2,3-d]嘧啶-6-基]-苯酚)；(R)-6-(4-羥苯基)-4-[(1-苯基乙基)胺基]-7H-吡咯並[2,3-d]嘧啶；CL-387785 (N-[4-[(3-溴苯基) 胺基]-6-喹唑啉基]-2-丁炔醯胺)；EKB-569 (N-[4-[(3-氯-4-氟苯基)胺基]-3-氰基-7-乙氧基-6-喹啉基]-4-(二甲基胺基)-2-丁烯醯胺) (Wyeth)；AG1478 (Pfizer)；AG1571 (SU 5271；Pfizer)；雙效 EGFR/HER2 酪胺酸激酶抑制劑諸如拉匹替尼 (TYKERB^®，GSK572016 或 N-[3-氯-4-[(3-氟苯基)甲氧基]苯基]-6[5[[[(2甲磺醯基)乙基]胺基]甲基]-2-呋喃基]-4-喹唑啉胺)。Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or directly interact with EGFR and prevent or reduce its signaling activity, and may alternatively be referred to as "EGFR antagonists." Examples of such agents include small molecules that bind to EGFR. EGFR antagonists include small molecules such as the compounds described in the following U.S. Patent Nos.: 5,616,582; 5,457,105; 5,475,001; 5,654,307; 5,679,683; 6,084,095; 6,265,410; 6,455,534; 6,521,620; 6,596,726; 6,713,484; 5,770,599; 6,140,332; 5,866,572; 6,399,602; 6,344,459; 6,602,863; 6,391,874; 6,344,455; 5,760,041; 6,002,008 and 5,747,498, and compounds described in the following PCT publications: WO98/14451, WO98/50038, WO99/09016 and WO99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-acrylamide, N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4-oxo-1-propoxy)-6-quinazolinyl]-dihydrochloride, Pfizer Inc.); ZD1839, (gefitinib (^IRESSA® ), 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-oxo-1-propoxy)quinazoline, AstraZeneca); ZM 105180 (6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2-(1-methyl-piperidin-4-yl)-pyrimidin[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[(1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[(1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine; CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynylamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-2-butenylamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual-acting EGFR/HER2 tyrosine kinase inhibitors such as lapitinib (TYKERB^® , GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[(2-methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamide).

化學治療劑還包括「酪胺酸激酶抑制劑」，包括前段描述之 EGFR 靶向藥物；胰島素受體酪胺酸激酶的抑制劑，包括退行性淋巴瘤激酶 (Alk) 抑制劑，諸如 AF-802 (也稱為 CH-5424802 或 Alectinib)、ASP3026、X396、LDK378、AP26113、Crizotinib (XALKORI^®) 及 Ceritinib (ZYKADIA^®)；小分子 HER2 酪胺酸激酶抑制劑，諸如可得自 Takeda 的 TAK165；CP-724,714 (ErbB2 的口服選擇性抑制劑受體酪胺酸激酶) (Pfizer 及 OSI)；雙 HER 抑制劑，諸如 EKB-569 (獲自 Wyeth)，其優先結合 EGFR 但抑制 HER2 及 EGFR 過表現之細胞兩者；拉帕替尼 (GSK572016；獲自 Glaxo-SmithKline)，HER2 及 EGFR 酪胺酸激酶抑制劑；PKI-166 (獲自 Novartis)；Pan-HER 抑制劑，諸如坎尼替尼 (CI-1033；Pharmacia)；Raf-1 抑制劑，諸如可得自 ISIS Pharmaceuticals 的抑制 Raf-1 信號傳導的反義劑 ISIS-5132；非 HER 靶向 TK 抑制劑，諸如甲磺酸伊馬替尼 (GLEEVEC^®，獲自 Glaxo SmithKline)；多靶向酪胺酸激酶抑制劑，諸如舒尼替尼 (SUTENT^®，獲自 Pfizer)；VEGF 受體酪胺酸激酶抑制劑，諸如 Vatalanib (PTK787/ZK222584，獲自 Novartis/Schering AG)；MAPK 細胞外調節激酶 I 抑制劑 CI-1040 (獲自 Pharmacia)；喹唑啉，諸如 PD 153035,4-(3-氯苯胺基)喹唑啉；吡啶並嘧啶；嘧啶並嘧啶；吡咯並嘧啶，諸如 CGP 59326、CGP 60261 及 CGP 62706；吡唑並嘧啶，4-(苯胺基)-7H-吡咯並[2,3-d]嘧啶；薑黃素 (二氟甲醯甲烷，4,5-雙(4-氟苯胺基)鄰苯二甲醯亞胺)；含硝基噻吩部分之酪胺酸；PD-0183805 (Warner-Lamber)；反義分子 (例如，與 HER 編碼核酸結合的分子)；喹喔啉 (美國專利號 5,804,396)；Tryphostin (美國專利號 5,804,396 )；ZD6474 (Astra Zeneca)；PTK-787 (Novartis/Schering AG)；pan-HER 抑制劑，諸如 CI-1033 (Pfizer)；Affinitac (ISIS 3521；Isis/Lilly)；甲磺酸伊馬替尼(imatinib mesylate) (GLEEVEC^®)；PKI 166 (Novartis)；GW2016 (Glaxo SmithKline)；CI-1033 (Pfizer)；EKB-569 (Wyeth)；Semaxinib (Pfizer)；ZD6474 (AstraZeneca)；PTK-787 (Novartis/Schering AG)；INC-1C11 (Imclone)、雷帕黴素 (西羅莫司，RAPAMUNE^®)；或如以下任何專利揭示中任一項所述：美國專利號 5,804,396；WO 1999/09016 (American Cyanamid)；WO 1998/43960 (American Cyanamid)；WO 1997/38983 (Warner Lambert)；WO 1999/06378 (Warner Lambert)；WO 1999/06396 (Warner Lambert)；WO 1996/30347 (Pfizer, Inc)；WO 1996/33978 (Zeneca)；WO 1996/3397 (Zeneca) 及 WO 1996/33980 (Zeneca)。Chemotherapy agents also include "tyrosine kinase inhibitors", including the EGFR targeted drugs described in the previous paragraph; inhibitors of insulin receptor tyrosine kinase, including anaplastic lymphoma kinase (Alk) inhibitors, such as AF-802 (also known as CH-5424802 or Alectinib), ASP3026, X396, LDK378, AP26113, Crizotinib (XALKORI^® ) and Ceritinib (ZYKADIA^® ); small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714 (oral selective inhibitor of ErbB2 receptor tyrosine kinase) (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially binds to EGFR but inhibits both HER2 and EGFR-overexpressing cells; lapatinib (GSK572016; available from Glaxo-SmithKline), a HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); Pan-HER inhibitors, such as canitinib (CI-1033; Pharmacia); Raf-1 inhibitors, such as the antisense agent ISIS-5132, available from ISIS Pharmaceuticals, which inhibits Raf-1 signaling; non-HER-targeted TK inhibitors, such as imatinib mesylate (GLEEVEC^® , available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors, such as sunitinib (SUTENT^® , obtained from Pfizer); VEGF receptor tyrosine kinase inhibitors, such as Vatalanib (PTK787/ZK222584, obtained from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (obtained from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines, such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidine, 4-(anilino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin (difluoromethane, 4,5-bis(4-fluoroanilino)phthalimide); tyrosine containing a nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecules (e.g., molecules that bind to HER encoding nucleic acids); quinoxaline (U.S. Patent No. 5,804,396); Tryphostin (U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors, such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly); imatinib mesylate (GLEEVEC^® ); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone); rapamycin (sirolimus, RAPAMUNE^® ); or as disclosed in any of the following patents: U.S. Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); WO 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

術語「蒽環類」涉及一種化學治療劑，一種用於誘導細胞凋亡，較佳地藉由抑制拓撲異構酶 II 中 DNA 重新結合來誘導細胞凋亡之抗癌劑。實例包括多柔比星 (多柔比星)、道諾黴素、表柔比星、伊達比星、紫紅黴素 (rhodomycin)、吡柔比星、戊柔比星、N-三氟乙醯基多柔比星-14-戊酸酯、阿克拉黴素、𠰌啉代多柔比星 (𠰌啉代-DOX)、氰基𠰌啉代多柔比星 (cyanomorpholino-DOX)、2-吡咯代多柔比星 (2-PDOX)、5-亞胺基道黴素 (5-iminodaunomycin)、米托蒽醌及阿克拉黴素 A (aclacinomycin A ) (阿柔比星)。在一些態樣中，蒽環類與烷化劑例如，多柔比星共同環磷醯胺共同投予 (接受 AC 治療)。The term "anthracycline" refers to a class of chemotherapeutic agents, anticancer agents used to induce apoptosis, preferably by inhibiting DNA rebinding in topoisomerase II. Examples include doxorubicin (doxorubicin), daunomycin, epirubicin, idarubicin, rhodomycin, pirarubicin, valrubicin, N-trifluoroacetyl doxorubicin-14-valerate, aclacinomycin, oxolino doxorubicin (oxolino-DOX), cyanomorpholino doxorubicin (cyanomorpholino-DOX), 2-pyrrolidoxorubicin (2-PDOX), 5-iminodaunomycin (5-iminodaunomycin), mitoxantrone and aclacinomycin A (aclacinomycin). In some aspects, anthracyclines are co-administered with an alkylating agent, such as doxorubicin, and cyclophosphamide (ac treatment).

如本文所用，「烷化劑」是藉由將烷基連接至 DNA 而引起 DNA 損傷之化學治療劑。烷化劑包括環磷醯胺及 N,N',N''-三亞乙基硫代磷醯胺。As used herein, an "alkylating agent" is a chemical therapeutic agent that causes DNA damage by attaching an alkyl group to DNA. Alkylating agents include cyclophosphamide and N,N',N''-triethylenethiophosphamide.

如本文所用，術語「比較者」或「比較組」係指在研究 (例如臨床試驗) 中用為治療或治療組比較基礎的參考 (例如，參考患者群體)。例如，比較組可為臨床試驗中的對照組。比較組可包括已接受對照治療 (諸如一種或多種先前批准的治療或上市產品) 的患者群體。As used herein, the term "comparator" or "comparator group" refers to a reference (e.g., a reference patient population) used as a basis for comparison of treatments or treatment groups in a study (e.g., a clinical trial). For example, a comparator group can be a control group in a clinical trial. A comparator group can include a patient population that has received a control treatment (e.g., one or more previously approved treatments or marketed products).

如本文所用，「參考樣品」、「參考細胞」、「參考組織」、「對照樣品」、「對照細胞」或「對照組織」係指用於比較目的之樣品、細胞、組織、標準或水平。在一個實施例中，參考樣品、參考細胞、參考組織、對照樣品、對照細胞或對照組織獲自同一個體之身體 (例如，組織或細胞) 之健康及/或未患病部位。舉例而言，與患病細胞或組織相鄰之健康及/或未患病細胞或組織 (例如，與腫瘤相鄰之細胞或組織)。在另一個實施例中，參考樣品獲自同一個體之身體之未經治療之組織及/或細胞。在又一個實施例中，參考樣品、參考細胞、參考組織、對照樣品、對照細胞或對照組織獲自並非該個體的其他個體之身體 (例如，組織或細胞) 之健康及/或未患病部位。在另一個實施例中，參考樣品、參考細胞、參考組織、對照樣品、對照細胞或對照組織獲自並非該個體的個體之身體之未經治療之組織及/或細胞。As used herein, "reference sample", "reference cell", "reference tissue", "control sample", "control cell" or "control tissue" refers to a sample, cell, tissue, standard or level used for comparison purposes. In one embodiment, the reference sample, reference cell, reference tissue, control sample, control cell or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cell) of the same individual. For example, healthy and/or non-diseased cells or tissues adjacent to diseased cells or tissues (e.g., cells or tissues adjacent to tumors). In another embodiment, the reference sample is obtained from untreated tissues and/or cells of the body of the same individual. In yet another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from a healthy and/or non-diseased part of the body (e.g., tissue or cell) of another individual other than the individual. In another embodiment, the reference sample, reference cell, reference tissue, control sample, control cell, or control tissue is obtained from untreated tissues and/or cells of the body of an individual other than the individual.

除非另有說明，否則如本文所用之術語「TIGIT」或「具有 Ig 及 ITIM 域的 T 細胞免疫受體」係指來自任何脊椎動物來源的任何天然 TIGIT，包括哺乳動物諸如靈長類動物 (例如人) 及齧齒動物 (例如，小鼠及大鼠)。TIGIT 在本領域中也稱為 DKFZp667A205、FLJ39873、含 V-set 及免疫球蛋白域的蛋白 9、含 V-set 及跨膜域的蛋白 3、VSIG9、VSTM3 及 WUCAM。該術語涵蓋「全長」未加工的 TIGIT (例如，具有 SEQ ID NO: 30 之胺基酸序列的全長人 TIGIT) 以及在細胞中加工所產生的任何形式之 TIGIT (例如，經加工的無訊息序列的人 TIGIT，其具有 SEQ ID NO: 31)。該術語亦涵蓋天然生成之 TIGIT 變異體，例如，剪接變異體或對偶基因變異體。例示性人 TIGIT 的胺基酸序列可參見 UniProt 登錄號 Q495A1。Unless otherwise indicated, the term "TIGIT" or "T cell immune receptor with Ig and ITIM domains" as used herein refers to any native TIGIT from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats). TIGIT is also known in the art as DKFZp667A205, FLJ39873, protein containing V-set and immunoglobulin domains 9, protein containing V-set and transmembrane domains 3, VSIG9, VSTM3, and WUCAM. The term encompasses "full-length" unprocessed TIGIT (e.g., full-length human TIGIT having an amino acid sequence of SEQ ID NO: 30) as well as any form of TIGIT produced by processing in a cell (e.g., processed human TIGIT with a messageless sequence having SEQ ID NO: 31). The term also encompasses naturally occurring TIGIT variants, such as splice variants or allelic variants. The amino acid sequence of an exemplary human TIGIT can be found in UniProt Accession No. Q495A1.

如本文所用，「替瑞利尤單抗」是在開放單株技術 (OMT) 大鼠中衍生的完全人 IgG1/κMAb，其結合 TIGIT 並且包含 SEQ ID NO: 33 之重鏈序列及 SEQ ID NO: 34 之輕鏈序列。替瑞利尤單抗包含 Fc 域中的兩個 N-連接的醣基化位點 (N306)。替瑞利尤單抗亦描述於：WHO 藥物資訊 (國際非專利藥品名稱)，擬定 INN：清單 117，第 31 卷，第 2 號，發佈於 2017 年 6 月 9 日 (參見第 343 頁)。As used herein, "tirelimumab" is a fully human IgG1/κ MAb derived in open monoclonal technology (OMT) rats that binds to TIGIT and comprises a heavy chain sequence of SEQ ID NO: 33 and a light chain sequence of SEQ ID NO: 34. Tirelimumab comprises two N-linked glycosylation sites (N306) in the Fc domain. Tirelimumab is also described in: WHO Drug Information (International Nonproprietary Medicinal Products Name), Proposed INN: List 117, Volume 31, Number 2, published on June 9, 2017 (see page 343).

術語「抗 TIGIT 拮抗劑抗體」 係指能夠以足夠高的親及力結合 TIGIT，使其實質上或完全抑制 TIGIT 的生物學活性的抗體或其抗原結合片段或變異體。例如，抗 TIGIT 拮抗劑抗體可阻斷藉由 PVR、PVRL2 及/或 PVRL3 的傳訊，從而使 T 細胞 (例如，增殖、細胞因子生成、靶細胞殺除) 從功能障礙狀態恢復到抗原刺激的功能應答。例如，抗 TIGIT 拮抗劑抗體可以不影響 PVR-CD226 交互作用而阻斷藉由 PVR 的信號傳導。本領域的普通技術人員將會理解，在一些實例中，抗 TIGIT 拮抗劑抗體可拮抗一種 TIGIT 活性而不影響另一種 TIGIT 活性。例如，用於本文所述之某些方法或用途的抗 TIGIT 拮抗劑抗體為抗 TIGIT 拮抗劑抗體，其回應於 PVR 交互作用、PVRL3 交互作用或 PVRL2 交互作用之一者而拮抗 TIGIT 活性，例如，對其他任何 TIGIT 交互作用無影響或影響極小。在一個態樣，抗 TIGIT 拮抗劑抗體與無關、非 TIGIT 蛋白質結合之程度低於該抗體與 TIGIT 結合約 10%，其藉由例如，放射免疫測定法 (RIA) 所測量。在某些態樣中，與 TIGIT 結合之抗 TIGIT 拮抗劑抗體之解離常數 (K_D) ≤ 1μM、≤ 100 nM、≤ 10 nM、≤ 1 nM、≤ 0.1 nM、≤ 0.01 nM 或 ≤ 0.001 nM (例如，10^-8M 或更小，例如，10^-8M 至 10^-13M，例如，10^-9M 至 10^-13M)。在某些態樣中，抗 TIGIT 拮抗劑抗體與來自不同物種的 TIGIT 中保守的 TIGIT 表位或 TIGIT 上允許跨物種反應的表位結合。在一些態樣中，抗 TIGIT 結合抗體具有完整的 Fc 介導的效應子功能 (例如，替瑞利尤單抗、維博利單抗 (vibostolimab)、艾替利單抗 (etigilimab)、EOS084448 或 TJ-T6)。在一些態樣中，抗 TIGIT 結合抗體具有增強的 Fc 介導的效應子功能 (例如，SGN-TGT)。在其他態樣中，抗 TIGIT 拮抗劑抗體缺乏 Fc 介導的效應子功能的抗體 (例如，度納利單抗 (domvanalimab)、BMS-986207、ASP8374 或 COM902)。在一些態樣中，抗 TIGIT 結合抗體是 IgG1 類抗體 (例如，替瑞利尤單抗、維博利單抗、度納利單抗、BMS-986207、艾替利單抗、BGB-A1217、SGN-TGT、EOS084448 (EOS-448)、TJ-T6 或 AB308)。在其他態樣中，抗 TIGIT 結合抗體是 IgG4 類抗體 (例如，ASP8374 或 COM902)。在一個態樣中，抗 TIGIT 拮抗劑抗體為替瑞利尤單抗。The term "anti-TIGIT antagonist antibody" refers to an antibody or antigen-binding fragment or variant thereof that binds to TIGIT with sufficiently high affinity to substantially or completely inhibit the biological activity of TIGIT. For example, an anti-TIGIT antagonist antibody can block signaling through PVR, PVRL2 and/or PVRL3, thereby restoring T cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to a functional response to antigen stimulation. For example, an anti-TIGIT antagonist antibody can block signaling through PVR without affecting the PVR-CD226 interaction. One of ordinary skill in the art will appreciate that in some instances, an anti-TIGIT antagonist antibody may antagonize one TIGIT activity without affecting another TIGIT activity. For example, an anti-TIGIT antagonist antibody for use in certain methods or uses described herein is an anti-TIGIT antagonist antibody that antagonizes TIGIT activity in response to one of a PVR interaction, a PVRL3 interaction, or a PVRL2 interaction, e.g., has no effect or minimal effect on any other TIGIT interaction. In one aspect, the extent of binding of the anti-TIGIT antagonist antibody to an unrelated, non-TIGIT protein is less than about 10% of the binding of the antibody to TIGIT, as measured, e.g., by radioimmunoassay (RIA). In certain aspects, the anti-TIGIT antagonist antibody binds to TIGIT with a dissociation constant (K_D ) of ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10^-8 M or less, e.g., 10^-8 M to 10^-13 M, e.g., 10^-9 M to 10^-13 M). In certain aspects, the anti-TIGIT antagonist antibody binds to a TIGIT epitope that is conserved among TIGIT from different species or an epitope on TIGIT that allows cross-species reactivity. In some embodiments, the anti-TIGIT binding antibody has intact Fc-mediated effector function (e.g., tisleliumab, vibostolimab, etigilimab, EOS084448, or TJ-T6). In some embodiments, the anti-TIGIT binding antibody has enhanced Fc-mediated effector function (e.g., SGN-TGT). In other embodiments, the anti-TIGIT antagonist antibody lacks Fc-mediated effector function (e.g., domvanalimab, BMS-986207, ASP8374, or COM902). In some embodiments, the anti-TIGIT binding antibody is an IgG1 class antibody (e.g., tisleliumab, vilbotrinumab, dunalimab, BMS-986207, etilizumab, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6 or AB308). In other embodiments, the anti-TIGIT binding antibody is an IgG4 class antibody (e.g., ASP8374 or COM902). In one embodiment, the anti-TIGIT antagonist antibody is tisleliumab.

術語「計畫性死亡配體 1」及「PD-L1」在本文中係指天然序列人類 PD-L1 多肽。天然序列 PD-L1 多肽係提供於 Uniprot 登錄號 Q9NZQ7 下。例如，天然序列 PD-L1 可以具有如 Uniprot 登錄號 Q9NZQ7-1 (同功型 1) (SEQ ID NO: 32) 中列出的胺基酸序列。在另一實例中，天然序列 PD-L1 可以具有如 Uniprot 登錄號 Q9NZQ7-2 (同功型 2) 中列出的胺基酸序列。在另一實例中，天然序列 PD-L1 可以具有如 Uniprot 登錄號 Q9NZQ7-3 (同功型 3) 中列出的胺基酸序列。PD-L1 在本領域中亦稱為「計畫性細胞死亡 1 配體 1」、「PDCD1LG1」、「CD274」、「B7-H」及「PDL1」。The terms "planned death ligand 1" and "PD-L1" herein refer to native sequence human PD-L1 polypeptides. Native sequence PD-L1 polypeptides are provided under Uniprot Accession No. Q9NZQ7. For example, native sequence PD-L1 may have an amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-1 (isoform 1) (SEQ ID NO: 32). In another example, native sequence PD-L1 may have an amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-2 (isoform 2). In another example, native sequence PD-L1 may have an amino acid sequence as set forth in Uniprot Accession No. Q9NZQ7-3 (isoform 3). PD-L1 is also known in the field as "planned cell death 1 ligand 1", "PDCD1LG1", "CD274", "B7-H" and "PDL1".

為了本文的目的，「阿替利珠單抗」為結合 PD-L1 並且包括 SEQ ID NO: 1 之重鏈序列及 SEQ ID NO: 2 之輕鏈序列的 Fc-改造的、人源化、非醣基化 IgG1 κ 免疫黏附素。使用 Fc 區胺基酸殘基的 EU 編號，阿替利珠單抗在重鏈的位置 297 處包含單一胺基酸取代 (天冬醯胺取代為丙胺酸) (N297A)，這導致非醣基化抗體與 Fc 受體的最小限度結合。阿替利珠單抗還描述於 WHO 藥物資訊 (國際非專利藥物名稱)，擬定 INN：List 112, Vol. 28, No. 4, 發佈於 2015 年 1 月 16 日 (參見第 485 頁)。For purposes of this document, "atezolizumab" is an Fc-engineered, humanized, non-glycosylated IgG1 κ immunoadhesin that binds PD-L1 and comprises the heavy chain sequence of SEQ ID NO: 1 and the light chain sequence of SEQ ID NO: 2. Using EU numbering of amino acid residues in the Fc region, atezolizumab contains a single amino acid substitution (asparagine to alanine) (N297A) at position 297 of the heavy chain, which results in minimal binding of the non-glycosylated antibody to Fc receptors. Atezolizumab is also described in the WHO Drug Information (International Nonproprietary Name), Proposed INN: List 112, Vol. 28, No. 4, published on January 16, 2015 (see page 485).

術語「PD-1 軸結合拮抗劑」係指一種分子，其抑制 PD-1 軸結合配偶體與其一個或多個結合配偶體的交互作用，從而消除由 PD-1 信號軸的信號傳導引起的 T 細胞功能障礙，其結果是恢復或增強 T 細胞功能 (例如，增殖、細胞因子產生及/或靶細胞殺除)。如本文所用，PD-1 軸結合拮抗劑包括 PD-L1 結合拮抗劑、PD-1 結合拮抗劑及 PD-L2 結合拮抗劑。在一些實例中，PD-1 軸結合拮抗劑包括 PD-L1 結合拮抗劑或 PD-1 結合拮抗劑。在一個較佳的態樣中，PD-1 軸結合拮抗劑為 PD-L1 結合拮抗劑。The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners, thereby eliminating T cell dysfunction caused by signal transduction of the PD-1 signaling axis, resulting in restoration or enhancement of T cell function (e.g., proliferation, cytokine production and/or target cell killing). As used herein, PD-1 axis binding antagonists include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. In some examples, PD-1 axis binding antagonists include PD-L1 binding antagonists or PD-1 binding antagonists. In a preferred aspect, the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

術語「PD-L1 結合拮抗劑」係指一種分子，其減少、阻斷、抑制、消除或干擾由 PD-L1 與其任一種或多種結合配偶體 (諸如 PD-1 及/或 B7-1) 之交互作用引起的信號轉導。在一些實例中，PD-L1 結合拮抗劑為抑制 PD-L1 與其結合配偶體之結合的分子。在具體態樣中，PD-L1 結合拮抗劑抑制 PD-L1 與 PD-1 及/或 B7-1 之結合。在一些實例中，PD‑L1 結合拮抗劑包括抗 PD-L1 抗體、其抗原結合片段、免疫黏附素、融合蛋白、寡肽以及減少、阻斷、抑制、消除或干擾由 PD-L1 與其一種或多種結合配偶體 (諸如，PD-1 及/或 B7-1) 之交互作用引起的信號轉導的其他分子。在一個實例中，PD-L1 結合拮抗劑減少了由 T 淋巴細胞上表現的細胞表面蛋白所介導或藉由其表現的負共刺激信號 (藉由 PD-L1 介導的信號傳導)，從而減輕了功能障礙 T 細胞的功能障礙 (例如，增強效應子對抗原識別的應答)。在一些實例中，PD-L1 結合拮抗劑與 PD-L1 結合。在一些實例中，PD-L1 結合拮抗劑為抗 PD-L1 抗體 (例如，抗 PD-L1 拮抗劑抗體)。例示性抗 PD-L1 拮抗劑抗體包括阿替利珠單抗、MDX-1105、MEDI4736 (度伐魯單抗)、MSB0010718C (阿維魯單抗，avelumab)、SHR-1316、CS1001、恩沃利單抗 (envafolimab)、TQB2450、ZKAB001、LP-002、CX-072、IMC-001、KL-A167、APL-502、柯希利單抗 (cosibelimab)、洛達利單抗 (lodapolimab)、FAZ053、TG-1501、BGB-A333、BCD-135、AK-106、LDP、GR1405、HLX20、MSB2311、RC98、PDL-GEX、KD036、KY1003、YBL-007 及 HS-636。在一些態樣中，抗 PD-L1 抗體為阿替利珠單抗、MDX-1105、MEDI4736 (度伐魯單抗) 或 MSB0010718C (阿維魯單抗)。在一個具體態樣中，PD-L1 結合拮抗劑為 MDX-1105。在另一具體態樣中，PD-L1 結合拮抗劑為 MEDI4736 (度伐魯單抗)。在另一具體態樣中，PD-L1 結合拮抗劑為 MSB0010718C (阿維魯單抗)。在其他態樣中，PD-L1 結合拮抗劑可以為小分子，例如，GS-4224、INCB086550、MAX-10181、INCB090244、CA-170 或 ABSK041，其在一些實例中可以口服投予。其他例示性 PD-L1 結合拮抗劑包括 AVA-004、MT-6035、VXM10、LYN192、GB7003 及 JS-003。在一較佳態樣中，PD-L1 結合拮抗劑為阿替利珠單抗。The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, eliminates or interferes with signal transduction caused by the interaction of PD-L1 with any one or more of its binding partners (such as PD-1 and/or B7-1). In some examples, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partner. In a specific aspect, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and/or B7-1. In some examples, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners (e.g., PD-1 and/or B7-1). In one example, the PD-L1 binding antagonist reduces negative co-stimulatory signals mediated by or expressed by cell surface proteins expressed on T lymphocytes (through PD-L1-mediated signaling), thereby reducing the dysfunction of dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In some instances, the PD-L1 binding antagonist binds to PD-L1. In some instances, the PD-L1 binding antagonist is an anti-PD-L1 antibody (e.g., an anti-PD-L1 antagonist antibody). Exemplary anti-PD-L1 antagonist antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, envafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodalimab (lodapolimab), FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007, and HS-636. In some embodiments, the anti-PD-L1 antibody is atezolizumab, MDX-1105, MEDI4736 (durvalumab), or MSB0010718C (avelumab). In one embodiment, the PD-L1 binding antagonist is MDX-1105. In another embodiment, the PD-L1 binding antagonist is MEDI4736 (durvalumab). In another embodiment, the PD-L1 binding antagonist is MSB0010718C (avelumab). In other embodiments, the PD-L1 binding antagonist can be a small molecule, for example, GS-4224, INCB086550, MAX-10181, INCB090244, CA-170 or ABSK041, which can be administered orally in some examples. Other exemplary PD-L1 binding antagonists include AVA-004, MT-6035, VXM10, LYN192, GB7003 and JS-003. In a preferred embodiment, the PD-L1 binding antagonist is atezolizumab.

術語「PD-1 結合拮抗劑」係指一種分子，其減少、阻斷、抑制、消除或干擾由 PD-1 與其一種或多種結合配偶體 (諸如 PD-L1 及/或 PD-L2) 之交互作用引起的信號轉導。PD-1 (程序性死亡 1) 在本技術領域中亦稱為「程序性細胞死亡 1」、「PDCD1」、「CD279」及「SLEB2」。例示性的人 PD-1 顯示於 UniProtKB/Swiss-Prot 登錄號 Q15116。在一些實例中，PD-1 結合拮抗劑為抑制 PD-1 與其一種或多種結合配偶體之結合的分子。在具體態樣中，PD-1 結合拮抗劑抑制 PD-1 與 PD-L1 及/或 PD-L2 之結合。例如，PD-1 結合拮抗劑包括抗 PD-1 抗體、其抗原結合片段、免疫黏附素、融合蛋白、寡肽以及減少、阻斷、抑制、消除或干擾由 PD-1 與 PD-L1 及/或 PD-L2 之交互作用引起的訊號轉導的其他分子。在一個實例中，PD-1 結合拮抗劑減少了由 T 淋巴細胞上表現的細胞表面蛋白所介導或藉由其表現的負共刺激信號 (藉由 PD-1 介導的信號傳導)，從而減輕了功能障礙 T 細胞的功能障礙 (例如，增強效應子對抗原識別的應答)。在一些實例中，PD-1 結合拮抗劑與 PD-1 結合。在一些實例中，PD-1 結合拮抗劑為抗 PD-1 抗體 (例如，抗 PD-1 拮抗劑抗體)。例示性抗 PD-1 拮抗劑抗體包括納武利尤單抗 (nivolumab)、帕博利珠單抗、MEDI-0680、PDR001 (spartalizumab)、REGN2810 (西米普利單抗，cemiplimab)、BGB-108、普羅格利單抗 (prolgolimab)、卡瑞利珠單抗 (camrelizumab)、信迪利單抗 (sintilimab)、替雷利珠單抗 (tislelizumab)、特瑞普利單抗 (toripalimab)、多塔利單抗 (dostarlimab)、瑞弗利單抗 (retifanlimab)、薩善利單抗 (sasanlimab)、派安普利單抗 (penpulimab)、CS1003、HLX10、SCT-I10A、賽帕利單抗 (zimberelimab)、巴替利單抗 (balstilimab)、杰諾單抗 (genolimzumab)、BI 754091、西利單抗 (cetrelimab)、YBL-006、BAT1306、HX008、布格利單抗 (budigalimab)、AMG 404、CX-188、JTX-4014、609A、Sym021、LZM009、F520、SG001、AM0001、ENUM 244C8、ENUM 388D4、STI-1110、AK-103 及 hAb21。在具體態樣中，PD-1 結合拮抗劑為 MDX-1106 (納武利尤單抗 (nivolumab))。在另一具體態樣中，PD-1 結合拮抗劑為 MK-3475 (帕博利珠單抗 (pembrolizumab))。在另一具體態樣中，PD-1 結合拮抗劑為 PD-L2 Fc 融合蛋白，例如，AMP-224。在另一具體態樣中，PD-1 結合拮抗劑為 MED1-0680。在另一具體態樣中，PD-1 結合拮抗劑為 PDR001 (spartalizumab)。在另一具體態樣中，PD-1 結合拮抗劑為 REGN2810 (西米普利單抗)。在另一具體態樣中，PD-1 結合拮抗劑為 BGB-108。在另一具體態樣中，PD-1 結合拮抗劑為普羅格利單抗。在另一具體態樣中，PD-1 結合拮抗劑為卡瑞利珠單抗。在另一具體態樣中，PD-1 結合拮抗劑為信迪利單抗。在另一具體態樣中，PD-1 結合拮抗劑為替雷利珠單抗。在另一具體態樣中，PD-1 結合拮抗劑為特瑞普利單抗。其他額外的例示性 PD-1 結合拮抗劑包括 BION-004、CB201、AUNP-012、ADG104 及 LBL-006。The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates or interferes with signal transduction caused by the interaction of PD-1 with one or more of its binding partners (such as PD-L1 and/or PD-L2). PD-1 (programmed death 1) is also known in the art as "programmed cell death 1", "PDCD1", "CD279" and "SLEB2". Exemplary human PD-1 is shown in UniProtKB/Swiss-Prot Accession No. Q15116. In some instances, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In a specific aspect, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and/or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, eliminate, or interfere with signal transduction caused by the interaction of PD-1 with PD-L1 and/or PD-L2. In one example, a PD-1 binding antagonist reduces negative co-stimulatory signals mediated by or expressed by cell surface proteins expressed on T lymphocytes (via PD-1 mediated signaling), thereby reducing dysfunction of dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In some examples, a PD-1 binding antagonist binds to PD-1. In some examples, a PD-1 binding antagonist is an anti-PD-1 antibody (e.g., an anti-PD-1 antagonist antibody). Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, batilimab In one embodiment, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In another embodiment, the PD-1 binding antagonist is a PD-L2 Fc fusion protein, e.g., AMP-224. In another embodiment, the PD-1 binding antagonist is MED1-0680. In another embodiment, the PD-1 binding antagonist is PDR001 (spartalizumab). In another embodiment, the PD-1 binding antagonist is REGN2810 (simiprilimab). In another embodiment, the PD-1 binding antagonist is BGB-108. In another embodiment, the PD-1 binding antagonist is proglitinomab. In another embodiment, the PD-1 binding antagonist is carrelizumab. In another embodiment, the PD-1 binding antagonist is sintilimab. In another embodiment, the PD-1 binding antagonist is tislelizumab. In another embodiment, the PD-1 binding antagonist is toripalimab. Other additional exemplary PD-1 binding antagonists include BION-004, CB201, AUNP-012, ADG104, and LBL-006.

術語「PD-L2 結合拮抗劑」指代一種分子，其減少、阻斷、抑制、消除或干擾由 PD-L2 與其任一種或多種結合配偶體 (諸如 PD-1) 之交互作用引起的信號轉導。PD-L2 (程序性死亡配體 2) 在本領域中亦稱為「程序性細胞死亡 1 配體 2」、「PDCD1LG2」、「CD273」、「B7-DC」及「PDL2」。例示性的人 PD-L2 顯示於 UniProtKB/Swiss-Prot 登錄號 Q9BQ51。在一些實例中，PD-L2 結合拮抗劑為抑制 PD-L2 與其一種或多種結合配偶體之結合的分子。在具體態樣，PD-L2 結合拮抗劑抑制 PD-L2 與 PD-1 之結合。示例性 PD-L2 結合拮抗劑包括抗 PD-L2 抗體、其抗原結合片段、免疫黏附素、融合蛋白、寡肽以及減少、阻斷、抑制、消除或干擾由 PD-L2 與其任一種或多種結合配偶體 (諸如 PD-1) 之交互作用引起的訊號轉導的其他分子。在一個態樣，PD-L2 結合拮抗劑減少了由 T 淋巴細胞上表現的細胞表面蛋白所介導或藉由其表現的負共刺激信號 (藉由 PD‑L2 介導的信號傳導)，從而減輕了功能障礙 T 細胞的功能障礙 (例如，增強效應子對抗原識別的應答)。在一些態樣中，PD-L2 結合拮抗劑與 PD-L2 結合。在一些態樣中，PD-L2 結合拮抗劑為免疫黏附素。在其他態樣中，PD-L2 結合拮抗劑為抗 PD-L2 拮抗劑抗體。The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates or interferes with signal transduction caused by the interaction of PD-L2 with any one or more of its binding partners, such as PD-1. PD-L2 (programmed death ligand 2) is also known in the art as "programmed cell death 1 ligand 2", "PDCD1LG2", "CD273", "B7-DC" and "PDL2". An exemplary human PD-L2 is shown in UniProtKB/Swiss-Prot Accession No. Q9BQ51. In some instances, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific aspect, a PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. Exemplary PD-L2 binding antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signal transduction caused by the interaction of PD-L2 with any one or more of its binding partners (such as PD-1). In one aspect, a PD-L2 binding antagonist reduces negative co-stimulatory signals mediated by or expressed by cell surface proteins expressed on T lymphocytes (via PD-L2-mediated signaling), thereby reducing dysfunction of dysfunctional T cells (e.g., enhancing effector responses to antigen recognition). In some aspects, a PD-L2 binding antagonist binds to PD-L2. In some aspects, a PD-L2 binding antagonist is an immunoadhesin. In other aspects, a PD-L2 binding antagonist is an anti-PD-L2 antagonist antibody.

術語「癌症」係指由身體之部分中的異常細胞不受控制的分裂所引起的疾病。在一個實例中，癌症為肺癌，例如 IIB 期 NSCLC、IIIA 期 NSCLC、或 T3N2 IIIB 期 NSCLC。The term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. In one example, the cancer is lung cancer, such as stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC.

術語「腫瘤」係指所有贅生性細胞的生長及增殖，無論是惡性還是良性，以及所有癌前及癌細胞及組織。術語「癌症」、「癌性」、「細胞增生性疾病」、「增生性疾病」及「腫瘤」在本文中並不互相排斥。The term "tumor" refers to all proliferative cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. The terms "cancer", "cancerous", "cell proliferative disorder", "proliferative disorder" and "tumor" are not mutually exclusive in this document.

如本文所用，「腫瘤細胞」係指存在於腫瘤或其樣品中的任何腫瘤細胞。使用本領域已知的及/或本文描述的方法，可以將腫瘤細胞與腫瘤樣品中可能存在的其他細胞區分開，例如，基質細胞及腫瘤浸潤免疫細胞。As used herein, "tumor cell" refers to any tumor cell present in a tumor or a sample thereof. Tumor cells can be distinguished from other cells that may be present in a tumor sample, for example, stromal cells and tumor-infiltrating immune cells, using methods known in the art and/or described herein.

如本文所用，「治療」包含使用有效量的治療劑 (例如，PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)；抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)；及/或化學治療劑 (例如，鉑類化學治療劑)) 之有效癌症治療。本文的治療尤其包括輔助療法、新輔助療法、非轉移性癌症療法 (例如，局部晚期癌症療法) 及轉移性癌症療法。治療可以是一線治療 (例如，患者可能先前未接受過治療或未接受過先前全身性療法)，或者是二線或晚期治療。As used herein, "treatment" includes effective cancer treatment using an effective amount of a therapeutic agent (e.g., a PD-1 axis binding antagonist (e.g., atezolizumab); an anti-TIGIT antagonist antibody (e.g., tisleliumab); and/or a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent)). Treatment herein specifically includes adjuvant therapy, neoadjuvant therapy, non-metastatic cancer therapy (e.g., locally advanced cancer therapy), and metastatic cancer therapy. Treatment can be first-line therapy (e.g., the patient may not have received prior treatment or has not received prior systemic therapy), or second-line or advanced therapy.

「有效量」的化合物 (例如，PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)；抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)；及/或化學治療劑 (例如，鉑類化學治療劑)) 係實現所需治療結果 (諸如特定疾病或疾患 (例如，癌症，例如，NSCLC，例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的總存活或無進展存活的可測量增加) 所需的至少最小量。本文之有效量可根據諸如疾病狀態、患者年齡、性別及體重、以及該抗體於該個體體內引起所欲應答之因素而改變。有效量亦為該治療之任意毒性或有害效應被治療有益效應超過的量。對於預防性使用，有益或期望的結果諸如：消除或降低風險、減輕嚴重程度或延遲疾病發作，包括疾病的生化、組織學及/或行為症狀、其併發症以及疾病發展過程中出現的中間病理表型。對於治療用途，有益或期望的結果包括臨床結果，諸如：減少疾病引起的一種或多種症狀 (例如，減少或延遲與癌症有關的疼痛、有症狀的骨骼相關事件 (SSE)；根據歐洲癌症研究與治療組織生活品質問卷 (EORTC QLQ-C30) 得到的症狀減少，例如，疲勞、噁心、嘔吐、疼痛、呼吸困難、失眠、食慾不振、便秘、腹瀉或身體情感、認知或社會功能的一般位準)；疼痛減輕，例如按 10 點疼痛嚴重程度 (以最糟糕的程度衡量) 的數值量表 (NRS) 進行衡量；及/或按照健康相關的生活品質生活品質 (HRQoL) 問卷得到的與肺癌相關的症狀減輕 (藉由肺癌 (SILC) 量表中的症狀進行評估 (例如，咳嗽、呼吸困難及胸痛的惡化時間 (TTD))；受累於疾病的患者的生活品質的提高；治療疾病所需的其他藥物的劑量的減少；藉由例如靶向治療增強另一種藥物的療效；延緩疾病惡化 (例如，無惡化存活或放射線照相無惡化存活 (rPFS))；明確的臨床惡化延緩 (例如，癌症相關的疼痛惡化，有症狀的骨骼相關事件，美國東部腫瘤協作組 (ECOG) 體能狀態 (PS) 惡化 (例如，疾病如何影響患者的日常生活能力)，及/或開始下一次全身性抗癌療法)，及/或延緩肺特異性抗原惡化的時間)；及/或存活期延長。就癌症或腫瘤而言，有效量之藥物可具有以下效果：減少癌細胞數；減小腫瘤尺寸；抑制 (亦即，在一定程度上減緩或在理想情況下終止) 癌細胞浸潤入周邊器官中；抑制 (亦即，在一定程度上減緩或在理想情況下終止) 腫瘤轉移；在一定程度上抑制腫瘤生長；及/或在一定程度上減輕與該疾患相關之症狀中的一者或多者。有效量可於一次或多次投予中投予。出於本發明的目的，藥物、化合物或藥物組成物的有效量為足以直接或間接完成預防性或治療性治療的量。如在臨床背景中理解，藥物、化合物或藥物組成物之有效量可與或不與另一藥物、化合物或醫藥組成物聯合而達成。因此，在投予一種或多種治療劑之上下文中可慮及「有效量」，且若單個藥劑與一種或多種其他藥劑聯合而可實現或已實現所需結果，則該單個藥劑可視為以有效量給出。An "effective amount" of a compound (e.g., a PD-1 axis binding antagonist (e.g., atezolizumab); an anti-TIGIT antagonist antibody (e.g., tisleliumab); and/or a chemotherapeutic agent (e.g., a platinum-based chemotherapeutic agent)) is at least the minimum amount required to achieve a desired treatment outcome, such as a measurable increase in overall survival or progression-free survival for a particular disease or condition (e.g., cancer, e.g., NSCLC, e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC). The effective amount herein may vary depending on factors such as the disease state, the patient's age, sex, and weight, and the desired response elicited by the antibody in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the beneficial effects of the treatment. For prophylactic use, beneficial or desired results include: eliminating or reducing the risk, reducing the severity, or delaying the onset of a disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that occur during the course of disease development. For therapeutic uses, beneficial or desired outcomes include clinical outcomes such as: reduction in one or more disease-related symptoms (e.g., reduction or delay in cancer-related pain, symptomatic skeletal-related events (SSEs); reduction in symptoms as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), such as fatigue, nausea, vomiting, pain, dyspnea, insomnia, loss of appetite, constipation, diarrhea, or general level of physical-emotional, cognitive, or social functioning); reduction in pain, such as measured by a 10-point numerical rating scale (NRS) of pain severity (measured as the worst possible severity); and/or reduction in lung cancer-related symptoms as measured by the Health-Related Quality of Life (HRQoL) Questionnaire (e.g., time to worsening (TTD) of cough, dyspnea, and chest pain) as assessed by the SILC scale; improved quality of life for patients affected by the disease; reduction in the dose of other drugs needed to treat the disease; augmentation of the efficacy of another drug, such as by targeted therapy; delay in disease worsening (e.g., progression-free survival or radiographic progression-free survival (rPFS)); demonstrated delay in clinical worsening (e.g., worsening of cancer-related pain, symptomatic skeletal events, worsening of Eastern Cooperative Oncology Group (ECOG) performance status (PS) (e.g., how the disease affects the patient's ability to live daily), and/or to start the next systemic anticancer therapy), and/or to delay the time to lung-specific antigen deterioration); and/or to prolong survival. In the case of cancer or tumors, an effective amount of a drug may have the following effects: reducing the number of cancer cells; reducing the size of tumors; inhibiting (i.e., slowing down to some extent or, ideally, stopping) the infiltration of cancer cells into peripheral organs; inhibiting (i.e., slowing down to some extent or, ideally, stopping) tumor metastasis; inhibiting tumor growth to some extent; and/or alleviating to some extent one or more of the symptoms associated with the disease. An effective amount may be administered in one or more administrations. For the purposes of the present invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to accomplish, directly or indirectly, a preventive or therapeutic treatment. As understood in a clinical context, an effective amount of a drug, compound, or pharmaceutical composition may be achieved with or without combination with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if it can achieve or has achieved the desired result in combination with one or more other agents.

如本文所用，「存活」係指患者仍存活，包括總存活以及無惡化存活。As used herein, "survival" means that the patient is still alive, including overall survival and progression-free survival.

如本文所用，「無疾病存活」及「DFS」係指從疾病 (例如，癌症，例如，NSCLC) 的診斷日期或開始治療日期到出現疾病 (例如，癌症，例如，NSCLC) 的局部或遠端復發、新的原發性疾病 (例如，癌症，例如，NSCLC) 或任何原因導致的死亡的時間長度。例如，DFS 可定義為從首次研究治療到出現疾病的局部或遠端復發、新的原發性疾病或任何原因導致的死亡的時間。As used herein, "disease-free survival" and "DFS" refer to the length of time from the date of diagnosis of a disease (e.g., cancer, e.g., NSCLC) or the date of initiation of treatment to the occurrence of local or distant recurrence of the disease (e.g., cancer, e.g., NSCLC), a new primary disease (e.g., cancer, e.g., NSCLC), or death from any cause. For example, DFS can be defined as the time from the first study treatment to the occurrence of local or distant recurrence of the disease, a new primary disease, or death from any cause.

如本文所用，「整體存活期」及「OS」係指距疾病 (例如，癌症) 的診斷日期或開始治療日期患者仍存活的時長。例如，OS 可定義為自首次研究治療至任何原因造成之死亡的時間。As used herein, "overall survival" and "OS" refer to the length of time a patient is alive from the date of diagnosis of a disease (e.g., cancer) or the date of initiation of treatment. For example, OS may be defined as the time from the first study treatment to death from any cause.

如本文所用，「完全反應」及「CR」係指全部標靶病灶消失。As used herein, "complete response" and "CR" refer to the disappearance of all target lesions.

如本文所用，「部分反應」及「PR」係指標靶病灶的最長直徑 (SLD) 之和減小至少 30%，以治療之前的基線 SLD 作為參考。As used herein, "partial response" and "PR" refer to a reduction of at least 30% in the sum of the longest diameters of target lesions (SLD), relative to the baseline SLD before treatment.

如本文所用，「進行性疾病」及「PD」係指標靶病變的 SLD 至少增加 20%，以研究中的最小總及 (最低點)，包括基線作為參考。As used herein, "progressive disease" and "PD" refer to at least a 20% increase in the SLD of the target lesion, with the smallest sum (nadir) in the study, including the baseline, as reference.

如本文所用，「疾病穩定」及「SD」係指既未充分萎縮至滿足 PR 的要求又未充分增加至滿足 PD 的要求。As used herein, "stable disease" and "SD" refer to neither sufficient shrinkage to meet the requirements of PR nor sufficient increase to meet the requirements of PD.

如本文所用，「個體」或「個體」意指哺乳動物，包括但不限於人或非人哺乳動物諸如牛、馬、犬、綿羊或貓。在一些實施例中，個體為人。患者亦為本文之個體。As used herein, "subject" or "subject" means a mammal, including but not limited to a human or a non-human mammal such as a cow, horse, dog, sheep or cat. In some embodiments, the subject is a human. A patient is also a subject herein.

如本文所用，在免疫組織化學 (IHC) 測定法 (例如，使用抗體 SP142、SP263、22C3 或 28-8 對 PD-L1 進行 IHC 測定法染色) 的背景中，「PD-L1 陽性腫瘤細胞比例」是在樣品染色後，在任何強度下表現出部分或全部膜染色 (不包括細胞質染色) 的活腫瘤細胞相對於樣品中存在的所有活瘤細胞的百分比。因此，PD-L1 陽性腫瘤細胞比例可使用 PD-L1 IHC SP142 (Ventana) 測定法進行計算，例如，藉由公式 PD-L1 陽性腫瘤細胞比例 = (PD-L1 陽性腫瘤細胞數)/(PD-L1 陽性及 PD-L1 陰性腫瘤細胞總數) 進行計算，其中，將腫瘤細胞及所有非腫瘤細胞 (例如，腫瘤浸潤免疫細胞、正常細胞、壞死細胞及碎片) 的 PD-L1 細胞質染色排除在評估及評分之外。應當理解，任何給定的診斷性 PD-L1 抗體可對應於可用於得出 PD-L1 陽性腫瘤細胞比例的特定 IHC 測定法方案及/或評分術語。例如，PD-L1 陽性腫瘤細胞比例可以分別使用在 Benchmark ULTRA 上進行的 OPTIVIEW® 檢測、在 AutostainerLink 48 上進行的 EnVision Flex、在 Benchmark ULTRA 上進行的 OPTIVIEW® 檢測及擴增或在 AutostainerLink 48 上進行的 EnVision Flex，從經 SP263、22C3、SP142 或 28-8 染色的腫瘤細胞樣品得到。As used herein, in the context of an immunohistochemistry (IHC) assay (e.g., an IHC assay staining for PD-L1 using antibodies SP142, SP263, 22C3, or 28-8), the "proportion of PD-L1-positive tumor cells" is the percentage of live tumor cells that exhibit partial or complete membrane staining (excluding cytoplasmic staining) at any intensity relative to all live tumor cells present in the sample after staining of the sample. Therefore, the proportion of PD-L1-positive tumor cells can be calculated using the PD-L1 IHC SP142 (Ventana) assay, for example, by the formula PD-L1-positive tumor cell proportion = (number of PD-L1-positive tumor cells)/(total number of PD-L1-positive and PD-L1-negative tumor cells), where PD-L1 cytoplasmic staining of tumor cells and all non-tumor cells (e.g., tumor-infiltrating immune cells, normal cells, necrotic cells, and debris) are excluded from evaluation and scoring. It should be understood that any given diagnostic PD-L1 antibody may correspond to a particular IHC assay protocol and/or scoring terminology that can be used to derive the proportion of PD-L1 positive tumor cells. For example, the proportion of PD-L1 positive tumor cells can be derived from tumor cell samples stained with SP263, 22C3, SP142, or 28-8 using the OPTIVIEW® assay performed on the Benchmark ULTRA, the EnVision Flex performed on the AutostainerLink 48, the OPTIVIEW® assay and expansion performed on the Benchmark ULTRA, or the EnVision Flex performed on the AutostainerLink 48, respectively.

如本文所用，「Ventana SP142 IHC 測定法」根據 Ventana PD-L1 (SP142) 測定法包裝說明書 (Tucson，AZ：Ventana Medical Systems, Inc.) 進行，該說明書全文以引用方式併入本文。As used herein, the "Ventana SP142 IHC assay" is performed according to the Ventana PD-L1 (SP142) assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

如本文所用，「Ventana SP263 IHC 測定法」根據 Ventana PD-L1 (SP263) 測定包裝說明書 (Tucson，AZ：Ventana Medical Systems, Inc.) 進行，該說明書全文以引用方式併入本文。As used herein, the "Ventana SP263 IHC assay" was performed according to the Ventana PD-L1 (SP263) assay package insert (Tucson, AZ: Ventana Medical Systems, Inc.), which is incorporated herein by reference in its entirety.

如本文所用，「pharmDx 22C3 IHC 測定法」係根據 PD-L1 IHC 22C3 pharmDx 包裝說明書 (Carpinteria，CA：Dako，Agilent Pathology Solutions) 進行，該說明書全文以引用方式併入本文。As used herein, the "pharmDx 22C3 IHC assay" is performed according to the PD-L1 IHC 22C3 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

如本文所用，「pharmDx 28-8 IHC 測定法」係根據 PD-L1 IHC 28-8 pharmDx 包裝說明書 (Carpinteria，CA：Dako，Agilent Pathology Solutions) 進行，該說明書全文以引用方式併入本文。As used herein, the "pharmDx 28-8 IHC assay" is performed according to the PD-L1 IHC 28-8 pharmDx package insert (Carpinteria, CA: Dako, Agilent Pathology Solutions), which is incorporated herein by reference in its entirety.

術語「藥品仿單」用於指涉通常包含在治療性產品的商業包裝中的說明，該說明包含有關使用此等治療性產品的適應症、用法、劑量、投予途徑、組合療法、禁忌症及/或警告等資訊。The term "product leaflet" is used to refer to instructions customarily included in commercial packages of therapeutic products that contain information about the indications, usage, dosage, routes of administration, combination therapy, contraindications and/or warnings for the use of such therapeutic products.

如本文所用，「與……組合」係指投予除另一種治療方式之外的一種治療方式，例如，包括投予 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及抗 TIGIT 拮抗劑抗體 (例如替瑞利尤單抗)。 因此，「與……聯合」係指在向患者投予一種治療方式之前、之中或之後投予另一種治療方式。As used herein, "in combination with" refers to administering one therapeutic modality in addition to another therapeutic modality, including, for example, administration of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tisleliumab). Thus, "in combination with" refers to administering one therapeutic modality before, during, or after the administration of another therapeutic modality to a patient.

與一種或多種其他藥物「同時」投予之藥物係與一種或多種其他藥物在同一治療週期、在治療的同一天、以及視情況與一種或多種其他藥物同時投予。例如，對於每四週給予之癌症療法，同時投予之藥物各自在各四週 (28 天) 給藥週期之第 1 天投予。A drug that is administered "concurrently" with one or more other drugs is administered during the same treatment cycle, on the same day of treatment, and, as appropriate, concurrently with one or more other drugs. For example, for a cancer therapy given every four weeks, the concurrently administered drugs are each administered on Day 1 of each four-week (28-day) dosing cycle.

本文中之術語「抗體」具體而言涵蓋單株抗體 (包括全長單株抗體)、多株抗體、多特異性抗體 (例如雙特異性抗體) 及抗體片段，只要其等展現所需生物活性。在一個實例中，抗體為全長單株抗體。The term "antibody" herein specifically encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (such as bispecific antibodies) and antibody fragments, as long as they exhibit the desired biological activity. In one example, the antibody is a full-length monoclonal antibody.

如本文所用，術語 IgG「同功型」或「亞型」係指由其恆定區的化學及抗原特性所定義之免疫球蛋白的任何亞型。As used herein, the term IgG "isotype" or "subtype" refers to any subtype of immunoglobulins defined by the chemical and antigenic properties of its constant regions.

根據其重鏈恆定域之胺基酸序列，抗體 (免疫球蛋白) 可歸類為不同的類別。有五大類免疫球蛋白：IgA、IgD、IgE、IgG 及 IgM，且彼等中的幾種可進一步分為亞型 (同功型)，例如，IgG1、IgG2、IgG3、IgG4、IgA1 及 IgA2。對應於不同類別之免疫球蛋白的重鏈恆定域分別稱為 α、γ、ɛ、γ 及 μ。不同類別之免疫球蛋白的次單位結構及三維構型為熟知的且一般描述於例如 Abbas等人,Cellular and Mol. Immunology, 第 4 版. (W.B.Saunders, Co., 2000) 所述。抗體可以是較大融合分子的一部分，其藉由抗體與一種或多種其他蛋白質或肽的共價或非共價締合形成。Antibodies (immunoglobulins) can be classified into different classes according to the amino acid sequences of their heavy chain constant domains. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, and several of them can be further divided into subtypes (isotypes), for example, IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2. The heavy chain constant domains corresponding to the different classes of immunoglobulins are called α, γ, ɛ, γ and μ, respectively. The subunit structures and three-dimensional configurations of the different classes of immunoglobulins are well known and generally described in, for example, Abbas et al.,Cellular and Mol. Immunology , 4th edition. (WB Saunders, Co., 2000). An antibody may be part of a larger fusion molecule formed by covalent or non-covalent association of the antibody with one or more other proteins or peptides.

術語「全長抗體」、「完整抗體」及「全抗體」在本文中可互換使用以指呈其基本上完整形式、不為如下文所定義之抗體片段的抗體。該等術語指包含 Fc 區域的抗體。The terms "full-length antibody", "intact antibody" and "whole antibody" are used interchangeably herein to refer to an antibody in its substantially intact form, not as an antibody fragment as defined below. These terms refer to an antibody that includes an Fc region.

本文中的術語「Fc 區域」，用於定義包含至少一部分恆定區域的免疫球蛋白重鏈的 C 端區域。該術語包括天然序列 Fc 區域及變異體 Fc 區域。在一個態樣中，人 IgG 重鏈 Fc 區從 Cys226 或從 Pro230 延伸至重鏈的羧基端。但是，由宿主細胞產生的抗體可能經歷重鏈 C 端的一種或多種，特別是一種或兩種胺基酸之轉譯後切割。因此，由宿主細胞藉由表現編碼全長重鏈的特定核酸分子而產生的抗體可包括全長重鏈，或者可包括全長重鏈的切割變體。重鏈的最後兩個 C 端胺基酸為甘胺酸 (G446) 及離胺酸 (K447)。因此，可以存在或可以不存在 Fc 區域之 C 端離胺酸 (Lys447) 或 C 端甘胺酸 (Gly446) 及離胺酸 (Lys447)。除非另有說明，否則包括 Fc 區域之重鏈之胺基酸序列在本文中表示不含 C 端離胺酸 (Lys447)。在一個態樣中，包含在本文所揭示之抗體中的包括本文所指定之 Fc 區的重鏈包含額外的 C 端甘胺酸-離胺酸二肽 (G446 及 K447)。在一個態樣中，包含在本文揭示的抗體中的包括本文指定的 Fc 區域的重鏈包含額外的 C 端甘胺酸殘基 (G446)。在一個態樣中，包含在本文揭示的抗體中的包括本文指定的 Fc 區域的重鏈包含額外 C 端離胺酸殘基 (K447)。在一個實施例中，Fc 區包含重鏈的單個胺基酸取代 N297A。除非本文另有說明，否則 Fc 區域或恆定區中胺基酸殘基之編號根據 EU 編號系統 (也稱為 EU 指數) 進行，如 Kabat 等人所述 (Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991) (另見上文)。The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of the constant region. The term includes native sequence Fc regions and variant Fc regions. In one aspect, the human IgG heavy chain Fc region extends from Cys226 or from Pro230 to the carboxyl terminus of the heavy chain. However, antibodies produced by host cells may undergo post-translational cleavage of one or more, particularly one or two, amino acids at the C-terminus of the heavy chain. Thus, antibodies produced by host cells by expressing a specific nucleic acid molecule encoding a full-length heavy chain may include the full-length heavy chain, or may include a cleavage variant of the full-length heavy chain. The last two C-terminal amino acids of the heavy chain are glycine (G446) and lysine (K447). Thus, the C-terminal lysine (Lys447) or C-terminal glycine (Gly446) and lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified, the amino acid sequence of the heavy chain comprising the Fc region is herein indicated as being free of the C-terminal lysine (Lys447). In one aspect, the heavy chain comprising the Fc region specified herein contained in the antibodies disclosed herein comprises an additional C-terminal glycine-lysine dipeptide (G446 and K447). In one aspect, the heavy chain comprising the Fc region specified herein contained in the antibodies disclosed herein comprises an additional C-terminal glycine residue (G446). In one aspect, the heavy chain comprising the Fc region specified herein contained in the antibodies disclosed herein comprises an additional C-terminal lysine residue (K447). In one embodiment, the Fc region comprises a single amino acid substitution N297A of the heavy chain. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or the constant region is according to the EU numbering system (also known as the EU index) as described by Kabat et al.(Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991) (see also above).

當提到可變域中的殘基時，一般使用 Kabat 編號系統 (大約為輕鏈的殘基 1-107 及重鏈的殘基 1-113) (例如，Kabat 等人,Sequences of Immunological Interest.第 5 版 Public Health Service, National Institutes of Health, Bethesda, Md. (1991))。當提及免疫球蛋白重鏈恆定區域中的殘基時，通常使用「EU 編號系統」或「EU 索引」 (例如，Kabat 等人報導的 EU 索引 (同上文))。「如 Kabat 中的 EU 索引」係指人類 IgG1 EU 抗體的殘基編號。When referring to residues in the variable domains, the Kabat numbering system is generally used (approximately residues 1-107 for the light chain and residues 1-113 for the heavy chain) (e.g., Kabat et al.,Sequences of Immunological Interest . 5th ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)). When referring to residues in the constant region of the immunoglobulin heavy chain, the "EU numbering system" or "EU index" is generally used (e.g., the EU index as reported by Kabat et al. (supra)). The "EU index as in Kabat" refers to the residue numbering of the human IgG1 EU antibody.

「裸抗體」係指未與異源部分 (例如，細胞毒性部分) 或放射性標記結合之抗體。裸抗體可存在於醫藥組成物中。"Naked antibody" refers to an antibody that is not conjugated to a foreign moiety (e.g., a cytotoxic moiety) or a radiolabel. Naked antibodies can be present in pharmaceutical compositions.

如本文所用的術語「單株抗體」係指獲自實質上同源抗體群體之抗體，即包含群體的個別抗體是相同的及/或結合相同的抗原決定位，除了例如含有天然生成之突變或於單株抗體製劑生產過程中產生的可能的變異體抗體之外，此等變異體通常係以少量存在。與通常包括針對不同決定位 (抗原決定位) 之不同抗體之多株抗體製劑相反，單株抗體製劑之各單株抗體係針對於抗原上的單一決定位。因此，修飾詞「單株」表示抗體之特徵係獲自實質上同質之抗體群體，且不應解釋為需要藉由任何特定方法產生抗體。例如，意欲根據本發明使用的單株抗體可藉由多種技術來製造，包括但不限於融合瘤方法、重組 DNA 方法、噬菌體展示方法、及利用包含全部或部分人免疫球蛋白基因座之轉殖基因動物之方法。The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous antibody population, i.e., the individual antibodies comprising the population are identical and/or bind to the same antigenic determinant, except for possible variant antibodies that contain, for example, naturally occurring mutations or that arise during the production of the monoclonal antibody preparation, such variants are generally present in small amounts. In contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (antigenic determinants), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on the antigen. Thus, the modifier "monoclonal" indicates that the characteristics of the antibody are obtained from a substantially homogeneous antibody population, and should not be construed as requiring the antibody to be produced by any particular method. For example, monoclonal antibodies intended for use according to the present invention can be produced by a variety of techniques, including but not limited to fusion tumor methods, recombinant DNA methods, phage display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci.

如本文所用，術語「高度可變區」或「HVR」係指抗體可變域中序列高變並決定抗原結合特異性的各個區域，例如「互補決定區」(「CDR」)。As used herein, the term "hypervariable region" or "HVR" refers to the regions of the antibody variable domain whose sequences are highly variable and which determine the antigen binding specificity, such as the "complementary determining region" ("CDR").

通常，抗體包括六個 CDR：三個在 VH 中 (CDR-H1、CDR-H2、CDR-H3)，及三個在 VL 中 (CDR-L1、CDR-L2、CDR-L3)。本文中，例示性 CDR 包括： (a) 高度可變環存在於胺基酸殘基 26-32 (L1)、50-52 (L2)、91-96 (L3)、26-32 (H1)、53-55 (H2)、及 96-101 (H3) 處 (Chothia 及 Lesk，J. Mol. Biol.196:901-917 (1987))； (b) CDR 存在於胺基酸殘基 24-34 (L1)、50-56 (L2)、89-97 (L3)、31-35b (H1)、50-65 (H2)、及 95-102 (H3)處 (Kabat 等人，Sequences of Proteins of Immunological Interest，第 5 版 Public Health Service，National Institutes of Health，Bethesda, MD (1991))；及 (c) 抗原接觸存在於胺基酸殘基 27c-36 (L1)、46-55 (L2)、89-96 (L3)、30-35b (H1)、47-58 (H2)、及 93-101 (H3) 處 (MacCallum 等人J. Mol. Biol.262: 732-745 (1996))。Typically, antibodies include six CDRs: three in the VH (CDR-H1, CDR-H2, CDR-H3), and three in the VL (CDR-L1, CDR-L2, CDR-L3). Herein, exemplary CDRs include: (a) highly variable loops present at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk,J. Mol. Biol. 196:901-917 (1987)); (b) CDRs present at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al.,Sequences of Proteins of Immunological Interest , 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)); and (c) antigenic contacts are present at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al.J. Mol. Biol. 262: 732-745 (1996)).

除非另有說明，否則 CDR 根據 Kabat 等人在上述文獻中描述之方法來判定。本領域之技術人員將理解，也可以根據 Chothia在上述文獻、McCallum在上述文獻中描述之方法或任何其他科學上接受之命名系統來判定 CDR 名稱。Unless otherwise indicated, CDRs are determined according tothe method described by Kabat et al., supra . Those skilled in the art will appreciate that CDR names may also be determined according to the method described by Chothia,supra , McCallum, supra , or any other scientifically accepted nomenclature system.

「框架」或「FR」係指互補決定區 (CDR) 之外的可變域殘基。可變域之 FR 通常由四個 FR 域組成：FR1、FR2、FR3、及 FR4。因此，CDR 及 FR 序列通常以如下順序出現在 VH (或 VL) 中：FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR-L3)-FR4。"Framework" or "FR" refers to the variable domain residues outside the complementary determining regions (CDRs). The FR of a variable domain is usually composed of four FR domains: FR1, FR2, FR3, and FR4. Therefore, CDR and FR sequences usually appear in the following order in VH (or VL): FR1-CDR-H1(CDR-L1)-FR2-CDR-H2(CDR-L2)-FR3-CDR-H3(CDR-L3)-FR4.

術語「如 Kabat 中的可變域殘基編號」或「如 Kabat 中的胺基酸位置編號」及其變異體係指用於 Kabat 等人 (同上文) 中抗體彙編的重鏈可變域或輕鏈可變域的編號系統。使用該編號系統，實際線性胺基酸序列可含有較少或額外的胺基酸，其對應於可變域的 FR 或 HVR 的縮短或插入。例如，重鏈可變域可包括在 H2 的殘基 52 之後的單個胺基酸插入 (根據 Kabat，殘基 52a) 及在重鏈 FR 殘基 82 之後的插入殘基 (例如，根據 Kabat，殘基 82a、82b、及 82c 等)。可藉由比對給定抗體之序列同源性區與「標準」Kabat 編號序列來判定該抗體之殘基的 Kabat 編號。The term "variable domain residue numbering as in Kabat" or "amino acid position numbering as in Kabat" and variants thereof refer to the numbering system used for the heavy chain variable domain or light chain variable domain of the antibody compilation in Kabat et al. (supra). Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to shortening or insertions of the FR or HVR of the variable domain. For example, the heavy chain variable domain may include a single amino acid insertion after residue 52 of H2 (residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbers of residues in a given antibody can be determined by aligning regions of sequence homology with a "standard" Kabat numbering sequence.

如本文所使用，術語「單特異性」抗體表示具有一個或多個結合位點的抗體，各結合位點結合相同抗原的相同表位。如本文所用，術語「雙特異性」抗體意指抗體能夠與至少兩個不同的抗原特異性地結合，例如兩個結合位點，各結合位點均由一對抗體重鏈可變域 (VH) 及抗體輕鏈可變域 (VL) 形成，該等結合點與不同抗原結合或與同一抗原上之不同抗原決定基結合。該雙特異性抗體為 1+1 格式。其他雙特異性抗體形式為 2+1 格式 (包含針對第一抗原或表位之兩個結合位點以及針對第二抗原或表位之一個結合位點) 或 2+2 格式 (包含針對第一抗原或表位之兩個結合位點以及針對第二抗原或表位之兩個結合位點)。通常，雙特異性抗體包含兩個抗原結合位點，其中各抗原結合位點對不同抗原具有特異性。As used herein, the term "monospecific" antibody refers to an antibody having one or more binding sites, each binding site binding to the same epitope of the same antigen. As used herein, the term "bispecific" antibody means an antibody capable of specifically binding to at least two different antigens, such as two binding sites, each binding site formed by a pair of antibody heavy chain variable domains (VH) and antibody light chain variable domains (VL), the binding sites binding to different antigens or binding to different antigenic determinants on the same antigen. The bispecific antibody is in a 1+1 format. Other bispecific antibody formats are the 2+1 format (comprising two binding sites for a first antigen or epitope and one binding site for a second antigen or epitope) or the 2+2 format (comprising two binding sites for a first antigen or epitope and two binding sites for a second antigen or epitope). Typically, bispecific antibodies contain two antigen binding sites, where each antigen binding site is specific for a different antigen.

如本申請中所使用，術語「價」表示指定數目之結合域在抗原結合分子中的存在。因此，術語「二價」、「四價」及「六價」表示抗原結合分子內分別存在兩個結合域、四個結合域及六個結合域。根據本發明的雙特異性抗體至少為「二價的」，並且可為「三價的」或「多價的」(例如「四價的」或「六價的」)。於特定態樣中，本發明之抗體具有兩個或更多個結合位點並且為雙特異性的。亦即，即使在存在多於兩個結合位點的情況下 (即抗體是三價或多價的)，抗體亦可為雙特異性的。As used in this application, the term "valent" refers to the presence of a specified number of binding domains in an antigen binding molecule. Thus, the terms "bivalent", "tetravalent" and "hexavalent" refer to the presence of two binding domains, four binding domains and six binding domains, respectively, in an antigen binding molecule. A bispecific antibody according to the present invention is at least "bivalent" and may be "trivalent" or "multivalent" (e.g., "tetravalent" or "hexavalent"). In a particular aspect, an antibody of the present invention has two or more binding sites and is bispecific. That is, an antibody may be bispecific even in the presence of more than two binding sites (i.e., the antibody is trivalent or multivalent).

「抗體片段」係指除完整抗體以外的分子，其包含結合完整抗體所結合抗原之完整抗體的一部分。抗體片段之實例包括但不限於 Fv、Fab、Fab'、Fab’-SH、F(ab')₂；雙功能抗體、三功能抗體、四功能抗體、交叉-Fab 片段、線性抗體；單鏈抗體分子 (例如 scFv)；由抗體片段形成之多特異性抗體及單域抗體。關於某些抗體片段的綜述，參見 Hudson 等人，Nat Med 9，129-134 (2003)。關於 scFv 片段的綜述，請參見 Plückthun，The Pharmacology of Monoclonal Antibodies，第 113 卷，Rosenburg 及 Moore 編，Springer-Verlag，New York，第 269-315 頁 (1994)；亦可參見 WO 93/16185；及美國專利第 5,571,894 號及第 5,587,458 號。關於包含補救受體結合抗原決定位殘基且具有增加的活體內半衰期之 Fab 及 F(ab')₂片段的論述，參見美國第 5,869,046 號專利。雙功能抗體為具有兩個抗原結合域之抗體片段，其可為二價或雙特異性的，參見例如 EP 404,097；WO 1993/01161；Hudson 等人，Nat Med 9, 129-134 (2003)；及 Hollinger 等人，Proc Natl Acad Sci USA 90, 6444-6448 (1993)。Hudson 等人，Nat Med 9，129-134 (2003) 中亦描述三功能抗體及四功能抗體。單域抗體為包含抗體之重鏈可變域之全部或部分或抗體之輕鏈可變域之全部或部分之抗體片段。在某些實施例中，單域抗體為人類單域抗體 (Domantis, Inc.，Waltham, MA；參見例如美國專利第 6,248,516 B1 號)。此外，抗體片段包含單鏈多肽，其具有 VH 域 (亦即能與 VL 域一起組裝至功能性抗原結合位點) 或 VL 域 (亦即能與 VH 域一起組裝至功能性抗原結合位點) 之特徵，且藉此提供全長抗體之抗原結合性質。抗體片段可藉由各種技術製造，包括但不限於如本文揭示的完整抗體之蛋白水解消化以及重組宿主細胞 (例如，大腸桿菌或噬菌體) 之產生。"Antibody fragment" refers to a molecule other than an intact antibody, which comprises a portion of an intact antibody that binds to an antigen bound by the intact antibody. Examples of antibody fragments include, but are not limited to, Fv, Fab, Fab', Fab'-SH, F(ab')₂ ; bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, cross-Fab fragments, linear antibodies; single-chain antibody molecules (e.g., scFv); multispecific antibodies and single-domain antibodies formed from antibody fragments. For a review of certain antibody fragments, see Hudson et al., Nat Med 9, 129-134 (2003). For a general description of scFv fragments, see Plückthun, The Pharmacology of Monoclonal Antibodies, Vol. 113, Rosenburg and Moore, eds., Springer-Verlag, New York, pp. 269-315 (1994); see also WO 93/16185; and U.S. Patent Nos. 5,571,894 and 5,587,458. For a discussion of Fab and F(ab')₂ fragments that contain antigen-binding residues that rescue receptor binding and have increased in vivo half-life, see U.S. Patent No. 5,869,046. Bifunctional antibodies are antibody fragments having two antigen binding domains, which may be bivalent or bispecific, see, e.g., EP 404,097; WO 1993/01161; Hudson et al., Nat Med 9, 129-134 (2003); and Hollinger et al., Proc Natl Acad Sci USA 90, 6444-6448 (1993). Trifunctional antibodies and tetrafunctional antibodies are also described in Hudson et al., Nat Med 9, 129-134 (2003). Single domain antibodies are antibody fragments comprising all or part of the heavy chain variable domain of an antibody or all or part of the light chain variable domain of an antibody. In certain embodiments, the single domain antibody is a human single domain antibody (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1). In addition, antibody fragments comprise single polypeptide chains having the characteristics of a VH domain (i.e., capable of assembling together with a VL domain into a functional antigen binding site) or a VL domain (i.e., capable of assembling together with a VH domain into a functional antigen binding site) and thereby providing the antigen binding properties of a full-length antibody. Antibody fragments can be produced by a variety of techniques, including but not limited to proteolytic digestion of intact antibodies as disclosed herein and production by recombinant host cells (e.g.,E. coli or phage).

木瓜酵素對完整抗體之消化產生兩個相同的抗原結合片段，稱為「Fab」片段，其各自包含重鏈可變域及輕鏈可變域以及輕鏈之恆定域及重鏈之第一恆定域 (CH1)。因此，如本文所用，術語「Fab 片段」係指包含輕鏈片段的抗體片段，該輕鏈片段包含 VL 域及輕鏈之恆定域 (CL)，以及 VH 域及重鏈之第一恆定域 (CH1)。Fab' 片段與 Fab 片段不同之處在於，在重鏈 CH1 域之羧基端添加少數殘基，包括來自抗體鉸鏈區的一個或多個半胱胺酸。Fab’-SH 為 Fab’ 片段，其中恆定域之半胱胺酸殘基攜帶一個游離硫醇基團。胃蛋白酶處理產生 F(ab')₂片段，該片段具有兩個抗原結合位點 (兩個 Fab 片段) 及一部分 Fc 區。Papain digestion of intact antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each of which contains a heavy chain variable domain and a light chain variable domain and a light chain constant domain and a heavy chain first constant domain (CH1). Therefore, as used herein, the term "Fab fragment" refers to an antibody fragment containing a light chain fragment, which contains a VL domain and a light chain constant domain (CL), and a VH domain and a heavy chain first constant domain (CH1). Fab' fragments differ from Fab fragments in that a few residues are added to the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is a Fab' fragment in which the cysteine residue of the constant domain carries a free thiol group. Pepsin treatment produces a F(ab')₂ fragment that has two antigen-binding sites (two Fab fragments) and a portion of the Fc region.

術語「cross-Fab 片段」或「xFab 片段」或「交叉 Fab 片段」 係指其中重鏈及輕鏈之可變區或恆定區發生交換的 Fab 片段。可能存在交叉 Fab 分子之兩種不同鏈組成且包含於本發明之雙特異性抗體中：一方面，交換 Fab 重鏈及輕鏈之可變區，亦即交叉 Fab 分子包含由輕鏈可變區 (VL) 及重鏈恆定區 (CH1) 構成之肽鏈，及由重鏈可變區 (VH) 及輕鏈恆定區 (CL) 構成之肽鏈。此互換型 Fab 分子亦稱為交叉 Fab_(VLVH)。另一方面，當 Fab 重鏈與輕鏈之恆定區交換時，交叉 Fab 分子包含由重鏈可變區 (VH) 及輕鏈恆定區 (CL) 構成之肽鏈，及由輕鏈可變區 (VL) 及重鏈恆定區 (CH1) 構成之肽鏈。這種互換型 Fab 分子亦稱為交叉 Fab_(CLCH1)。The term "cross-Fab fragment" or "xFab fragment" or "cross-Fab fragment" refers to a Fab fragment in which the variable regions or constant regions of the heavy and light chains are exchanged. Two different chain compositions of the cross-Fab molecule may exist and are included in the bispecific antibody of the present invention: on the one hand, the variable regions of the heavy and light chains of the Fab are exchanged, that is, the cross-Fab molecule comprises a peptide chain composed of the light chain variable region (VL) and the heavy chain constant region (CH1), and a peptide chain composed of the heavy chain variable region (VH) and the light chain constant region (CL). This interchanging Fab molecule is also called cross-Fab_(VLVH) . On the other hand, when the constant regions of the heavy chain and light chain of Fab are exchanged, the crossover Fab molecule contains a peptide chain composed of the heavy chain variable region (VH) and the light chain constant region (CL), and a peptide chain composed of the light chain variable region (VL) and the heavy chain constant region (CH1). This type of exchange Fab molecule is also called crossover Fab_(CLCH1) .

「單鏈 Fab 片段」或「scFab」為由抗體重鏈可變域 (VH)、抗體恆定域 1 (CH1)、抗體輕鏈可變域 (VL)、抗體輕鏈恆定域 (CL) 及連接子組成之多肽，其中該等抗體域及該連接子按 N 端至 C 端方向之次序具有以下中之一者：a) VH-CH1-連接子-VL-CL，b) VL-CL-連接子-VH-CH1，c) VH-CL-連接子-VL-CH1 或 d) VL-CH1-連接子-VH-CL；且其中該連接子為至少 30 個胺基酸，較佳為 32 與 50 個胺基酸之間的多肽。該等單鏈 Fab 片段通過 CL 域與 CH1 域之間的天然雙硫鍵達到穩定。此外，此等單鏈 Fab 分子可經由插入半胱胺酸殘基 (例如，根據 Kabat 編號，可變重鏈之位置 44 及可變輕鏈之位置 100) 來產生鏈間二硫鍵而得以進一步穩定化。"Single-chain Fab fragment" or "scFab" is a polypeptide composed of an antibody heavy chain variable domain (VH), an antibody constant domain 1 (CH1), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, wherein the antibody domains and the linker have one of the following in the order from N-terminal to C-terminal direction: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1 or d) VL-CH1-linker-VH-CL; and wherein the linker is a polypeptide of at least 30 amino acids, preferably between 32 and 50 amino acids. These single-chain Fab fragments are stabilized by the native disulfide bonds between the CL domain and the CH1 domain. In addition, these single-chain Fab molecules can be further stabilized by the insertion of cysteine residues (e.g., position 44 of the variable heavy chain and position 100 of the variable light chain according to Kabat numbering) to generate interchain disulfide bonds.

「交叉單鏈 Fab 片段」或「x-scFab」為由抗體重鏈可變域 (VH)、抗體恆定域 1 (CH1)、抗體輕鏈可變域 (VL)、抗體輕鏈恆定域 (CL) 及連接子組成之多肽，其中該等抗體域及該連接子按 N 端至 C 端方向之次序具有以下中之一者：a) VH-CL-連接子-VL-CH1 及 b) VL-CH1-連接子-VH-CL；其中 VH 與 VL 一起形成與抗原特異性地結合之抗原結合域，且其中該連接子為至少 30 個胺基酸之多肽。此外，此等 x-scFab 分子可經由插入半胱胺酸殘基 (例如，根據 Kabat 編號，可變重鏈中之位置 44 及可變輕鏈中之位置 100) 來產生鏈間雙硫鍵而得以進一步穩定化。"Cross-linked Fab fragment" or "x-scFab" is a polypeptide composed of an antibody heavy chain variable domain (VH), an antibody constant domain 1 (CH1), an antibody light chain variable domain (VL), an antibody light chain constant domain (CL) and a linker, wherein the antibody domains and the linker have one of the following in the order from N-terminal to C-terminal direction: a) VH-CL-linker-VL-CH1 and b) VL-CH1-linker-VH-CL; wherein VH and VL together form an antigen-binding domain that specifically binds to an antigen, and wherein the linker is a polypeptide of at least 30 amino acids. In addition, these x-scFab molecules can be further stabilized by the insertion of cysteine residues (e.g., position 44 in the variable heavy chain and position 100 in the variable light chain according to Kabat numbering) to generate interchain disulfide bonds.

「單鏈可變片段 (scFv)」為抗體之重鏈 (V_H) 及輕鏈 (V_L) 之可變區之融合蛋白，其與十至約 25 個胺基酸之短連接子肽連接。連接子通常富含甘胺酸以具有可撓性，以及絲胺酸或蘇胺酸以具有可溶性，且可連接 V_H之 N 端與 V_L之 C 端，或反之亦然。儘管移除恆定區且引入連接子，但此蛋白質保持原始抗體之特異性。scFv 抗體例如描述於 Houston, J.S., Methods in Enzymol. 203 (1991) 46-96)。此外，抗體片段包含單鏈多肽，其具有 VH 域 (亦即能與 VL 域一起組裝至功能性抗原結合位點) 或 VL 域 (亦即能與 VH 域一起組裝至功能性抗原結合位點) 之特徵，且藉此提供全長抗體之抗原結合性質。A "single-chain variable fragment (scFv)" is a fusion protein of the variable regions of the heavy chain (_VH ) and light chain (_VL ) of an antibody, connected to a short linker peptide of ten to about 25 amino acids. The linker is usually rich in glycine for flexibility and serine or threonine for solubility, and may connect the N-terminus of the_VH to the C-terminus of the_VL , orvice versa . Despite the removal of the constant regions and the introduction of the linker, this protein retains the specificity of the original antibody. scFv antibodies are described, for example, in Houston, JS, Methods in Enzymol. 203 (1991) 46-96). Furthermore, antibody fragments comprise single polypeptides which have the characteristics of a VH domain (ie, capable of assembling together with a VL domain into a functional antigen binding site) or a VL domain (ie, capable of assembling together with a VH domain into a functional antigen binding site) and thereby provide the antigen binding properties of a full-length antibody.

術語「效應功能」，係指歸因於抗體的 Fc 區域的那些生物活性，其隨抗體同型而變化。抗體效用功能的實例包括：C1q 結合及補體依賴性細胞毒性 (CDC)、Fc 受體結合、抗體依賴型細胞媒介的細胞毒性 (ADCC)、抗體依賴型細胞吞噬作用 (ADCP)、細胞激素分泌、抗原呈現細胞攝取之免疫複合物媒介抗原、細胞表面受體 (例如，B 細胞受體) 下調及 B 細胞活化。The term "effector function" refers to those biological activities attributed to the Fc region of an antibody, which vary with the antibody isotype. Examples of antibody effector functions include: C1q binding and complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), cytokine secretion, immune complex-mediated antigen uptake by antigen-presenting cells, downregulation of cell surface receptors (e.g., B cell receptors), and B cell activation.

「活化 Fc 受體」為 Fc 受體在與抗體之 Fc 區接合之後，引發信號傳遞事件，刺激帶有受體之細胞以進行效應功能。活化 Fc 受體包括 FcγRIIIa (CD16a)、FcγRI (CD64)、FcγRIIa (CD32) 及 FcαRI (CD89)。特定活化 Fc 受體為人類 FcγRIIIa (參見 UniProt 寄存編號 P08637，版本 141)。"Activating Fc receptors" are Fc receptors that, upon binding to the Fc region of an antibody, initiate a signaling event that stimulates cells bearing the receptor to perform effector functions. Activating Fc receptors include FcγRIIIa (CD16a), FcγRI (CD64), FcγRIIa (CD32), and FcαRI (CD89). A specific activating Fc receptor is human FcγRIIIa (see UniProt accession number P08637, version 141).

相對於參考多肽序列之「百分比 (%) 胺基酸序列同一性」，係指候選序列中胺基酸殘基與參考多肽序列中之胺基酸殘基相同之百分比，在比對序列並引入差異後 (如有必要)，可實現最大的序列同一性百分比，並且不考慮將任何保留取代作為序列同一性之一部分。為判定百分比胺基酸序列同一性之目的而進行的比對可藉由本領域中技術範圍內之各種方式實現，例如，使用公眾可取得的電腦軟體諸如 BLAST、BLAST-2、ALIGN 或 Megalign (DNASTAR) 軟體。熟習此項技術者可判定用於比對序列之適當參數，包括在所比較之序列的全長上達成最大比對所需之任何演算法。然而，出於本文的目的，使用序列比較電腦程式 ALIGN-2 產生 % 胺基酸序列同一性值。ALIGN-2 序列比較電腦程式由建南德克公司 (Genentech，Inc.) 編寫，原始程式碼已與用戶文檔一起存檔於美國版權局，華盛頓特區，20559，並以美國版權註冊號 TXU510087 進行註冊。ALIGN-2 程式可從加利福尼亞南三藩市的建南德克公司 (Genentech，Inc.) 公眾可取得，亦可以從原始程式碼進行編譯。ALIGN-2 程式應編譯為在 UNIX 作業系統 (包括數位 UNIX V4.0D) 上使用。所有序列比較參數均由 ALIGN-2 程式設置，並且沒有變化。"Percent (%) amino acid sequence identity" relative to a reference polypeptide sequence refers to the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing differences (if necessary) to achieve the maximum percent sequence identity, and not considering any substitutions that remain as part of the sequence identity. Alignment for the purpose of determining percent amino acid sequence identity can be achieved in various ways within the skill in the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithm needed to achieve maximal alignment over the full length of the sequences being compared. However, for the purposes of this article, the % amino acid sequence identity values are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was written by Genentech, Inc., and the source code has been deposited with user documentation in the U.S. Copyright Office, Washington, D.C. 20559, and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available from Genentech, Inc., South San Francisco, California, and may be compiled from source code. The ALIGN-2 program should be compiled for use on UNIX operating systems, including digital UNIX V4.0D. All sequence comparison parameters were set by the ALIGN-2 program and were not changed.

在使用 ALIGN-2 進行胺基酸序列比較的情況下，既定胺基酸序列 A 對、與、或相對於既定胺基酸序列 B 的 % 胺基酸序列同一性 (其可替代性地表述為既定胺基酸序列 A，其對、與、或相對於既定胺基酸序列 B 具有或包含一定 % 的胺基酸序列同一性) 計算如下： 100 乘以分數 X/Y 其中 X 為序列比對程式 ALIGN-2 在 A 與 B 程式比對中評分為同一匹配的胺基酸殘基數，Y 為 B 中胺基酸殘基的總數。應當理解的是，在胺基酸序列 A 的長度不等於胺基酸序列 B 的長度的情況下，A 與 B 的 % 胺基酸序列同一性將不等於 B 與 A 的 % 胺基酸序列同一性。除非另有特別說明，否則如前一段所述，使用 ALIGN-2 電腦程式獲得本文使用的所有 % 胺基酸序列同一值。II.治療及方法及用途When using ALIGN-2 for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B (which can alternatively be expressed as a given amino acid sequence A that has or contains a certain % amino acid sequence identity to, with, or relative to a given amino acid sequence B) is calculated as follows: 100 multiplied by the score X/Y where X is the number of amino acid residues scored as identical matches by the sequence alignment program ALIGN-2 in the alignment of A and B, and Y is the total number of amino acid residues in B. It should be understood that where the length of amino acid sequence A is not equal to the length of amino acid sequence B, the % amino acid sequence identity of A to B will not be equal to the % amino acid sequence identity of B to A. Unless otherwise specifically stated, all % amino acid sequence identity values used herein were obtained using the ALIGN-2 computer program as described in the preceding paragraph.II.Treatment and Methods and Uses

本文提供了治療患有非小細胞肺癌 (NSCLC) (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的個體 (例如，人類個體) 的方法，該方法包含向該個體投予一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，其中，在投予該抗 TIGIT 拮抗劑抗體及該 PD-1 軸結合拮抗劑之前，該 NSCLC 已完全切除且個體已接受輔助化學療法 (例如，輔助鉑類化學療法)。Provided herein are methods of treating an individual (e.g., a human individual) having non-small cell lung cancer (NSCLC) (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC), the method comprising administering to the individual one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab), wherein, prior to administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the individual has received adjuvant chemotherapy (e.g., adjuvant platinum chemotherapy).

因此，在一些態樣中，本文提供了治療患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的個體 (例如，人類個體) 的方法，該方法包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中，在投予替瑞利尤單抗及阿替利珠單抗之前，該 NSCLC 已完全切除且個體已接受輔助化學療法 (例如，輔助鉑類化學療法)。Thus, in some aspects, provided herein are methods of treating an individual (e.g., a human individual) having NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC), the method comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein, prior to administering tisleliumab and atezolizumab, the NSCLC has been completely resected and the individual has received adjuvant chemotherapy (e.g., adjuvant platinum-based chemotherapy).

本文亦提供了治療患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的個體 (例如，人類個體) 的方法，該方法包含向該個體投予輔助化學療法 (例如，輔助鉑類化學療法)，接著投予一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，其中，在投予輔助化學療法以及抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑之前，該 NSCLC 已完全切除。Also provided herein are methods of treating an individual (e.g., a human individual) having NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC), the method comprising administering to the individual adjuvant chemotherapy (e.g., adjuvant platinum chemotherapy), followed by one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the NSCLC has been completely resected prior to administering the adjuvant chemotherapy and the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist.

因此，在一些態樣中，本文提供了治療患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的個體 (例如，人類個體) 的方法，該方法包含向該個體投予輔助化學療法 (例如，輔助鉑類化學療法)，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中，在投予輔助化學療法以及替瑞利尤單抗及阿替利珠單抗之前， 該 NSCLC 已完全切除。Thus, in some aspects, provided herein are methods of treating an individual (e.g., a human individual) having NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC), the method comprising administering to the individual adjuvant chemotherapy (e.g., adjuvant platinum chemotherapy) followed by administering one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected prior to administering the adjuvant chemotherapy and the tisleliumab and atezolizumab.

本文亦提供了 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及/或抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，其使用於本文提供的方法中之任一者。例如，在一個態樣中，本發明提供了 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及/或抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，其使用於治療患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的個體 (例如，人類個體) 的方法，該方法包含向該個體投予一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，其中，在投予該抗 TIGIT 拮抗劑抗體及該 PD-1 軸結合拮抗劑之前，該 NSCLC 已完全切除且個體已接受輔助化學療法 (例如，輔助鉑類化學療法)。Also provided herein are PD-1 axis binding antagonists (e.g., atezolizumab) and/or anti-TIGIT antagonist antibodies (e.g., tisleliumab) for use in any of the methods provided herein. For example, in one aspect, the present invention provides a PD-1 axis binding antagonist (e.g., atezolizumab) and/or an anti-TIGIT antagonist antibody (e.g., tisleliumab) for use in a method of treating an individual (e.g., a human individual) having NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC), the method comprising administering to the individual one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab), wherein, prior to administering the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC The tumor was completely resected and the individual received adjuvant chemotherapy (e.g., adjuvant platinum chemotherapy).

本文進一步提供了 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及/或抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 在藥物的製造中之用途，該藥物用於根據本文提供的方法中之任一者治療患者。A. NSCLC的手術切除Further provided herein is the use of a PD-1 axis binding antagonist (e.g., atezolizumab) and/or an anti-TIGIT antagonist antibody (e.g., tisleliumab) in the manufacture of a medicament for treating a patient according to any of the methods provided herein.A.Surgical resection of NSCLC

本揭露提供了用於已完成 NSCLC 手術切除 (例如，產生無殘留腫瘤且所有手術切緣均呈侵襲性癌陰性的切除) 的個體的輔助治療方法。手術切除可係例如肺葉切除術、袖式肺葉切除術、雙肺葉切除術或肺切除術。癌症類型及分期The present disclosure provides methods for adjuvant treatment of an individual who has completed surgical resection of NSCLC (e.g., a resection that resulted in no residual tumor and all surgical margins were negative for invasive cancer). The surgical resection can be, for example, a lobectomy, a sleeve lobectomy, a bilobectomy, or a pneumonectomy.Cancer Type and Stage

在一些態樣中，手術切除的 NSCLC 為 IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC，根據國際抗癌聯盟/美國癌症聯合委員會 (UICC/AJCC) 分期系統第 8 版 (Detterbeck 等人,Chest, 151: 193-203, 2017)。In some aspects, the surgically resected NSCLC is stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC according to the Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system, 8th edition (Detterbeck et al.,Chest , 151: 193-203, 2017).

在一些態樣中，NSCLC 為鱗狀 NSCLC。在其他態樣中，NSCLC 為非鱗狀 NSCLC。EGFR/ALK狀態In some aspects, the NSCLC is squamous NSCLC. In other aspects, the NSCLC is non-squamous NSCLC.EGFR/ALKstatus

在一些態樣中，個體不具有上皮生長因子受體 (EGFR) 基因體腫瘤畸變 (例如，不具有EGFR基因的突變) 並且不具有退行性淋巴瘤激酶 (ALK) 基因體腫瘤畸變 (例如，不具有ALK融合癌基因)。例如，在一些態樣中，針對 EGFR 及 ALK 畸變，對手術切除的 NSCLC 進行測試，並且發現不具有此類畸變。在其他態樣中，個體俱有未知的 EGFR 及/或 ALK 狀態 (例如，尚未針對 EGFR 及/或 ALK 基因體腫瘤畸變對來自個體的腫瘤樣品進行測試)。例如，在一個態樣中，NSCLC 為鱗狀 NSCLC 並且尚未針對 EGFR 或 ALK 基因體腫瘤畸變進行評定。PD-L1狀態In some aspects, the individual does not have an epidermal growth factor receptor (EGFR) genomic tumor aberration (e.g., does not have a mutation inthe EGFR gene) and does not have an anaplastic lymphoma kinase (ALK) genomic tumor aberration (e.g., does not have anALK fusion oncogene). For example, in some aspects, a surgically resected NSCLC was tested for EGFR and ALK aberrations and found not to have such aberrations. In other aspects, the individual has an unknown EGFR and/or ALK status (e.g., a tumor sample from the individual has not been tested for EGFR and/or ALK genomic tumor aberrations). For example, in one aspect, the NSCLC is squamous NSCLC and has not been assessed for EGFR or ALK genomic tumor aberrations.PD-L1Status

在本文提供的方法中之任一者的一些態樣中，從個體獲得的腫瘤樣品 (例如，NSCLC 樣品) 的 PD-L1 陽性腫瘤細胞分數已藉由免疫組織化學 (IHC) 測定法來判定。用於評定來自個體的樣品中 PD-L1 表現的示例性測定及方法在下文第 IIE 部分中提供。In some aspects of any of the methods provided herein, the PD-L1 positive tumor cell fraction of a tumor sample (e.g., a NSCLC sample) obtained from an individual has been determined by an immunohistochemistry (IHC) assay. Exemplary assays and methods for assessing PD-L1 expression in a sample from an individual are provided in Section IIE below.

例如，在一些態樣中，PD-L1 陽性腫瘤細胞分數藉由用抗 PD-L1 抗體進行陽性染色來判定，其中該抗 PD-L1 抗體為 SP263、22C3、SP142 或 28-8 (例如，使用 Ventana SP263 IHC 測定法、pharmDx 22C3 IHC 測定法、Ventana SP142 IHC 測定法或 pharmDx 28-8 IHC 測定法來判定 PD-L1 陽性腫瘤細胞分數)。For example, in some aspects, the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142, or 28-8 (e.g., the PD-L1 positive tumor cell fraction is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay).

在一些態樣中，從個體獲得的腫瘤樣品的 PD-L1 陽性腫瘤細胞分數已使用 Ventana SP263 IHC 測定法來判定。在一些態樣中，從個體獲得的腫瘤樣品已被判定具有等於或大於1% (≥ 1% TC) 的任何 PD-L1 膜染色高於背景的腫瘤細胞百分比 (TC)，如使用 Ventana SP263 IHC 測定法所測量的 (例如，腫瘤樣品的 TC 為至少 1%、5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55 %、60%、65%、70% 或 75%)。在一些態樣中，從個體獲得的腫瘤樣品已被判定具有等於或大於 1% 且小於 50% 的 TC (例如，已被判定具有約 1-5%、5-10%、10-15%、15-20%、20-25%、25-30%、30-35%、35-40%、40-45% 或 45-49.99% 的 TC)。 在一些態樣中，從個體獲得的腫瘤樣品已被判定具有等於或大於 50% (≥ 50% TC) 的 TC，如使用 Ventana SP263 IHC 測定法所測量的 (例如，腫瘤樣品的 TC 為至少 50%、55%、60%、65%、70% 或 75%)。在一些態樣中，從個體獲得的腫瘤樣品已被判定具有小於或等於 1% 的 TC。先前治療In some aspects, the PD-L1 positive tumor cell fraction of a tumor sample obtained from an individual has been determined using the Ventana SP263 IHC assay. In some aspects, a tumor sample obtained from an individual has been determined to have a percentage of tumor cells (TC) with any PD-L1 membrane staining above background equal to or greater than 1% (≥ 1% TC) as measured using the Ventana SP263 IHC assay (e.g., the TC of the tumor sample is at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%). In some aspects, a tumor sample obtained from an individual has been determined to have a TC equal to or greater than 1% and less than 50% (e.g., has been determined to have a TC of about 1-5%, 5-10%, 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, or 45-49.99%). In some aspects, a tumor sample obtained from an individual has been determined to have a TC equal to or greater than 50% (≥ 50% TC) as measured using the Ventana SP263 IHC assay (e.g., the TC of the tumor sample is at least 50%, 55%, 60%, 65%, 70%, or 75%). In some aspects, a tumor sample obtained from an individual has been determined to have a TC less than or equal to 1%.Previous treatment

在一些態樣中，個體在手術前尚未針對 NSCLC 進行治療 (例如，在手術前未接受過抗癌療法，例如，在手術前未接受過化學療法或癌症免疫療法)。B.輔助化學療法In some aspects, the individual has not been treated for NSCLC prior to surgery (e.g., has not received anticancer therapy prior to surgery, e.g., has not received chemotherapy or cancer immunotherapy prior to surgery).B.Adjuvant Chemotherapy

手術切除後，向根據本文提供的方法治療的個體投予輔助化學療法。Following surgical resection, adjuvant chemotherapy is administered to individuals treated according to the methods provided herein.

輔助化學療法可以一個或多個給藥週期投予。在一些態樣中，向個體投予介於一個給藥週期與四個給藥週期之間之輔助化學療法 (例如，向個體投予一、二、三或四個給藥週期)。因此，在一些態樣中，個體在一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗之前已接受介於一個給藥週期與四個給藥週期之間之輔助化學療法。在一些態樣中，個體在一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗之前已接受四個給藥週期之輔助化學療法。可替代地，在一些態樣中，向個體投予多於四個給藥週期 (例如，5、6、7、8、9、10 或多於 10 個給藥週期)。Adjuvant chemotherapy can be administered for one or more dosing cycles. In some aspects, between one dosing cycle and four dosing cycles of adjuvant chemotherapy are administered to the subject (e.g., one, two, three, or four dosing cycles are administered to the subject). Thus, in some aspects, the subject has received between one dosing cycle and four dosing cycles of adjuvant chemotherapy prior to one or more dosing cycles of tisleliumab and atezolizumab. In some aspects, the subject has received four dosing cycles of adjuvant chemotherapy prior to one or more dosing cycles of tisleliumab and atezolizumab. Alternatively, in some aspects, more than four dosing cycles (e.g., 5, 6, 7, 8, 9, 10 or more dosing cycles) are administered to a subject.

在一些態樣中，輔助化學療法為輔助鉑類化學療法。輔助鉑類化學療法可為輔助鉑類雙效化學療法。In some embodiments, the adjuvant chemotherapy is adjuvant platinum chemotherapy. The adjuvant platinum chemotherapy can be adjuvant platinum dual-effect chemotherapy.

鉑類雙效化學療法包括但不限於包含 (a) 卡鉑或順鉑及 (b) 培美曲塞、吉西他濱、多西紫杉醇、長春瑞濱、依托泊苷或紫杉醇的化學療法。在一些態樣中，輔助化學療法為包含順鉑的鉑類雙效化學療法。在其他態樣中，輔助化學療法為包含卡鉑的鉑類雙效化學療法。Platinum-based double-acting chemotherapy includes, but is not limited to, chemotherapy comprising (a) carboplatin or cis-platinum and (b) pemetrexed, gemcitabine, docetaxel, vinorelbine, etoposide or paclitaxel. In some aspects, the adjuvant chemotherapy is a platinum-based double-acting chemotherapy comprising cis-platinum. In other aspects, the adjuvant chemotherapy is a platinum-based double-acting chemotherapy comprising carboplatin.

輔助化學療法可係基於組織學的，例如可基於個體的 NSCLC 是鱗狀還是非鱗狀組織學來選擇。Adjuvant chemotherapy can be histologically based, for example, it can be selected based on whether the individual's NSCLC has squamous or nonsquamous histology.

示例性的鉑類雙效化學療法描述於例如 Azzoli 等人,J Clin Oncol, 27(36): 6251-6266, 2009；NCCN/ESMO 指南 (National Comprehensive Cancer Network.NCCN Guidelines® Insights: Non–Small Cell Lung Cancer, 2023)；及下表 1 中。可考慮其他給藥方案 (例如，條件是與核准的對 NSCLC 輔助治療具有特異性的藥物標籤一致)。表1.示例性輔助化學療法方案較佳 (非鱗狀)• 順鉑 75 mg/m²第 1 天，培美曲塞 500 mg/m²第 1 天，每 21 天，持續 4 個週期。較佳 (鱗狀)•順鉑 75 mg/m²第 1 天，吉西他濱 1250 mg/m²第 1 天及第 8 天，每 21 天，持續 4 個週期 •順鉑 75 mg/m²第 1 天，多西紫杉醇 75 mg/m²第 1 天，每 21 天，持續 4 個週期其他建議•順鉑 50 mg/m²第 1 天及第 8 天，長春瑞濱 25 mg/m²第 1 天、第 8 天、第 15 天及第 22 天，每 28 天，持續 4 個週期 •順鉑 100 mg/m²第 1 天，長春瑞濱 30 mg/m²第 1 天、第 8 天、第 15 天及第 22 天，每 28 天，持續 4 個週期 •順鉑 75 至 80 mg/m²第 1 天，長春瑞濱 25 至 30 mg/m²第 1 天及第 8 天，每 21 天，持續 4 個週期 •順鉑 100 mg/m²第 1 天，依托泊苷 100 mg/m²第 1 天至第 3 天，每 28 天，持續 4 個週期在某些情況下有用用於並非是基於順鉑之療法的候選者之患者的化學療法方案•卡鉑，卡鉑血漿濃度與時間曲線下面積 (AUC) 6 第 1 天，紫杉醇 200 mg/m²第 1 天，每 21 天，持續 4 個週期 •卡鉑 AUC 5 第 1 天，吉西他濱 1000 mg/m²第 1 天及第 8 天，每 21 天，持續 4 個週期 •卡鉑 AUC 5 第 1 天，培美曲塞 500 mg/m²第 1 天，每 21 天，持續 4 個週期 (非鱗狀組織學)Exemplary platinum-based dual-acting chemotherapy is described, for example, in Azzoli et al.,J Clin Oncol , 27(36): 6251-6266, 2009; NCCN/ESMO guidelines (National Comprehensive Cancer Network. NCCN Guidelines® Insights: Non-Small Cell Lung Cancer, 2023); and in Table 1 below. Other dosing regimens may be considered (e.g., provided that they are consistent with approved drug labels specific for adjuvant treatment of NSCLC).Table1.Exemplary adjuvant chemotherapy regimensBetter (non-scaly) • Cisplatin 75 mg/m² on day 1 and pemetrexed 500 mg/m² on day 1 every 21 days for 4 cycles.Better (scaly) • Cisplatin 75 mg/m² on day 1, gemcitabine 1250 mg/m² on day 1 and day 8, every 21 days, for 4 cycles • Cisplatin 75 mg/m² on day 1, docetaxel 75 mg/m² on day 1, every 21 days, for 4 cyclesOther suggestions •Cis platinum 50 mg/^m2 on days 1 and 8, vinorelbine 25 mg/^m2 on days 1, 8, 15, and 22, every 28 days for 4 cycles •Cis platinum 100 mg/^m2 on day 1, vinorelbine 30 mg/^m2 on days 1, 8, 15, and 22, every 28 days for 4 cycles •Cis platinum 75 to 80 mg/^m2 on day 1, vinorelbine 25 to 30 mg/^m2 on days 1 and 8, every 21 days for 4 cycles •Cis platinum 100 mg/^m2 on day 1, etoposide 100 mg/^m2 on days 1 to 3, every 28 days for 4 cycles CyclesUseful in some casesChemotherapy regimens for patients who are not candidates for cisplatin-based therapy • Carboplatin, Carboplatin plasma concentration vs. time area under the curve (AUC) 6 Day 1, Paclitaxel 200 mg/m² Day 1, every 21 days for 4 cycles • Carboplatin AUC 5 Day 1, Gemcitabine 1000 mg/m² Day 1 and Day 8, every 21 days for 4 cycles • Carboplatin AUC 5 Day 1, Pemetrexed 500 mg/m² Day 1, every 21 days for 4 cycles (non-squamous histology)

例如，在一些態樣中，輔助鉑類化學療法包含順鉑。在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 21 天，並且在各 21 天給藥週期之第 1 天以約 75 至 80 mg/m²的劑量 (例如，以約 75 mg/m²的劑量) 靜脈內投予順鉑。在其他態樣中，鉑類輔助化學療法的各給藥週期之長度為 28 天，並且在各 28 天給藥週期之第 1 天及第 8 天以約 50 mg/m²的劑量或在各 28 天給藥週期之第 1 天以 50 mg/m²的劑量投予順鉑。For example, in some embodiments, the adjuvant platinum chemotherapy comprises cis-platinum. In some embodiments, the length of each dosing cycle of the platinum-adjuvant chemotherapy is 21 days, and cis-platinum is administered intravenously at a dose of about 75 to 80 mg/m² (e.g., at a dose of about 75 mg/m² ) on day 1 of each 21-day dosing cycle. In other embodiments, the length of each dosing cycle of the platinum-adjuvant chemotherapy is 28 days, and cis-platinum is administered at a dose of about 50 mg/m² on day 1 and day 8 of each 28-day dosing cycle or at a dose of 50 mg/m² on day 1 of each 28-day dosing cycle.

在一些態樣中，輔助鉑類化學療法包含卡鉑。在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 21 天，並且在各 21 天給藥週期之第 1 天以約遊離卡鉑血漿濃度對時間曲線下面積 (AUC) 5 或 AUC 6 的標靶劑量靜脈內投予卡鉑。In some embodiments, the adjuvant platinum chemotherapy comprises carboplatin. In some embodiments, each dosing cycle of the platinum-adjuvant chemotherapy is 21 days in length, and carboplatin is administered intravenously on day 1 of each 21-day dosing cycle at a target dose of about 5 or AUC 6 of the area under the free carboplatin plasma concentration versus time curve (AUC).

在一些態樣中，鉑類輔助化學療法進一步包含一種或多種另外的化學治療劑，例如，長春花屬生物鹼、紫杉烷、抗代謝物或其組合。在一些態樣中，長春花屬生物鹼為長春瑞濱；紫杉烷為多西紫杉醇；或抗代謝藥為吉西他濱或培美曲塞。In some embodiments, the platinum-based adjuvant chemotherapy further comprises one or more additional chemotherapeutic agents, such as a vinca alkaloid, a taxane, an anti-metabolite, or a combination thereof. In some embodiments, the vinca alkaloid is vinorelbine; the taxane is docetaxel; or the anti-metabolite is gemcitabine or pemetrexed.

在一些態樣中，個體患有非鱗狀 NSCLC，且鉑類輔助化學療法包含順鉑及培美曲塞。在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 21 天，其中在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，並且在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞。在一些態樣中，向個體投予 4 個週期的順鉑及培美曲塞。In some embodiments, the subject has non-squamous NSCLC and the platinum-based adjuvant chemotherapy comprises cis-platinum and pemetrexed. In some embodiments, each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days in length, wherein cis-platinum is administered intravenously at a dose of about 75 mg/m² on day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/m² on day 1 of each 21-day dosing cycle. In some embodiments, 4 cycles of cis-platinum and pemetrexed are administered to the subject.

在一些態樣中，個體患有鱗狀 NSCLC，且鉑類輔助化學療法包含順鉑及吉西他濱。在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 21 天，其中在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，並且在各 21 天給藥週期之第 1 天及第 8 天以約 1250 mg/m²的劑量投予吉西他濱。在一些態樣中，向個體投予 4 個週期的順鉑及吉西他濱。In some embodiments, the subject has squamous NSCLC and the platinum-adjuvant chemotherapy comprises cis-platinum and gemcitabine. In some embodiments, each dosing cycle of the platinum-adjuvant chemotherapy is 21 days in length, wherein cis-platinum is administered intravenously at a dose of about 75 mg/m² on day 1 of each 21-day dosing cycle, and gemcitabine is administered at a dose of about 1250 mg/m² on days 1 and 8 of each 21-day dosing cycle. In some embodiments, 4 cycles of cis-platinum and gemcitabine are administered to the subject.

在一些態樣中，個體患有鱗狀 NSCLC，且鉑類輔助化學療法包含順鉑及多西紫杉醇。在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 21 天，其中在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，並且在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量投予多西紫杉醇。在一些態樣中，向個體投予 4 個週期的順鉑及多西紫杉醇。In some embodiments, the subject has squamous NSCLC and the platinum-adjuvant chemotherapy comprises cis-platinum and docetaxel. In some embodiments, each dosing cycle of the platinum-adjuvant chemotherapy is 21 days in length, wherein cis-platinum is administered intravenously at a dose of about 75 mg/m² on day 1 of each 21-day dosing cycle, and docetaxel is administered at a dose of about 75 mg/m² on day 1 of each 21-day dosing cycle. In some embodiments, 4 cycles of cis-platinum and docetaxel are administered to the subject.

在一些態樣中，鉑類輔助化學療法包含順鉑及長春瑞濱。In some aspects, the platinum-adjuvant chemotherapy comprises cis-platinum and vinorelbine.

在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 28 天，其中在各 28 天給藥週期之第 1 天及第 8 天以約 50 mg/m²的劑量靜脈內投予順鉑，且在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 25 mg/m²的劑量投予長春瑞濱。在其他態樣中，在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，且在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 30 mg/m²的劑量投予長春瑞濱。在一些態樣中，向個體投予 4 個週期的順鉑及長春瑞濱。In some embodiments, the length of each dosing cycle of platinum-adjuvant chemotherapy is 28 days, wherein cisplatin is administered intravenously at a dose of about 50 mg/m² on day 1 and day 8 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 25 mg/m² on day 1, day 8, day 15, and day 22 of each 28-day dosing cycle. In other embodiments, cisplatin is administered intravenously at a dose of about 100 mg/m² on day 1 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 30 mg/m² on day 1, day 8, day 15, and day 22 of each 28-day dosing cycle. In some aspects, four cycles of cisplatin and vinblastine are administered to the individual.

在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 21 天，其中在各 21 天給藥週期之第 1 天及第 8 天以約 75 至 80 mg/m²的劑量靜脈內投予順鉑，且在各 21 天給藥週期之第 1 天及第 8 天以約 25 至 30 mg/m²的劑量投予長春瑞濱。在一些態樣中，向個體投予 4 個週期的順鉑及長春瑞濱。In some embodiments, each dosing cycle of platinum-adjuvant chemotherapy is 21 days in length, wherein cisplatin is administered intravenously at a dose of about 75 to 80 mg/m² on day 1 and day 8 of each 21-day dosing cycle, and vinorelbine is administered at a dose of about 25 to 30 mg/m² on day 1 and day 8 of each 21-day dosing cycle. In some embodiments, 4 cycles of cisplatin and vinorelbine are administered to a subject.

在一些態樣中，鉑類輔助化學療法包含順鉑及依托泊苷。在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 28 天，其中在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，並且在各 28 天給藥週期之第 1 天至第 3 天，以約 100 mg/m²的劑量投予依托泊苷。在一些態樣中，向個體投予 4 個週期的順鉑及依托泊苷。In some embodiments, the platinum-adjuvant chemotherapy comprises cis-platinum and etoposide. In some embodiments, each dosing cycle of the platinum-adjuvant chemotherapy is 28 days in length, wherein cis-platinum is administered intravenously at a dose of about 100 mg/m² on day 1 of each 28-day dosing cycle, and etoposide is administered at a dose of about 100 mg/m² on days 1 to 3 of each 28-day dosing cycle. In some embodiments, 4 cycles of cis-platinum and etoposide are administered to a subject.

在一些態樣中，鉑類輔助化學療法包含卡鉑及紫杉醇。在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 21 天，其中在各 21 天給藥週期之第 1 天以 AUC 6 靜脈內投予卡鉑，並且在各 21 天給藥週期之第 1 天以約 200 mg/m²的劑量投予紫杉醇。在一些態樣中，向個體投予 4 個週期的順鉑及紫杉醇。In some embodiments, the platinum-based adjuvant chemotherapy comprises carboplatin and paclitaxel. In some embodiments, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein carboplatin is administered intravenously at AUC 6 on day 1 of each 21-day dosing cycle, and paclitaxel is administered at a dose of about 200 mg/m² on day 1 of each 21-day dosing cycle. In some embodiments, 4 cycles of cisplatin and paclitaxel are administered to an individual.

在一些態樣中，鉑類輔助化學療法包含卡鉑及吉西他濱。在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 21 天，其中在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，並且在各 21 天給藥週期之第 1 天及第 8 天以約 1000 mg/m²的劑量投予吉西他濱。在一些態樣中，向個體投予 4 個週期的順鉑及吉西他濱。In some embodiments, the platinum-based adjuvant chemotherapy comprises carboplatin and gemcitabine. In some embodiments, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein carboplatin is administered intravenously at AUC 5 on day 1 of each 21-day dosing cycle, and gemcitabine is administered at a dose of about 1000 mg/m² on day 1 and day 8 of each 21-day dosing cycle. In some embodiments, 4 cycles of cisplatin and gemcitabine are administered to an individual.

在一些態樣中，鉑類輔助化學療法包含卡鉑及培美曲塞。在一些態樣中，鉑類輔助化學療法的各給藥週期之長度為 21 天，其中在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，並且在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞。在一些態樣中，向個體投予 4 個週期的順鉑及培美曲塞。C.包含抗TIGIT拮抗劑抗體及PD-1軸結合拮抗劑之輔助治療In some embodiments, the platinum-based adjuvant chemotherapy comprises carboplatin and pemetrexed. In some embodiments, the length of each dosing cycle of the platinum-based adjuvant chemotherapy is 21 days, wherein carboplatin is administered intravenously at AUC 5 on day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/m² on day 1 of each 21-day dosing cycle. In some embodiments, 4 cycles of cisplatin and pemetrexed are administered to an individual.C.Adjuvant therapycomprising an anti-TIGITantagonist antibody anda PD-1 axis binding antagonist

在如上所述的手術切除及輔助化學療法之後，向根據本文提供的方法治療的個體投予輔助療法，該輔助療法包含投予一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)。Following surgical resection and adjuvant chemotherapy as described above, an individual treated according to the methods provided herein is administered adjuvant therapy comprising administration of one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab).

在一些態樣中，被投予包含抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑的輔助療法的個體尚未經歷 NSCLC 的復發 (例如，在完全切除之後或者輔助化學療法期間或之後尚未經歷 NSCLC 的復發)。In some aspects, the individual administered the adjuvant therapy comprising an anti-TIGIT antagonist antibody and a PD-1 axis binding antagonist has not experienced a recurrence of NSCLC (e.g., has not experienced a recurrence of NSCLC after complete resection or during or after adjuvant chemotherapy).

在一些態樣中，個體在其手術日期後 12 週內開始輔助化學療法 (例如，一個或多個給藥週期之輔助化學療法在手術日期的一週、兩週、六週、七週或八週、九週、十週、十一週或十二週內 (例如，1 至 2 週、2 至 4 週、4 至 6 週或 6 至 8 週、8 至 10 週或 10 至 12 週內) 開始)。In some aspects, the subject begins adjuvant chemotherapy within 12 weeks of their surgery date (e.g., one or more dosing cycles of adjuvant chemotherapy begin within one, two, six, seven, or eight, nine, ten, eleven, or twelve weeks (e.g., 1 to 2 weeks, 2 to 4 weeks, 4 to 6 weeks, or 6 to 8 weeks, 8 to 10 weeks, or 10 to 12 weeks) of the surgery date).

在一些態樣中，除了手術切除及輔助化學療法之外，個體未接受針對 NSCLC 的抗癌療法。在一些態樣中，個體未接受過使用 CD137 促效劑或免疫查核點阻斷療法之先前治療。手術時機及輔助療法In some embodiments, the individual has not received prior anticancer therapy for NSCLC other than surgical resection andadjuvant chemotherapy . In some embodiments, the individual has not received prior treatment with a CD137 agonist or immune checkpoint blockade therapy.

一個或多個給藥週期之抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑可在手術切除及輔助化學療法完成後的任何適當時間開始 (例如，在個體已從手術及輔助化學療法中充分恢復時)。例如，在一些態樣中，一個或多個給藥週期之抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑在手術切除後至少六週開始 (例如，在手術切除後至少 6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29 或 30 週開始 (例如，在手術切除後至少 6 至 8 週、8 至 10 週、10 至 12 週、12 至 14 週、14 至 16 週、16 至 18 週、18 至 20 週、20 至 22 週、22 至 24 週、24 至 26 週、26 至 28 週或 28 至 30 週開始) 或者在手術切除後超過 30 週開始)。在其他態樣中，一個或多個給藥週期之抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑在手術切除後少於六週開始 (例如，在手術切除後 1、2、3、4、5 或 6 週內開始)。在一些態樣中，一個或多個給藥週期在手術切除後 26 週內開始。One or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist can be initiated at any appropriate time after completion of surgical resection and adjuvant chemotherapy (e.g., when the individual has adequately recovered from surgery and adjuvant chemotherapy). For example, in some aspects, one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist begin at least six weeks after surgical resection (e.g., at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 weeks after surgical resection (e.g., at least 6 to 8 weeks, 8 to 10 weeks, 10 to 12 weeks, 12 to 14 weeks, 14 to 16 weeks, 16 to 18 weeks, 18 to 20 weeks, 20 to 22 weeks after surgical resection). In some embodiments, one or more dosing cycles of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist begin less than six weeks after surgical resection (e.g., within 1, 2, 3, 4, 5, or 6 weeks after surgical resection). In some embodiments, one or more dosing cycles begin within 26 weeks after surgical resection.

在一些態樣中，一個或多個給藥週期之抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑在最後投予的一劑輔助化學療法後 10 週內 (例如，70 天內) 開始。例如，在一些態樣中，一個或多個給藥週期之抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑在最後投予的一劑輔助化學療法後 1 天、5 天、1 週、兩週、六週、七週、八週、九週或十週 (例如，1 至 2 週、2 至 4 週、4 至 6 週、6 至 8 週或 8 至 10 週內) 內開始。在其他態樣中，一個或多個給藥週期之抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑在最後投予的一劑輔助化學療法後超過 10 週開始。給藥及投予順序PD-1軸結合拮抗劑In some embodiments, one or more dosing cycles of anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists are initiated within 10 weeks (e.g., within 70 days) after the last dose of adjuvant chemotherapy. For example, in some embodiments, one or more dosing cycles of anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists are initiated within 1 day, 5 days, 1 week, 2 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, or 10 weeks (e.g., 1 to 2 weeks, 2 to 4 weeks, 4 to 6 weeks, 6 to 8 weeks, or 8 to 10 weeks) after the last dose of adjuvant chemotherapy. In other embodiments, one or more dosing cycles of anti-TIGIT antagonist antibodies and PD-1 axis binding antagonists are initiated more than 10 weeks after the last dose of adjuvant chemotherapy.Dosing and Order of Administration ofPD-1Axis Binding Antagonists

在一些態樣中，在一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 中之各者中，PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 每四週投予 (例如，以 28 天給藥週期投予，例如，在一個或多個 28 天給藥週期中之各者的約第 1 天 (例如，第 1 天 ± 3 天，例如，第 1 天) 投予)。示例性 PD-1 軸結合拮抗劑及其給藥方案在下文第 III 部分中提供。In some aspects, in each of the anti-TIGIT antagonist antibody (e.g., tisleliumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) in one or more dosing cycles, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered every four weeks (e.g., administered in a 28-day dosing cycle, e.g., administered on about day 1 (e.g., day 1 ± 3 days, e.g., day 1) of each of the one or more 28-day dosing cycles). Exemplary PD-1 axis binding antagonists and dosing regimens thereof are provided in Section III below.

在一些態樣中，PD-1 軸結合拮抗劑為阿替利珠單抗，並且阿替利珠單抗每四週以約 1680 mg 之固定劑量 (例如，1680 mg 之固定劑量) 投予。在一些態樣中，一個或多個給藥週期中之各者的長度為 28 天，並且阿替利珠單抗在各 28 天給藥週期的約第 1 天 (例如，第 1 天 ± 3 天，例如，第 1 天) 投予。因此，在一些態樣中，本文提供的方法包含每四週以約 1680 mg 之固定劑量向個體投予阿替利珠單抗。In some aspects, the PD-1 axis binding antagonist is atezolizumab, and atezolizumab is administered at a fixed dose of about 1680 mg (e.g., a fixed dose of 1680 mg) every four weeks. In some aspects, the length of each of the one or more dosing cycles is 28 days, and atezolizumab is administered on about day 1 (e.g., day 1 ± 3 days, e.g., day 1) of each 28-day dosing cycle. Thus, in some aspects, the methods provided herein comprise administering atezolizumab to a subject at a fixed dose of about 1680 mg every four weeks.

在一些態樣中，PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 係靜脈內投予。在其他態樣中，PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 係皮下投予。抗TIGIT拮抗劑抗體In some embodiments, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered intravenously. In other embodiments, the PD-1 axis binding antagonist (e.g., atezolizumab) is administered subcutaneously.Anti-TIGITAntagonist Antibodies

在一些態樣中，在一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 中之各者中，抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 每四週投予 (例如，以 28 天給藥週期投予，例如，在一個或多個 28 天給藥週期中之各者的約第 1 天 (例如，第 1 天 ± 3 天，例如，第 1 天) 投予)。示例性抗 TIGIT 拮抗劑抗體及其給藥方案在下文第 IV 部分中提供。In some aspects, in each of the anti-TIGIT antagonist antibody (e.g., tisleliumab) and the PD-1 axis binding antagonist (e.g., atezolizumab) in one or more dosing cycles, the anti-TIGIT antagonist antibody (e.g., tisleliumab) is administered every four weeks (e.g., administered in a 28-day dosing cycle, e.g., administered on about day 1 (e.g., day 1 ± 3 days, e.g., day 1) of each of the one or more 28-day dosing cycles). Exemplary anti-TIGIT antagonist antibodies and dosing regimens thereof are provided in Section IV below.

在一些態樣中，抗 TIGIT 拮抗劑抗體為替瑞利尤單抗，並且該替瑞利尤單抗每四週以約 840 mg 之固定劑量 (例如，840 mg 之劑量) 投予。在一些態樣中，一個或多個給藥週期中之各者的長度為 28 天，並且替瑞利尤單抗在各 28 天給藥週期的約第 1 天 (例如，第 1 天 ± 3 天，例如，第 1 天) 投予。因此，在一些態樣中，本文提供的方法包含每四週以約 840 mg 之固定劑量向個體投予替瑞利尤單抗。In some aspects, the anti-TIGIT antagonist antibody is tirilimumab, and the tirilimumab is administered at a fixed dose of about 840 mg (e.g., a dose of 840 mg) every four weeks. In some aspects, the length of each of the one or more dosing cycles is 28 days, and tirilimumab is administered on about day 1 (e.g., day 1 ± 3 days, e.g., day 1) of each 28-day dosing cycle. Thus, in some aspects, the methods provided herein comprise administering tirilimumab to a subject at a fixed dose of about 840 mg every four weeks.

在一些態樣中，抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 係靜脈內投予。在其他態樣中，抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 係皮下投予。投予順序及共同投予In some embodiments, the anti-TIGIT antagonist antibody (e.g., tisleliumab) is administered intravenously. In other embodiments, the anti-TIGIT antagonist antibody (e.g., tisleliumab) is administered subcutaneously.Order of Administration and Co-Administration

在一些態樣中，該方法包含共同投予 PD-1 軸結合拮抗劑及抗 TIGIT 拮抗劑抗體 (例如，包含共同投予替瑞利尤單抗及阿替利珠單抗)。In some aspects, the method comprises co-administering a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody (e.g., comprising co-administering tisleliumab and atezolizumab).

例如，在一些態樣中，該方法包含靜脈內 (IV) 共同輸注替瑞利尤單抗及阿替利珠單抗。在一些態樣中，共同輸注的替瑞利尤單抗及阿替利珠單抗在輸注之前混合 (例如，單獨調配並由投予藥物的醫師混合)，例如，在投予之前在 IV 袋中組合。在其他態樣中，將共同輸注的替瑞利尤單抗及阿替利珠單抗調配在一起 (亦即，不由投予藥物的醫師混合) 並且作為 IV 投予的固定劑量組合 (FDC) 投予。在一些態樣中，IV 投予的替瑞利尤單抗及阿替利珠單抗 (例如，FDC) 的共同輸注包含劑量為 1680 mg 的阿替利珠單抗及劑量為 840 mg 的替瑞利尤單抗。因此，在一些態樣中，本文提供的方法包含藉由靜脈內共同輸注向個體共同投予阿替利珠單抗及替瑞利尤單抗。For example, in some aspects, the method comprises co-infusion of tisleliumab and atezolizumab intravenously (IV). In some aspects, the tisleliumab and atezolizumab co-infused are mixed prior to infusion (e.g., separately formulated and mixed by a physician administering the medication), e.g., combined in an IV bag prior to administration. In other aspects, the tisleliumab and atezolizumab co-infused are formulated together (i.e., not mixed by a physician administering the medication) and administered as a fixed dose combination (FDC) administered IV. In some aspects, the co-infusion of tisleliumab and atezolizumab (e.g., FDC) administered IV comprises a dose of 1680 mg of atezolizumab and a dose of 840 mg of tisleliumab. Thus, in some aspects, the methods provided herein comprise co-administering atezolizumab and tisleliumab to a subject by intravenous co-infusion.

在一些態樣中，該方法包含替瑞利尤單抗及阿替利珠單抗的 SC 共同輸注。在一些態樣中，共同輸注的替瑞利尤單抗及阿替利珠單抗在輸注之前混合 (例如，單獨調配並由投予藥物的醫師混合)。在其他態樣中，將共同輸注的替瑞利尤單抗及阿替利珠單抗調配在一起 (亦即，不由投予藥物的醫師混合) 並且作為 SC 投予的 FDC 投予。在一些態樣中，SC 投予的替瑞利尤單抗及阿替利珠單抗 (例如，FDC) 的共同輸注包含劑量為 1875 mg 或 2000 mg 的阿替利珠單抗及劑量為 880 mg 的替瑞利尤單抗。在其他態樣中，SC 投予的替瑞利尤單抗及阿替利珠單抗 (例如，FDC) 的共同輸注包含劑量為 1875 mg 或 2000 mg 的阿替利珠單抗及劑量為 1000 mg 的替瑞利尤單抗。In some aspects, the method comprises SC co-infusion of tisleliumab and atezolizumab. In some aspects, the tisleliumab and atezolizumab for co-infusion are mixed prior to infusion (e.g., separately formulated and mixed by the physician administering the medication). In other aspects, the tisleliumab and atezolizumab for co-infusion are formulated together (i.e., not mixed by the physician administering the medication) and administered as a SC-administered FDC. In some aspects, the co-infusion of tisleliumab and atezolizumab (e.g., FDC) for SC administration comprises a dose of 1875 mg or 2000 mg of atezolizumab and a dose of 880 mg of tisleliumab. In other aspects, the co-infusion of tisleliumab and atezolizumab (e.g., FDC) administered SC comprises a dose of 1875 mg or 2000 mg of atezolizumab and a dose of 1000 mg of tisleliumab.

在一些態樣中，該方法包含替瑞利尤單抗及/或阿替利珠單抗之 IV 及 SC 投予兩者，例如，包含一個或多個 IV 投予劑量及一個或多個 SC 投予劑量之替瑞利尤單抗及/或阿替利珠單抗。例如，在一些態樣中，該方法包含投予至少一劑之替瑞利尤單抗及阿替利珠單抗作為 IV 投予的 FDC 並且包含投予至少一劑之替瑞利尤單抗及阿替利珠單抗作為 SC 投予的 FDC。In some aspects, the method comprises both IV and SC administration of tisleliumab and/or atezolizumab, e.g., comprises one or more IV administered doses and one or more SC administered doses of tisleliumab and/or atezolizumab. For example, in some aspects, the method comprises administering at least one dose of tisleliumab and atezolizumab as an IV administered FDC and comprises administering at least one dose of tisleliumab and atezolizumab as a SC administered FDC.

替瑞利尤單抗及阿替利珠單抗的示例性 IV 及 SC FDC 劑量及調配物提供於 PCT 公開號 WO 2023/122665 以及美國臨時專利申請號 63/493,691 (2023 年 3 月 31 日提交) 及 63/494,983 (2023 年 4 月 7 日提交) (均標題為“用抗 TIGIT 抗體治療腫瘤之方法”)，它們中之各者以全文引用的方式併入本文。Exemplary IV and SC FDC dosages and formulations of tisleliumab and atezolizumab are provided in PCT Publication No. WO 2023/122665 and U.S. Provisional Patent Application Nos. 63/493,691 (filed March 31, 2023) and 63/494,983 (filed April 7, 2023) (both entitled "Methods of Treating Tumors with Anti-TIGIT Antibodies"), each of which is incorporated herein by reference in its entirety.

可替代地，在一些態樣中，該方法包含 (i) 在抗 TIGIT 拮抗劑抗體之前向個體投予 (例如，靜脈內投予) PD-1 軸結合拮抗劑 (例如，在替瑞利尤單抗之前向個體投予阿替利珠單抗) 或 (ii) 在 PD-1 軸結合拮抗劑之前向個體投予 (例如，靜脈內投予) 抗 TIGIT 拮抗劑抗體 (例如，在替瑞利尤單抗之前向個體投予阿替利珠單抗)。給藥週期數Alternatively, in some aspects, the method comprises (i) administering (e.g., intravenously) a PD-1 axis binding antagonist to the individual prior to the anti-TIGIT antagonist antibody (e.g., administering atezolizumab to the individual prior to tisleliumab) or (ii) administering (e.g., intravenously) an anti-TIGIT axis binding antagonist to the individual prior to the PD-1 axis binding antagonist (e.g., administering atezolizumab to the individual prior to tisleliumab).Number of dosing cycles

本文提供的方法可包含向個體投予一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，例如可包含向個體投予單一給藥週期或 2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25 或超過 25 (例如，1 至 5、5 至 10、10 至 15、15 至 20 或 20 至 25) 個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)。在一些態樣中，向個體投予至多 13 個給藥週期 (例如，1、2、3、4、5、6、7、8、9、10、11、12 或 13 個給藥週期，例如，1 至 3、3 至 5、5 至 7、7 至 9、9 至 11 或 11 至 13 個給藥週期) 之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)。在一些態樣中，向個體投予 13 個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)。在一些態樣中，向個體投予若干給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，持續至多一年 (例如，連續投予，持續至多一年，例如，每兩週、每三週或每四週投予，持續至多一年)。D.從治療中獲益增加無疾病存活持續時間The methods provided herein may comprise administering to a subject one or more dosing cycles of an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab), for example, may comprise administering to a subject a single dosing cycle or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more than 25 (e.g., 1 to 5, 5 to 10, 10 to 15, 15 to 20, or 20 to 25) dosing cycles of an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab). In some embodiments, an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) are administered to a subject for up to 13 dosing cycles (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 dosing cycles, e.g., 1 to 3, 3 to 5, 5 to 7, 7 to 9, 9 to 11, or 11 to 13 dosing cycles). In some embodiments, an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) are administered to an individual for 13 dosing cycles. In some embodiments, an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) are administered to an individual for several dosing cycles for up to one year (e.g., continuously for up to one year, e.g., every two weeks, every three weeks, or every four weeks for up to one year).D.Increased duration of disease-free survivalfrom treatment

在一些態樣中，根據本文提供的方法中的任一者治療個體 (例如，用如本文提供的一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 治療) 使得與參考 DFS 相比無疾病存活 (DFS) 增加。在一些態樣中，參考 DFS 係已接受對照治療的個體群體中的 DFS (例如，係個體群體的平均或中值 DFS)。In some aspects, treatment of an individual according to any of the methods provided herein (e.g., treatment with an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) for one or more dosing cycles as provided herein) results in an increase in disease-free survival (DFS) compared to a reference DFS. In some aspects, the reference DFS is the DFS in a population of individuals who have received a control treatment (e.g., is the mean or median DFS for a population of individuals).

在一些實施例中，與參考 DFS 相比，本文所述之治療使個體的 DFS 延長至少約 2 個月 (例如，延長 2 至 120 個月、延長 2.5 至 100 個月、延長 3.0 至 80 個月、延長 4.0 至 60 個月、延長 5.0 至 48 個月、延長 6.0 至 36 個月、延長 8.0 至 24 個月、或延長 10 至 12 個月，例如，延長至少約 2.4 個月、2.5 個月、2.6 個月、2.7 個月、2.8 個月、2.9 個月、3.0 個月、3.1 個月、3.2 個月、3.3 個月、3.4 個月、3.5 個月、3.6 個月、3.7 個月、3.8 個月、3.9 個月、4.0 個月、4.1 個月、4.2 個月、4.3 個月、4.4 個月、4.5 個月、4.6 個月、4.7 個月、4.8 個月、4.9 個月、5.0 個月、5.1 個月、5.2 個月、5.3 個月、5.4 個月、5.5 個月、5.6 個月、5.7 個月、5.8 個月、5.9 個月、6.0 個月、6.5 個月、7.0 個月、7.5 個月、8.0 個月、8.5 個月、9.0 個月、9.5 個月、10 個月、10.5 個月、11 個月、11.5 個月、12 個月、13 個月、14 個月、15 個月、16 個月、17 個月、18 個月、19 個月、20 個月、21 個月、22 個月、23 個月、24 個月、25 個月、26 個月、27 個月、28 個月、29 個月、30 個月、31 個月、32 個月、33 個月、34 個月、35 個月或 36 個月)。In some embodiments, a treatment described herein prolongs a subject's DFS by at least about 2 months (e.g., 2 to 120 months longer, 2.5 to 100 months longer, 3.0 to 80 months longer, 4.0 to 60 months longer, 5.0 to 48 months longer, 6.0 to 36 months longer, 8.0 to 24 months longer, or 10 to 12 months longer, e.g., at least about 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months longer) compared to a reference DFS. 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months or 36 months).

在一些實施例中，該治療延長個體的 DFS 至少約 4 個月 (例如，延長 4 至 120 個月、延長 5 至 100 個月、延長 6 至 80 個月、延長 7 至 60 個月、延長 8 至 48 個月、延長 9 至 36 個月或延長 10 至 24 個月，例如，延長至少約 4.0 個月、4.1 個月、4.2 個月、4.3 個月、4.4 個月、4.5 個月、4.6 個月、4.7 個月、4.8 個月、4.9 個月、5.0 個月、5.1 個月、5.2 個月、5.3 個月、5.4 個月、5.5 個月、5.6 個月、5.7 個月、5.8 個月、5.9 個月、6.0 個月、6.5 個月、7.0 個月、7.5 個月、8.0 個月、8.5 個月、9.0 個月、9.5 個月、10 個月、10.5 個月、11 個月、11.5 個月、12 個月、13 個月、14 個月、15 個月、16 個月、17 個月、18 個月、19 個月、20 個月、21 個月、22 個月、23 個月、24 個月、25 個月、26 個月、27 個月、28 個月、29 個月、30 個月、31 個月、32 個月、33 個月、34 個月、35 個月或 36 個月)。在一些實施例中，該治療延長個體的 DFS 至少約 2 個月 (例如，延長 2 至 120 個月、延長 3 至 100 個月、延長 4 至 80 個月、延長 6 至 60 個月、延長 8 至 48 個月、延長 9 至 36 個月或延長 10 至 24 個月，例如，延長至少約 2.0 個月、2.1 個月、2.2 個月、2.3 個月、2.4 個月、2.5 個月、2.6 個月、2.7 個月、2.8 個月、2.9 個月、3.0 個月、3.1 個月、3.2 個月、3.3 個月、3.4 個月、3.5 個月、3.6 個月、3.7 個月、3.8 個月、3.9 個月、4.0 個月、4.1 個月、4.2 個月、4.3 個月、4.4 個月、4.5 個月、4.6 個月、4.7 個月、4.8 個月、4.9 個月、5.0 個月、5.1 個月、5.2 個月、5.3 個月、5.4 個月、5.5 個月、5.6 個月、5.7 個月、5.8 個月、5.9 個月、6.0 個月、6.5 個月、7.0 個月、7.5 個月、8.0 個月、8.5 個月、9.0 個月、9.5 個月、10 個月、10.5 個月、11 個月、11.5 個月、12 個月、13 個月、14 個月、15 個月、16 個月、17 個月、18 個月、19 個月、20 個月、21 個月、22 個月、23 個月、24 個月、25 個月、26 個月、27 個月、28 個月、29 個月、30 個月、31 個月、32 個月、33 個月、34 個月、35 個月或 36 個月)。In some embodiments, the treatment prolongs the subject's DFS by at least about 4 months (e.g., by 4 to 120 months, by 5 to 100 months, by 6 to 80 months, by 7 to 60 months, by 8 to 48 months, by 9 to 36 months, or by 10 to 24 months, e.g., by at least about 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months months, 35 months, or 36 months). In some embodiments, the treatment prolongs the subject's DFS by at least about 2 months (e.g., by 2 to 120 months, by 3 to 100 months, by 4 to 80 months, by 6 to 60 months, by 8 to 48 months, by 9 to 36 months, or by 10 to 24 months, e.g., by at least about 2.0 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.1 months, 6.2 months, 6.3 months, 6.4 months, 6.5 months, 6.6 months, 6.7 months, 6.8 months, 6.9 months, 7.0 months, 7.1 months, 7.2 months, 7.3 months, 7.4 months, 7.5 months, 7.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

在一些態樣中，參考 DFS 係患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的已根據包含以下的方法治療的個體群體中的 DFS (例如，平均或中值 DFS 持續時間)：向個體投予一個或多個給藥週期之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，其中該治療不包含投予抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，並且其中，在投予抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑之前，NSCLC 已完全切除並且個體已接受輔助化學療法 (例如，輔助鉑類化學療法)。In some aspects, the reference DFS is the DFS (e.g., mean or median DFS duration) in a population of individuals with NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC) who have been treated according to a method comprising: administering to the individual one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tisleliumab), and wherein, prior to administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC has been completely resected and the individual has received adjuvant chemotherapy (e.g., adjuvant platinum chemotherapy).

在其他態樣中，參考 DFS 係患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的已根據包含以下的方法治療的個體群體中的 DFS (例如，平均或中值 DFS 持續時間)：向個體投予 (i) 一個或多個給藥週期之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，其中該治療不包含投予抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，或 (ii) 一個或多個給藥週期之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，並且其中，在投予抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑之前，NSCLC 已完全切除並且個體未接受輔助化學療法。In other aspects, the reference DFS is the DFS (e.g., mean or median DFS duration) in a population of individuals with NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC) who have been treated according to a method comprising: administering to the individual (i) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tisleliumab), or (ii) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tisleliumab), and wherein, during the administration of the anti-TIGIT Prior to antagonist antibodies and PD-1 axis binding antagonists, the NSCLC had been completely resected and the individual had not received adjuvant chemotherapy.

在另一態樣中，參考 DFS 係患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的個體群體中的 DFS (例如，平均或中值 DFS 持續時間)，其中 NSCLC 已完全切除且個體未接受任何針對 NSCLC 之輔助治療。增加OS持續時間In another aspect, the reference DFS is the DFS (e.g., mean or median DFS duration) in a population of individuals with NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC) who have had completely resected NSCLC and who have not received any adjuvant therapy for NSCLC.IncreasedOSDuration

在一些態樣中，根據本文提供的方法中的任一者治療個體 (例如，用如本文提供的一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 治療) 使得與參考 OS 相比總存活 (OS) 增加。在一些態樣中，參考 OS 係已接受對照治療的個體群體中的 OS (例如，係個體群體的平均或中值 OS)。In some aspects, treatment of an individual according to any of the methods provided herein (e.g., treatment with an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) for one or more dosing cycles as provided herein) results in increased overall survival (OS) compared to a reference OS. In some aspects, the reference OS is the OS in a population of individuals who have received a control treatment (e.g., is the mean or median OS for a population of individuals).

在一些實施例中，OS 是由從治療開始到死亡的時間段來測量。在一些實例中，與參考 OS 相比，該治療使個體的 OS 延長至少約 2 個月 (例如，延長 2 至 120 個月、延長 3 至 110 個月、延長 4 至 100 個月、延長 5 至 80 個月、延長 6 至 60 個月、延長 7 至 48 個月、延長 8 至 36 個月或延長 10 至 24 個月，例如，延長至少約 2 個月、2.1 個月、2.2 個月、2.3 個月、2.4 個月、2.5 個月、2.6 個月、2.7 個月、2.8 個月、2.9 個月、3.0 個月、3.1 個月、3.2 個月、3.3 個月、3.4 個月、3.5 個月、3.6 個月、3.7 個月、3.8 個月、3.9 個月、4.0 個月、4.1 個月、4.2 個月、4.3 個月、4.4 個月、4.5 個月、4.6 個月、4.7 個月、4.8 個月、4.9 個月、5.0 個月、5.1 個月、5.2 個月、5.3 個月、5.4 個月、5.5 個月、5.6 個月、5.7 個月、5.8 個月、5.9 個月、6.0 個月、6.5 個月、7.0 個月、7.5 個月、8.0 個月、8.5 個月、9.0 個月、9.5 個月、10 個月、10.5 個月、11 個月、11.5 個月、12 個月、13 個月、14 個月、15 個月、16 個月、17 個月、18 個月、19 個月、20 個月、21 個月、22 個月、23 個月、24 個月、25 個月、26 個月、27 個月、28 個月、29 個月、30 個月、31 個月、32 個月、33 個月、34 個月、35 個月或 36 個月)。在一些實例中，該治療延長個體的 OS 至少約 3.3 個月 (例如，延長 3.3 至 120 個月、延長 4 至 100 個月、延長 5 至 80 個月、延長 6 至 60 個月、延長 7 至 48 個月、延長 8 至 36 個月或延長 10 至 24 個月，例如，延長至少約 3.3 個月、3.4 個月、3.5 個月、3.6 個月、3.7 個月、3.8 個月、3.9 個月、4.0 個月、4.1 個月、4.2 個月、4.3 個月、4.4 個月、4.5 個月、4.6 個月、4.7 個月、4.8 個月、4.9 個月、5.0 個月、5.1 個月、5.2 個月、5.3 個月、5.4 個月、5.5 個月、5.6 個月、5.7 個月、5.8 個月、5.9 個月、6.0 個月、6.5 個月、7.0 個月、7.5 個月、8.0 個月、8.5 個月、9.0 個月、9.5 個月、10 個月、10.5 個月、11 個月、11.5 個月、12 個月、13 個月、14 個月、15 個月、16 個月、17 個月、18 個月、19 個月、20 個月、21 個月、22 個月、23 個月、24 個月、25 個月、26 個月、27 個月、28 個月、29 個月、30 個月、31 個月、32 個月、33 個月、34 個月、35 個月或 36 個月)。在一些實例中，該治療延長個體的 OS 至少約 5.3 個月 (例如，延長 5.3 至 120, 延長 6 至 60 個月、延長 7 至 48 個月、延長 8 至 36 個月或延長 10 至 24 個月，例如，延長至少約 5.3 個月、5.5 個月、6.0 個月、6.5 個月、7.0 個月、7.5 個月、8.0 個月、8.5 個月、9.0 個月、9.5 個月、10 個月、10.5 個月、11 個月、11.5 個月、12 個月、13 個月、14 個月、15 個月、16 個月、17 個月、18 個月、19 個月、20 個月、21 個月、22 個月、23 個月、24 個月、25 個月、26 個月、27 個月、28 個月、29 個月、30 個月、31 個月、32 個月、33 個月、34 個月、35 個月或 36 個月)。In some embodiments, OS is measured by the time from the start of treatment to death. In some examples, the treatment prolongs the subject's OS by at least about 2 months compared to a reference OS (e.g., 2 to 120 months longer, 3 to 110 months longer, 4 to 100 months longer, 5 to 80 months longer, 6 to 60 months longer, 7 to 48 months longer, 8 to 36 months longer, or 10 to 24 months longer, e.g., at least about 2 months, 2.1 months, 2.2 months, 2.3 months, 2.4 months, 2.5 months, 2.6 months, 2.7 months, 2.8 months, 2.9 months, 3.0 months, 3.1 months, 3.2 months, 3.3 months longer, or 3.4 months longer). 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months). In some instances, the treatment prolongs the subject's OS by at least about 3.3 months (e.g., 3.3 to 120 months longer, 4 to 100 months longer, 5 to 80 months longer, 6 to 60 months longer, 7 to 48 months longer, 8 to 36 months longer, or 10 to 24 months longer, e.g., at least about 3.3 months, 3.4 months, 3.5 months, 3.6 months, 3.7 months, 3.8 months, 3.9 months, 4.0 months, 4.1 months, 4.2 months, 4.3 months, 4.4 months, 4.5 months, 4.6 months, 4.7 months, 4.8 months longer, or 5.6 months longer). months, 4.9 months, 5.0 months, 5.1 months, 5.2 months, 5.3 months, 5.4 months, 5.5 months, 5.6 months, 5.7 months, 5.8 months, 5.9 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months or 36 months). In some instances, the treatment prolongs the subject's OS by at least about 5.3 months (e.g., 5.3 to 120 months, 6 to 60 months, 7 to 48 months, 8 to 36 months, or 10 to 24 months, e.g., at least about 5.3 months, 5.5 months, 6.0 months, 6.5 months, 7.0 months, 7.5 months, 8.0 months, 8.5 months, 9.0 months, 9.5 months, 10 months, 10.5 months, 11 months, 11.5 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, or 36 months).

在一些態樣中，參考 OS 係患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的已根據包含以下的方法治療的個體群體中的 OS (例如，平均或中值 OS 持續時間)：向個體投予一個或多個給藥週期之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，其中該治療不包含投予抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，並且其中，在投予抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑之前，NSCLC 已完全切除並且個體已接受輔助化學療法 (例如，輔助鉑類化學療法)。In some aspects, the reference OS is the OS (e.g., mean or median OS duration) in a population of individuals with NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC) who have been treated according to a method comprising: administering to the individual one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tisleliumab), and wherein, prior to administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC was completely resected and the individual received adjuvant chemotherapy (e.g., adjuvant platinum chemotherapy).

在其他態樣中，參考 OS 係患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的已根據包含以下的方法治療的個體群體中的 OS (例如，平均或中值 OS 持續時間)：向個體投予 (i) 一個或多個給藥週期之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，其中該治療不包含投予抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，或 (ii) 一個或多個給藥週期之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，並且其中，在投予抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑之前，NSCLC 已完全切除並且個體未接受輔助化學療法。In other aspects, the reference OS is the OS (e.g., mean or median OS duration) in a population of individuals with NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC) who have been treated according to a method comprising: administering to the individual (i) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tisleliumab), or (ii) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tisleliumab), and wherein, during the administration of the anti-TIGIT Prior to antagonist antibodies and PD-1 axis binding antagonists, the NSCLC had been completely resected and the individual had not received adjuvant chemotherapy.

在另一態樣中，參考 OS 係患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的個體群體中的 OS (例如，平均或中值 OS 持續時間)，其中 NSCLC 已完全切除且個體未接受任何針對 NSCLC 之輔助治療。增加DFS率In another aspect, the reference OS is the OS (e.g., mean or median OS duration) in a population of individuals with NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC) who have had completely resected NSCLC and who have not received any adjuvant therapy for NSCLC.IncreasedDFSrate

在一些態樣中，根據本文提供的方法中的任一者治療個體 (例如，用如本文提供的一個或多個給藥週期之抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 治療) 使得與參考 DFS 率相比無疾病存活 (DFS) 率 (例如，3 年 DFS 率、5 年 DFS 率或 7 年 DFS 率) 增加。在一些態樣中，參考 DFS 率係已接受對照治療的個體群體中的 R0 切除率 (例如，係個體群體的平均或中值 DFS 率)。In some aspects, treating an individual according to any of the methods provided herein (e.g., treating with an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) for one or more dosing cycles as provided herein) results in an increase in disease-free survival (DFS) rate (e.g., 3-year DFS rate, 5-year DFS rate, or 7-year DFS rate) compared to a reference DFS rate. In some aspects, the reference DFS rate is an R0 resection rate in a population of individuals who have received a control treatment (e.g., is the mean or median DFS rate for a population of individuals).

在一些實施例中，治療使得個體群體的 3 年 DFS 率為至少約 10% (例如，約 10% 至約 100% (例如，約 10%, 11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、75%、80%、85%、90%、95% 或 100%))。In some embodiments, treatment results in a 3-year DFS rate of at least about 10% (e.g., about 10% to about 100% (e.g., about 10%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%,

在一些實施例中，治療使得個體群體的 5 年 DFS 率為至少約 10% (例如，約 10% 至約 100% (例如，約 10%, 11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、75%、80%、85%、90%、95% 或 100%))。In some embodiments, treatment results in a 5-year DFS rate of at least about 10% (e.g., about 10% to about 100% (e.g., about 10%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%,

在一些實施例中，治療使得個體群體的 7 年 DFS 率為至少約 10% (例如，約 10% 至約 100% (例如，約 10%, 11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、75%、80%、85%、90%、95% 或 100%))。In some embodiments, treatment results in a 7-year DFS rate of at least about 10% (e.g., about 10% to about 100% (e.g., about 10%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%, 100%,

在一些實施例中，與參考 DFS 率相比，本文描述的治療使根據該方法治療的個體群體的 DFS 率 (例如，3 年 DFS 率、5 年 DFS 率或 7 年 DFS 率) 增加至少約 5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、85%、100% 或超過 100%，例如，相對於參考 DFS 率，使 DFS 率增加 5% 至 10%、10% 至 20%、20% 至 30%、30% 至 40%、40% 至 50%、50% 至 60%、60% 至 70%、70% 至 80%、80% 至 90% 或 90% 至 100%。In some embodiments, a treatment described herein increases the DFS rate (e.g., 3-year DFS rate, 5-year DFS rate, or 7-year DFS rate) of a population of individuals treated according to the method by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 85%, 100%, or more than 100% compared to a reference DFS rate, e.g., an increase in DFS rate of 5% to 10%, 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% relative to a reference DFS rate. to 100%.

在一些態樣中，參考 DFS 率 (例如，3 年 DFS 率、5 年 DFS 率或 7 年 DFS 率) 係患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的已根據包含以下的方法治療的個體群體中的 DFS 切除率：向個體投予一個或多個給藥週期之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，其中該治療不包含投予抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，並且其中，在投予抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑之前，NSCLC 已完全切除並且個體已接受輔助化學療法 (例如，輔助鉑類化學療法)。In some aspects, the reference DFS rate (e.g., a 3-year DFS rate, a 5-year DFS rate, or a 7-year DFS rate) is a DFS resection rate in a population of individuals with NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC) who have been treated according to a method comprising: administering to the individual one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tisleliumab), and wherein, prior to administration of the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist, the NSCLC was completely resected and the individual received adjuvant chemotherapy (e.g., adjuvant platinum chemotherapy).

在其他態樣中，參考 DFS 率係患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的已根據包含以下的方法治療的個體群體中的 DFS 率：向個體投予 (i) 一個或多個給藥週期之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗)，其中該治療不包含投予抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，或 (ii) 一個或多個給藥週期之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，並且其中，在投予抗 TIGIT 拮抗劑抗體及 PD-1 軸結合拮抗劑之前，NSCLC 已完全切除並且個體未接受輔助化學療法。In other aspects, the reference DFS rate is a DFS rate in a population of individuals with NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC) who have been treated according to a method comprising administering to the individual (i) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab), wherein the treatment does not comprise administration of an anti-TIGIT antagonist antibody (e.g., tisleliumab), or (ii) one or more dosing cycles of a PD-1 axis binding antagonist (e.g., atezolizumab) and an anti-TIGIT antagonist antibody (e.g., tisleliumab), and wherein, during the administration of the anti-TIGIT antagonist antibody and the PD-1 Prior to axonal antagonists, the NSCLC had been completely resected and the individual had not received adjuvant chemotherapy.

在另一態樣中，參考 DFS 率係患有 NSCLC (例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的個體群體中的 DFS 率，其中 NSCLC 已完全切除且個體未接受任何針對 NSCLC 之輔助治療。E.評定PD-L1表現In another aspect, the reference DFS rate is the DFS rate in a population of individuals with NSCLC (e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC) in which the NSCLC was completely resected and the individuals did not receive any adjuvant therapy for NSCLC.E.Assessment ofPD-L1Expression

可以評估根據本文所述之任意方法、用途及所用組成物治療的個體的 PD-L1 表現。方法、用途及所用組成物可包括判定獲自個體的生物學樣品 (例如，腫瘤樣品，例如，NSCLC 樣品) 中 PD-L1 的表現水平。在一些實例中，已在開始治療前或開始治療後判定獲自個體之生物學樣品 (例如，腫瘤樣品) 中 PD-L1 的表現水平。可使用任何合適的方法來判定 PD-L1 表現。例如，PD-L1 表現可如美國專利申請公開號 US 2018/0030138A1 及 US 2018/0037655A1 中所述進行判定。可使用任何合適的腫瘤樣品，例如，福馬林固定且石蠟包埋 (FFPE) 的腫瘤樣品、存檔腫瘤樣品、新鮮的腫瘤樣品或冷凍的腫瘤樣品。The expression of PD-L1 in an individual treated according to any of the methods, uses, and compositions for use described herein may be assessed. The methods, uses, and compositions for use may include determining the expression level of PD-L1 in a biological sample obtained from the individual (e.g., a tumor sample, e.g., a NSCLC sample). In some examples, the expression level of PD-L1 in a biological sample obtained from the individual (e.g., a tumor sample) has been determined before or after the start of treatment. Any suitable method may be used to determine PD-L1 expression. For example, PD-L1 expression may be determined as described in U.S. Patent Application Publication Nos. US 2018/0030138A1 and US 2018/0037655A1. Any suitable tumor sample can be used, for example, formalin-fixed and paraffin-embedded (FFPE) tumor samples, archival tumor samples, fresh tumor samples, or frozen tumor samples.

例如，PD-L1 表現可根據表現可檢測之 PD-L1 表現水平的腫瘤浸潤免疫細胞所佔之腫瘤樣品的百分比來判定，作為表現可檢測之 PD-L1 表現水平的腫瘤樣品中腫瘤浸潤免疫細胞的百分比，及/或表現可檢測之 PD-L1 表現水平的腫瘤樣品中腫瘤細胞的百分比。應當理解，在前述實例中之任一者中，腫瘤浸潤免疫細胞所佔的腫瘤樣品的百分比可為腫瘤浸潤免疫細胞在獲自個體之腫瘤樣品切片中所覆蓋之腫瘤面積的百分比，例如，如藉由使用抗 PD-L1 抗體 (例如，SP142 抗體) 之 IHC 所評定。可使用任何合適的抗 PD-L1 抗體，包括例如，SP142 (Ventana)、SP263 (Ventana)、22C3 (Dako)、28-8 (Dako)、E1L3N (Cell Signaling Technology)、4059 (ProSci, Inc.)、h5H1 (Advanced Cell Diagnostics) 及 9A11。在一些實例中，抗 PD-L1 抗體為 SP142。在其他實例中，抗 PD-L1 抗體為 SP263。在一些實例中，抗 PD-L1 抗體為 22C3。在一些實例中，抗 PD-L1 抗體是28-8。For example, PD-L1 expression can be determined based on the percentage of tumor infiltrating immune cells in a tumor sample that express detectable levels of PD-L1 expression, as the percentage of tumor infiltrating immune cells in a tumor sample that express detectable levels of PD-L1 expression, and/or the percentage of tumor cells in a tumor sample that express detectable levels of PD-L1 expression. It should be understood that in any of the foregoing examples, the percentage of a tumor sample occupied by tumor-infiltrating immune cells can be the percentage of tumor area covered by tumor-infiltrating immune cells in a tumor sample section obtained from an individual, for example, as assessed by IHC using an anti-PD-L1 antibody (e.g., SP142 antibody). Any suitable anti-PD-L1 antibody can be used, including, for example, SP142 (Ventana), SP263 (Ventana), 22C3 (Dako), 28-8 (Dako), E1L3N (Cell Signaling Technology), 4059 (ProSci, Inc.), h5H1 (Advanced Cell Diagnostics), and 9A11. In some examples, the anti-PD-L1 antibody is SP142. In other instances, the anti-PD-L1 antibody is SP263. In some instances, the anti-PD-L1 antibody is 22C3. In some instances, the anti-PD-L1 antibody is 28-8.

在一些實例中，獲自個體之腫瘤樣品在以下項中具有可檢測的 PD-L1 表現水平：在腫瘤樣品中小於 1% 的腫瘤細胞中、在腫瘤樣品中 1% 或更多的腫瘤細胞中、在腫瘤樣品中 1% 至小於 5% 的腫瘤細胞中、在腫瘤樣品中 5% 或更多的腫瘤細胞中、在腫瘤樣品中 5% 至小於 50% 的腫瘤細胞中、或在腫瘤樣品中 50% 至更多的腫瘤細胞中。In some instances, a tumor sample obtained from an individual has detectable levels of PD-L1 expression in less than 1% of tumor cells in the tumor sample, in 1% or more of tumor cells in the tumor sample, in 1% to less than 5% of tumor cells in the tumor sample, in 5% or more of tumor cells in the tumor sample, in 5% to less than 50% of tumor cells in the tumor sample, or in 50% to more of tumor cells in the tumor sample.

在一些實例中，獲自個體之腫瘤樣品在腫瘤浸潤免疫細胞中具有可檢測的 PD-L1 表現水平，該等腫瘤浸潤免疫細胞包含小於 1% 的腫瘤樣品、多於 1% 的腫瘤樣品、1% 至小於 5% 的腫瘤樣品、多於 5% 的腫瘤樣品、5% 至少於 10% 的腫瘤樣品、或多於 10% 的腫瘤樣品。In some examples, a tumor sample obtained from an individual has detectable levels of PD-L1 expression in tumor-infiltrating immune cells that comprise less than 1% of the tumor sample, more than 1% of the tumor sample, 1% to less than 5% of the tumor sample, more than 5% of the tumor sample, 5% to less than 10% of the tumor sample, or more than 10% of the tumor sample.

在一些實例中，可以分別根據表 2 及/或表 3 中所示的診斷評估標準對腫瘤樣品在腫瘤浸潤的免疫細胞及/或腫瘤細胞中的 PD-L1 陽性進行評分。表2.腫瘤浸潤免疫細胞(IC) IHC診斷標準PD-L1診斷評定IC分數不存在任何可辨別之 PD-L1 染色 或 存在腫瘤浸潤免疫細胞中可辨別之任何強度的 PD-L1 染色，覆蓋腫瘤細胞、相關腫瘤內基質及連續腫瘤周邊結締組織增生性基質所佔腫瘤區域的 ＜1%IC0存在腫瘤浸潤免疫細胞中可辨別之任何強度的 PD-L1 染色，其覆蓋腫瘤細胞、相關腫瘤內基質及連續腫瘤周邊結締組織增生性基質所佔腫瘤區域的 ≥1% 至 ＜5%IC1存在腫瘤浸潤免疫細胞中可辨別之任何強度的 PD-L1 染色，其覆蓋腫瘤細胞、相關腫瘤內基質及連續腫瘤周邊結締組織增生性基質所佔腫瘤區域的 ≥5% 至 ＜10%IC2存在腫瘤浸潤免疫細胞中可辨別之任何強度的 PD-L1 染色，其覆蓋腫瘤細胞、相關腫瘤內基質及連續腫瘤周邊結締組織增生性基質所佔腫瘤區域的 ≥10%IC3表3.腫瘤細胞(TC) IHC診斷標準PD-L1診斷評定TC分數不存在任何可辨別之 PD-L1 染色 或 ＜1% 的腫瘤細胞中存在可辨別之任何強度的 PD-L1 染色TC0≥1% 至 ＜5% 的腫瘤細胞中存在可辨別的任何強度的 PD-L1 染色TC1≥5% 至 ＜50% 的腫瘤細胞中存在可辨別的任何強度的 PD-L1 染色TC2≥50% 的腫瘤細胞中存在可辨別之任何強度的 PD-L1 染色TC3In some examples, tumor samples can be scored for PD-L1 positivity in tumor-infiltrating immune cells and/or tumor cells according to the diagnostic assessment criteria shown in Table 2 and/or Table 3, respectively.Table2.Tumor-Infiltrating Immune Cell(IC) IHCDiagnostic CriteriaPD-L1diagnostic assessmentICscore Absence of any discernible PD-L1 staining or presence of any intensity of discernible PD-L1 staining in tumor-infiltrating immune cells covering <1% of the tumor area in tumor cells, associated intratumoral stroma, and contiguous peritumoral connective tissue proliferative stroma IC0 Presence of PD-L1 staining of any intensity discernible in tumor-infiltrating immune cells covering ≥1% to <5% of the tumor area in tumor cells, associated intratumoral stroma, and contiguous peritumoral connective tissue proliferative stroma IC1 Presence of PD-L1 staining of any intensity discernible in tumor-infiltrating immune cells covering ≥5% to <10% of the tumor area in tumor cells, associated intratumoral stroma, and contiguous peritumoral connective tissue proliferative stroma IC2 Presence of PD-L1 staining of any intensity discernible in tumor-infiltrating immune cells covering ≥10% of the tumor area in tumor cells, associated intratumoral stroma, and contiguous peritumoral connective tissue proliferative stroma IC3Table3.Tumor cell(TC) IHCdiagnostic criteriaPD-L1diagnostic assessmentTCscore No discernible PD-L1 staining or discernible PD-L1 staining of any intensity in <1% of tumor cells TC0 PD-L1 staining of any intensity discernible in ≥1% to <5% of tumor cells TC1 PD-L1 staining of any intensity discernible in ≥5% to <50% of tumor cells TC2 PD-L1 staining of any intensity is discernible in ≥50% of tumor cells TC3

在一些實例中，在本文所述之任意方法、用途或所用組成物中，個體具有 PD-L1 選擇之腫瘤 (例如，如使用 SP142 抗體藉由 IHC 判定，在腫瘤樣品中表現 PD-L1 的腫瘤浸潤性免疫細胞 (IC) 佔腫瘤面積的比例大於或等於 5%)。在一些實例中，PD-L1 選擇性腫瘤是藉由免疫組織化學 (IHC) 測定法測得的表現 PD-L1 的免疫細胞 (IC) 佔腫瘤面積的比例大於或等於 5% 的腫瘤。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 SP142、SP263、22C3 或 28-8。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 SP142。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 SP263。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 22C3。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 22C3。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 28-8。In some instances, in any of the methods, uses, or compositions for use described herein, the individual has a PD-L1 selective tumor (e.g., tumor infiltrating immune cells (ICs) expressing PD-L1 in a tumor sample are greater than or equal to 5% of the tumor area as determined by IHC using the SP142 antibody). In some instances, a PD-L1 selective tumor is a tumor in which immune cells (ICs) expressing PD-L1 are greater than or equal to 5% of the tumor area as determined by an immunohistochemistry (IHC) assay. In some instances, the IHC assay uses anti-PD-L1 antibodies SP142, SP263, 22C3, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay uses anti-PD-L1 antibody 28-8.

在一些實例中，已判定表現 PD-L1 的 IC 占據腫瘤面積的比例大於或等於 5% (例如，使用 Ventana (SP142) PD-L1 IHC 測定法判定)。在一些實例中，已判定 IC 評分為 2 或 3 (例如，如使用 Ventana (SP142) PD-L1 IHC 測定法所判定)。在一些實例中，已判定表現 PD-L1 的 IC 占據腫瘤面積的比例大於或等於 1% (例如，使用 Ventana (SP142) PD-L1 IHC 測定法判定)。在一些實例中，已判定表現 PD-L1 的 IC 占據腫瘤面積的比例大於或等於 10% (例如，使用 Ventana (SP142) PD-L1 IHC 測定法判定)。在一些實例中，已判定表現 PD-L1 的 IC 占據腫瘤面積的比例大於或等於 1% 且小於 50% (例如，使用 Ventana (SP142) PD-L1 IHC 測定法判定)。在一些實例中，已判定表現 PD-L1 的 IC 占據腫瘤面積的比例大於或等於 1% 且小於 30% (例如，使用 Ventana (SP142) PD-L1 IHC 測定法判定)。In some instances, the IC for PD-L1 expression is determined to be greater than or equal to 5% of the tumor area (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC score is determined to be 2 or 3 (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC for PD-L1 expression is determined to be greater than or equal to 1% of the tumor area (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC for PD-L1 expression is determined to be greater than or equal to 10% of the tumor area (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC for expressing PD-L1 is determined to be greater than or equal to 1% and less than 50% of the tumor area (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay). In some instances, the IC for expressing PD-L1 is determined to be greater than or equal to 1% and less than 30% of the tumor area (e.g., as determined using the Ventana (SP142) PD-L1 IHC assay).

在一些實例中，在用於本文所述之任意方法、用途或組成物中，獲自個體之腫瘤樣品具有可檢測之 PD-L1 之蛋白質表現水平。在一些實例中，已藉由 IHC 測定法判定可檢測之 PD-L1 蛋白表現水平。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 SP142。在一些實例中，該腫瘤樣品業經判定具有在腫瘤浸潤免疫細胞中佔腫瘤樣品的大於或等於 5% 的可檢測到的 PD-L1 表現水平。在一些實例中，該腫瘤樣品業經判定具有在腫瘤浸潤免疫細胞中佔腫瘤樣品的大於或等於 1% 的可檢測到的 PD-L1 表現水平。在一些實例中，該腫瘤樣品業經判定具有在腫瘤浸潤免疫細胞中佔腫瘤樣品的大於或等於 1% 且小於 5% 的可檢測到的 PD-L1 表現水平。在一些實例中，該腫瘤樣品業經判定具有在腫瘤浸潤免疫細胞中佔腫瘤樣品的大於或等於 5% 且小於 10% 的可檢測到的 PD-L1 表現水平。在一些實例中，該腫瘤樣品業經判定具有在腫瘤浸潤免疫細胞中佔腫瘤樣品的大於或等於 10% 的可檢測到的 PD-L1 表現水平。在一些實例中，該腫瘤樣品業經判定具有大於或等於腫瘤樣品中腫瘤細胞的 1% 的可檢測到的 PD-L1 表現水平。在一些實例中，該腫瘤樣品業經判定具有大於或等於腫瘤樣品中腫瘤細胞的 1% 且小於 5% 的可檢測到的 PD-L1 表現水平。在一些實例中，該腫瘤樣品業經判定具有大於或等於腫瘤樣品中腫瘤細胞的 5% 且小於 50% 的可檢測到的 PD-L1 表現水平。在一些實例中，該腫瘤樣品業經判定具有大於或等於腫瘤樣品中腫瘤細胞的 50% 的可檢測到的 PD-L1 表現水平。In some examples, for use in any of the methods, uses, or compositions described herein, a tumor sample obtained from an individual has a detectable protein expression level of PD-L1. In some examples, the detectable protein expression level of PD-L1 has been determined by an IHC assay. In some examples, the IHC assay uses anti-PD-L1 antibody SP142. In some examples, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells greater than or equal to 5% of the tumor sample. In some examples, the tumor sample has been determined to have a detectable expression level of PD-L1 in tumor-infiltrating immune cells greater than or equal to 1% of the tumor sample. In some instances, the tumor sample is determined to have a detectable PD-L1 expression level of greater than or equal to 1% and less than 5% of the tumor infiltrating immune cells of the tumor sample. In some instances, the tumor sample is determined to have a detectable PD-L1 expression level of greater than or equal to 5% and less than 10% of the tumor infiltrating immune cells of the tumor sample. In some instances, the tumor sample is determined to have a detectable PD-L1 expression level of greater than or equal to 10% of the tumor infiltrating immune cells of the tumor sample. In some instances, the tumor sample is determined to have a detectable PD-L1 expression level greater than or equal to 1% of the tumor cells in the tumor sample. In some instances, the tumor sample is determined to have a detectable PD-L1 expression level greater than or equal to 1% and less than 5% of the tumor cells in the tumor sample. In some instances, the tumor sample is determined to have a detectable PD-L1 expression level greater than or equal to 5% and less than 50% of the tumor cells in the tumor sample. In some instances, the tumor sample is determined to have a detectable PD-L1 expression level greater than or equal to 50% of the tumor cells in the tumor sample.

在一些實例中，在本文所述之任意方法、用途或所用組成物中，個體具有 PD-L1 選擇之腫瘤 (例如，高 PD-L1 (例如，如使用 SP263 抗體藉由 IHC 判定，在腫瘤樣品中 PD-L1 腫瘤比例評分 (TPS) 大於或等於 50%))。在一些實例中，PD-L1 選擇之腫瘤是 PD-L1 高選擇之腫瘤。在一些實例中，PD-L1 選擇之腫瘤是藉由免疫組織化學 (IHC) 測定法測得的 TPS 大於或等於 50% 的腫瘤。In some instances, in any of the methods, uses, or compositions for use described herein, the subject has a PD-L1 selected tumor (e.g., high PD-L1 (e.g., a PD-L1 tumor proportion score (TPS) greater than or equal to 50% in a tumor sample as determined by IHC using the SP263 antibody)). In some instances, the PD-L1 selected tumor is a PD-L1 high selected tumor. In some instances, the PD-L1 selected tumor is a tumor with a TPS greater than or equal to 50% as measured by an immunohistochemistry (IHC) assay.

在一些實例中，已判定 TPS 大於或等於 50% (例如，使用 Ventana (SP263) PD-L1 IHC 測定法判定)。在一些實例中，已判定 TPS 小於 50% (例如，如使用 Ventana (SP263) PD-L1 IHC 測定法所判定)。在一些實例中，已判定 TPS 大於或等於 1% (例如，使用 Ventana (SP263) PD-L1 IHC 測定法判定)。在一些實例中，已判定 TPS 大於或等於 1% 且小於 50% (例如，如使用 Ventana (SP263) PD-L1 IHC 測定法所判定)。In some instances, the TPS is determined to be greater than or equal to 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS is determined to be less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS is determined to be greater than or equal to 1% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay). In some instances, the TPS is determined to be greater than or equal to 1% and less than 50% (e.g., as determined using the Ventana (SP263) PD-L1 IHC assay).

在一些實例中，IHC 測定法使用抗 PD-L1 抗體 SP263、SP142、22C3 或 28-8。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 SP263。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 SP142。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 22C3。In some instances, the IHC assay uses anti-PD-L1 antibody SP263, SP142, 22C3, or 28-8. In some instances, the IHC assay uses anti-PD-L1 antibody SP263. In some instances, the IHC assay uses anti-PD-L1 antibody SP142. In some instances, the IHC assay uses anti-PD-L1 antibody 22C3.

在一些實例中，在用於本文所述之任意方法、用途或組成物中，獲自個體之腫瘤樣品具有可檢測之 PD-L1 之蛋白質表現水平。在一些實例中，已藉由 IHC 測定法判定可檢測之 PD-L1 蛋白表現水平。在一些實例中，IHC 測定法使用抗 PD-L1 抗體 SP263。在一些實例中，已判定腫瘤樣品具有佔腫瘤樣品的大於或等於 50% 的 PD-L1 陽性腫瘤細胞分數。在一些實例中，已判定腫瘤樣品具有佔腫瘤樣品的小於 50% 的 PD-L1 陽性腫瘤細胞分數。在一些實例中，已判定腫瘤樣品具有佔腫瘤樣品的大於或等於 1% 且小於 50% 的 PD-L1 陽性腫瘤細胞分數。In some examples, for use in any of the methods, uses, or compositions described herein, a tumor sample obtained from an individual has a detectable protein expression level of PD-L1. In some examples, the detectable protein expression level of PD-L1 has been determined by an IHC assay. In some examples, the IHC assay uses anti-PD-L1 antibody SP263. In some examples, the tumor sample has been determined to have a PD-L1 positive tumor cell fraction greater than or equal to 50% of the tumor sample. In some examples, the tumor sample has been determined to have a PD-L1 positive tumor cell fraction less than 50% of the tumor sample. In some instances, a tumor sample is determined to have a PD-L1 positive tumor cell fraction of greater than or equal to 1% and less than 50% of the tumor sample.

在一些實例中，IHC 測定法使用抗 PD-L1 抗體 22C3。在一些實例中，IHC 測定法是 pharmDx 22C3 IHC 測定法。在一些實例中，藉由用抗 PD-L1 抗體 22C3 進行陽性染色判定的 PD-L1 陽性腫瘤細胞分數大於或等於 50%。在一些實施例中，已判定腫瘤樣品具有大於或等於 10 的組合陽性評分 (CPS) 或佔腫瘤樣品的大於或等於 1% 的腫瘤比例評分 (TPS)，例如，如使用抗 PD-L1 抗體 22C3 作為 pharmDx 22C3 IHC 測定法之一部分所判定。在一些實施例中，已判定腫瘤樣品在具有大於或等於 10 的 CPS 或佔腫瘤樣品的大於或等於 1% 且小於 50% 的 TPS，例如，如使用抗 PD-L1 抗體 22C3 作為 pharmDx 22C3 IHC 測定法之一部分所判定。在一些實施例中，已判定腫瘤樣品在具有大於或等於 20 的CPS 或佔腫瘤樣品的大於或等於 50% 的 TPS，例如，如使用抗 PD-L1 抗體 22C3 作為 pharmDx 22C3 IHC 測定法之一部分所判定。在一些實施例中，已判定 CPS 大於或等於 1 之腫瘤樣品與具有大於或等於 5% 之 TIC 的腫瘤樣品相當。In some instances, the IHC assay uses anti-PD-L1 antibody 22C3. In some instances, the IHC assay is a pharmDx 22C3 IHC assay. In some instances, the fraction of PD-L1 positive tumor cells as determined by positive staining with anti-PD-L1 antibody 22C3 is greater than or equal to 50%. In some embodiments, a tumor sample has been determined to have a combined positivity score (CPS) greater than or equal to 10 or a tumor proportion score (TPS) greater than or equal to 1% of the tumor sample, e.g., as determined using anti-PD-L1 antibody 22C3 as part of a pharmDx 22C3 IHC assay. In some embodiments, a tumor sample is determined to have a CPS greater than or equal to 10 or a TPS greater than or equal to 1% and less than 50% of the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of a pharmDx 22C3 IHC assay. In some embodiments, a tumor sample is determined to have a CPS greater than or equal to 20 or a TPS greater than or equal to 50% of the tumor sample, e.g., as determined using the anti-PD-L1 antibody 22C3 as part of a pharmDx 22C3 IHC assay. In some embodiments, a tumor sample having a CPS greater than or equal to 1 is determined to be equivalent to a tumor sample having a TIC greater than or equal to 5%.

在一些實例中，IHC 測定法使用抗 PD-L1 抗體 28-8。在一些實例中，IHC 測定法是 pharmDx 28-8 IHC 測定法。在一些實例中，藉由用抗 PD-L1 抗體 28-8 進行陽性染色判定的 PD-L1 陽性腫瘤細胞分數大於或等於 50%。In some instances, the IHC assay uses anti-PD-L1 antibody 28-8. In some instances, the IHC assay is a pharmDx 28-8 IHC assay. In some instances, the PD-L1 positive tumor cell fraction as determined by positive staining with anti-PD-L1 antibody 28-8 is greater than or equal to 50%.

在一些實例中，在用於本文所述之任意方法、用途或組成物中，獲自個體之腫瘤樣品具有可檢測之 PD-L1 之核酸表現水平。在一些實例中，可檢測之 PD-L1 之核酸表現水平已藉由 RNA-seq、RT-qPCR、qPCR、多重 qPCR 或 RT-qPCR、微陣列分析、SAGE、MassARRAY 技術、ISH 或其組合來判定。在一些實例中，樣品選自由以下所組成之群組：組織樣品、全血樣品、血清樣品及血漿樣品。在一些實例中，組織樣品為腫瘤樣品。在一些實例中，腫瘤樣品包含腫瘤浸潤免疫細胞、腫瘤細胞、基質細胞及其任意組合。III.PD-1軸結合拮抗劑In some examples, in any of the methods, uses or compositions described herein, a tumor sample obtained from an individual has a detectable nucleic acid expression level of PD-L1. In some examples, the detectable nucleic acid expression level of PD-L1 has been determined by RNA-seq, RT-qPCR, qPCR, multiplex qPCR or RT-qPCR, microarray analysis, SAGE, MassARRAY technology, ISH or a combination thereof. In some examples, the sample is selected from the group consisting of: a tissue sample, a whole blood sample, a serum sample and a plasma sample. In some examples, the tissue sample is a tumor sample. In some examples, the tumor sample comprises tumor infiltrating immune cells, tumor cells, stromal cells and any combination thereof.III. PD-1axis binding antagonists

PD-1 軸結合拮抗劑可包括 PD-L1 結合拮抗劑、PD-1 結合拮抗劑及 PD-L2 結合拮抗劑。任何適當的 PD-1 軸結合拮抗劑可用於治療患有癌症 (例如，NSCLC，例如，IIB 期 NSCLC、IIIA 期 NSCLC 或 T3N2 IIIB 期 NSCLC) 的個體。A. PD-L1結合拮抗劑PD-1 axis binding antagonists may include PD-L1 binding antagonists, PD-1 binding antagonists, and PD-L2 binding antagonists. Any suitable PD-1 axis binding antagonist may be used to treat an individual having cancer (e.g., NSCLC, e.g., stage IIB NSCLC, stage IIIA NSCLC, or T3N2 stage IIIB NSCLC).A. PD-L1binding antagonists

在一些實例中，PD-L1 結合拮抗劑抑制 PD-L1 與其配體結合配偶體中之一者或多者之結合。在其他實例中，PD-L1 結合拮抗劑抑制 PD-L1 與 PD-1 之結合。在又一其他實例中，PD-L1 結合拮抗劑抑制 PD-L1 與 B7-1 之結合。在一些實例中，PD-L1 結合拮抗劑抑制 PD-L1 與 PD-1 及 B7-1 兩者之結合。PD-L1 結合拮抗劑可以是但不限於抗體、其抗原結合片段、免疫黏附素、融合蛋白、寡肽或小分子。在一些實例中，PD-L1 結合拮抗劑為抑制 PD-L1 的小分子 (例如，GS-4224、INCB086550、MAX-10181、INCB090244、CA-170 或 ABSK041)。在一些實例中，PD-L1 結合拮抗劑為抑制 PD-L1 及 VISTA 的小分子。在一些實例中，PD-L1 結合拮抗劑為 CA-170 (亦稱為 AUPM-170)。在一些實例中，PD-L1 結合拮抗劑為抑制 PD-L1 及 TIM3 的小分子。在一些實例中，該小分子為 WO 2015/033301 及/或 WO 2015/033299 中所述化合物。In some examples, a PD-L1 binding antagonist inhibits binding of PD-L1 to one or more of its ligand binding partners. In other examples, PD-L1 binding antagonists inhibit the binding of PD-L1 to PD-1. In yet other examples, a PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1. In some examples, PD-L1 binding antagonists inhibit the binding of PD-L1 to both PD-1 and B7-1. PD-L1 binding antagonists may be, but are not limited to, antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, or small molecules. In some examples, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 (e.g., GS-4224, INCB086550, MAX-10181, INCB090244, CA-170, or ABSK041). In some examples, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and VISTA. In some examples, the PD-L1 binding antagonist is CA-170 (also known as AUPM-170). In some examples, the PD-L1 binding antagonist is a small molecule that inhibits PD-L1 and TIM3. In some examples, the small molecule is a compound described in WO 2015/033301 and/or WO 2015/033299.

在一些實例中，PD-L1 結合拮抗劑為抗 PD-L1 抗體。本文涵蓋且描述多種抗PD-L1抗體。在本文之任意實例中，分離的抗 PD-L1 抗體可以結合人 PD-L1，例如，UniProtKB/Swiss-Prot 登錄號 Q9NZQ7-1 中所示的人 PD-L1，或其變異體。在一些實例中，抗 PD-L1 抗體能夠抑制 PD-L1 與 PD-1 之間及/或 PD-L1 與 B7-1 之間的結合。在一些實例中，抗 PD-L1 抗體為單株抗體。在一些實例中，抗 PD-L1 拮抗劑抗體為選自由以下所組成之群組的抗體片段：Fab、Fab'-SH、Fv、scFv 及 (Fab')₂片段。在一些實例中，抗 PD-L1 抗體為人源化抗體。在一些實例中，抗 PD-L1 抗體為人抗體。例示性抗 PD-L1 抗體包括阿替利珠單抗、MDX-1105、MEDI4736 (度伐魯單抗)、MSB0010718C (阿維魯單抗，avelumab)、SHR-1316、CS1001、恩沃利單抗 (envafolimab)、TQB2450、ZKAB001、LP-002、CX-072、IMC-001、KL-A167、APL-502、柯希利單抗 (cosibelimab)、洛達利單抗 (lodapolimab)、FAZ053、TG-1501、BGB-A333、BCD-135、AK-106、LDP、GR1405、HLX20、MSB2311、RC98、PDL-GEX、KD036、KY1003、YBL-007 及 HS-636。可用於本發明方法的抗 PD-L1 抗體的實例及其製備方法描述於國際專利申請公開號 WO 2010/077634 及美國專利號 8,217,149，其各自藉由引用的方式以其整體併入本文。In some examples, the PD-L1 binding antagonist is an anti-PD-L1 antibody. A variety of anti-PD-L1 antibodies are contemplated and described herein. In any example herein, the isolated anti-PD-L1 antibody can bind to human PD-L1, for example, human PD-L1 shown in UniProtKB/Swiss-Prot Accession No. Q9NZQ7-1, or a variant thereof. In some examples, the anti-PD-L1 antibody is capable of inhibiting the binding between PD-L1 and PD-1 and/or between PD-L1 and B7-1. In some examples, the anti-PD-L1 antibody is a monoclonal antibody. In some examples, the anti-PD-L1 antagonist antibody is an antibody fragment selected from the group consisting of: Fab, Fab'-SH, Fv, scFv and (Fab')₂ fragments. In some instances, the anti-PD-L1 antibody is a humanized antibody. In some instances, the anti-PD-L1 antibody is a human antibody. Exemplary anti-PD-L1 antibodies include atezolizumab, MDX-1105, MEDI4736 (durvalumab), MSB0010718C (avelumab), SHR-1316, CS1001, envafolimab, TQB2450, ZKAB001, LP-002, CX-072, IMC-001, KL-A167, APL-502, cosibelimab, lodapolimab, FAZ053, TG-1501, BGB-A333, BCD-135, AK-106, LDP, GR1405, HLX20, MSB2311, RC98, PDL-GEX, KD036, KY1003, YBL-007 and HS-636. Examples of anti-PD-L1 antibodies that can be used in the methods of the present invention and methods for their preparation are described in International Patent Application Publication No. WO 2010/077634 and U.S. Patent No. 8,217,149, each of which is incorporated herein by reference in its entirety.

在一些實例中，抗 PD-L1 拮抗劑抗體包含： (a) HVR-H1、HVR-H2 及 HVR-H3 序列，其分別為 GFTFSDSWIH (SEQ ID NO: 3)、AWISPYGGSTYYADSVKG (SEQ ID NO: 4) 及 RHWPGGFDY (SEQ ID NO: 5)，以及 (b) HVR-L1、HVR-L2 及 HVR-L3 序列，其分別為 RASQDVSTAVA (SEQ ID NO: 6)、SASFLYS (SEQ ID NO: 7) 及 QQYLYHPAT (SEQ ID NO: 8)。In some embodiments, the anti-PD-L1 antagonist antibody comprises:(a) HVR-H1, HVR-H2, and HVR-H3 sequences, which are GFTFSDSWIH (SEQ ID NO: 3), AWISPYGGSTYYADSVKG (SEQ ID NO: 4), and RHWPGGFDY (SEQ ID NO: 5), respectively, and(b) HVR-L1, HVR-L2, and HVR-L3 sequences, which are RASQDVSTAVA (SEQ ID NO: 6), SASFLYS (SEQ ID NO: 7), and QQYLYHPAT (SEQ ID NO: 8), respectively.

在一個實施例中，抗 PD-L1 抗體包含： (a) 重鏈可變區 (VH)，其包含胺基酸序列： EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 9)，及 (b) 輕鏈可變區 (VL)，其包含胺基酸序列： DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 10)。In one embodiment, the anti-PD-L1 antibody comprises:(a) a heavy chain variable region (VH) comprising the amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO: 9), and(b) a light chain variable region (VL) comprising the amino acid sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 10).

在一些實例中，抗 PD-L1 抗體包含 (a) 包含胺基酸序列的 VH，該胺基酸序列與 SEQ ID NO: 9 之序列具有至少 95% 序列同一性 (例如，至少 95%、96%、97%、98% 或 99% 序列同一性) 或具有 SEQ ID NO:9 之序列；(b) 包含胺基酸序列的 VL，該胺基酸序列與 SEQ ID NO: 10 之序列具有至少 95% 序列同一性 (例如，至少 95%、96%、97%、98% 或 99% 序列同一性) 或具有 SEQ ID NO: 10；或 (c) 如 (a) 中之 VH 及如 (b) 中之 VL。In some examples, the anti-PD-L1 antibody comprises (a) a VH comprising an amino acid sequence that has at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to the sequence of SEQ ID NO: 9, or has the sequence of SEQ ID NO: 9; (b) a VL comprising an amino acid sequence that has at least 95% sequence identity (e.g., at least 95%, 96%, 97%, 98%, or 99% sequence identity) to the sequence of SEQ ID NO: 10, or has SEQ ID NO: 10; or (c) a VH as in (a) and a VL as in (b).

在一個實施例中，抗 PD-L1 抗體包含阿替利珠單抗，其包含： (a) 重鏈胺基酸序列： EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 1)，及 (b) 輕鏈胺基酸序列： DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 2)。In one embodiment, the anti-PD-L1 antibody comprises atezolizumab, which comprises:(a) heavy chain amino acid sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO: 1), and (b) Light chain amino acid sequence: DIQMTQSPSSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 2).

在一些實例中，抗 PD-L1 抗體為阿維魯單抗 (CAS 登錄號：1537032-82-8)。阿維魯單抗(Avelumab)，亦稱為 MSB0010718C，為人單株 IgG1 抗 PD-L1 抗體 (Merck KGaA, Pfizer)。In some instances, the anti-PD-L1 antibody is avelumab (CAS Registry Number: 1537032-82-8). Avelumab, also known as MSB0010718C, is a human monoclonal IgG1 anti-PD-L1 antibody (Merck KGaA, Pfizer).

在一些實例中，抗 PD-L1 抗體為度伐魯單抗 (CAS 登錄號：1428935-60-7)。度伐魯單抗，亦稱為 MEDI4736，為 WO 2011/066389 及 US 2013/034559 所述之 Fc 優化的人單株 IgG1 κ 抗 PD-L1 抗體 (MedImmune, AstraZeneca)。In some embodiments, the anti-PD-L1 antibody is durvalumab (CAS Registry No.: 1428935-60-7). Durvalumab, also known as MEDI4736, is an Fc-optimized human monoclonal IgG1 κ anti-PD-L1 antibody described in WO 2011/066389 and US 2013/034559 (MedImmune, AstraZeneca).

在一些實例中，抗 PD-L1 抗體為 MDX-1105 (Bristol Myers Squibb)。MDX-1105，亦稱為 BMS-936559，為 WO 2007/005874 中所述之抗 PD-L1 抗體。In some embodiments, the anti-PD-L1 antibody is MDX-1105 (Bristol Myers Squibb). MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007/005874.

在一些實例中，抗 PD-L1 抗體為 LY3300054 (Eli Lilly)。In some instances, the anti-PD-L1 antibody is LY3300054 (Eli Lilly).

在一些實例中，抗 PD-L1 抗體為 STI-A1014 (Sorrento)。STI-A1014 為人抗 PD-L1 抗體。In some instances, the anti-PD-L1 antibody is STI-A1014 (Sorrento). STI-A1014 is a human anti-PD-L1 antibody.

在一些實例中，抗 PD-L1 抗體為 KN035 (Suzhou Alphamab)。KN035 為生成自駱駝噬菌體展示文庫之單域抗體 (dAB)。In some embodiments, the anti-PD-L1 antibody is KN035 (Suzhou Alphamab). KN035 is a single domain antibody (dAB) generated from a camel phage display library.

在一些實例中，抗 PD-L1 抗體包含可裂解部分或連接子，當裂解時 (例如，藉由腫瘤微環境中的蛋白酶)，該部分或連接子活化抗體抗原結合域以使其能夠結合其抗原，例如，藉由除去非結合的空間部分。在一些實例中，抗 PD-L1 抗體為 CX-072 (CytomX Therapeutics)。In some instances, the anti-PD-L1 antibody comprises a cleavable portion or linker that, when cleaved (e.g., by a protease in the tumor microenvironment), activates the antibody antigen binding domain to enable it to bind its antigen, e.g., by removing a non-binding spatial portion. In some instances, the anti-PD-L1 antibody is CX-072 (CytomX Therapeutics).

在一些實例中，抗 PD-L1 抗體包含 US 20160108123、WO 2016/000619、WO 2012/145493、美國專利號 9,205,148、WO 2013/181634 或 WO 2016/061142 所述之抗 PD-L1 抗體的六個 HVR 序列 (例如，三個重鏈 HVR 及三個輕鏈 HVR) 及/或重鏈可變域及輕鏈可變域。In some examples, the anti-PD-L1 antibody comprises six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and/or heavy chain variable domains and light chain variable domains of an anti-PD-L1 antibody described in US 20160108123, WO 2016/000619, WO 2012/145493, U.S. Patent No. 9,205,148, WO 2013/181634, or WO 2016/061142.

在還一具體態樣中，抗 PD-L1 抗體具有降低的或最小的效應功能。在還一具體態樣中，最小的效應功能來自「較少效應子 Fc 突變」或去醣基化突變。在還一實例下，較少效應子 Fc 突變為恆定區中的 N297A 或 D265A/N297A 取代。在還一實例下，較少效應子 Fc 突變係恆定區中的 N297A 取代。在一些實例中，分離的抗 PD-L1 抗體為無醣基化的。抗體的醣基化通常為 N-連接的或 O-連接的。N-連接係指碳水化合物部分與天冬醯胺酸殘基的側鏈相聯。三肽序列，天冬醯胺酸-X-絲胺酸及天冬醯胺酸-X-蘇胺酸，其中 X 為除脯胺酸外的任何胺基酸，為將碳水化合物部分與天冬醯胺酸側鏈酶促接附之識別序列。因此，多肽中這些三肽序列中任一個的存在產生潛在的醣基化位點。O-連接的醣基化係指 N-乙醯基半乳糖胺、半乳糖或木糖中的一種糖與羥基胺基酸 (最常見的是絲胺酸或蘇胺酸) 相聯，儘管 5-羥基脯胺酸或 5-羥基離胺酸亦可使用。藉由改變胺基酸序列以去除上述三肽序列中之一者 (對於 N-連接的醣基化位點)，可方便地從抗體上去除醣基化位點。可藉由用另一胺基酸殘基 (例如，甘胺酸、丙胺酸或保留式取代) 取代醣基化位點內的天冬醯胺、絲胺酸或蘇胺酸殘基來進行改變。B. PD-1結合拮抗劑In yet another embodiment, the anti-PD-L1 antibody has reduced or minimal effector function. In yet another embodiment, the minimal effector function results from a "less effector Fc mutation" or a deglycosylation mutation. In yet another embodiment, the less effector Fc mutation is an N297A or D265A/N297A substitution in the constant region. In yet another embodiment, the less effector Fc mutation is an N297A substitution in the constant region. In some embodiments, the isolated anti-PD-L1 antibody is aglycosylated. Glycosylation of an antibody is typically N-linked or O-linked. N-linked refers to the carbohydrate moiety being attached to the side chain of the asparagine residue. The tripeptide sequences, asparagine-X-serine and asparagine-X-threonine, where X is any amino acid except proline, are recognition sequences for enzymatic attachment of a carbohydrate moiety to the side chain of asparagine. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxy amino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxylysine may also be used. Glycosylation sites can be conveniently removed from antibodies by altering the amino acid sequence to remove one of the above tripeptide sequences (for N-linked glycosylation sites). The alteration can be made by replacing the asparagine, serine, or threonine residue within the glycosylation site with another amino acid residue (e.g., glycine, alanine, or a conservative substitution).B. PD-1Binding Antagonists

在一些實例中，PD-1 軸結合拮抗劑為 PD-1 結合拮抗劑。例如，在一些實例中，PD-1 結合拮抗劑抑制 PD-1 與其配體結合配偶體中之一者或多者之結合。在一些實例中，PD-1 結合拮抗劑抑制 PD-1 與 PD-L1 之結合。在其他實例中，PD-1 結合拮抗劑抑制 PD-1 與 PD-L2 之結合。在又一其他實例中，PD-1 結合拮抗劑抑制 PD-1 與 PD-L1 及 PD-L2 兩者之結合。PD-1 結合拮抗劑可以是但不限於抗體、其抗原結合片段、免疫黏附素、融合蛋白、寡肽或小分子。在一些實例中，PD-1 結合拮抗劑為一種免疫黏附素 (例如，包含與恆定區 (例如，免疫球蛋白序列的 Fc 區域) 融合的 PD-L1 或 PD-L2 的胞外或 PD-1 結合部分序列的免疫黏附素)。例如，在一些實例中，PD-1 結合拮抗劑為 Fc 融合蛋白。在一些實例中，PD-1 結合拮抗劑為 AMP-224。AMP-224，亦稱為 B7-DCIg，為 WO 2010/027827 及 WO 2011/066342 所述之 PD-L2-Fc 融合可溶性受體。在一些實例中，PD-1 結合拮抗劑為肽或小分子化合物。在一些實例中，PD-1 結合拮抗劑為 AUNP-12 (PierreFabre/Aurigene)。參見，例如，WO 2012/168944、WO 2015/036927、WO 2015/044900、WO 2015/033303、WO 2013/144704、WO 2013/132317 及 WO 2011/161699。在一些實例中，PD-1 結合拮抗劑為抑制 PD-1 的小分子。In some examples, the PD-1 axis binding antagonist is a PD-1 binding antagonist. For example, in some examples, a PD-1 binding antagonist inhibits binding of PD-1 to one or more of its ligand binding partners. In some examples, PD-1 binding antagonists inhibit the binding of PD-1 to PD-L1. In other examples, PD-1 binding antagonists inhibit the binding of PD-1 to PD-L2. In yet other examples, PD-1 binding antagonists inhibit the binding of PD-1 to both PD-L1 and PD-L2. PD-1 binding antagonists may be, but are not limited to, antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, or small molecules. In some embodiments, the PD-1 binding antagonist is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion sequence of PD-L1 or PD-L2 fused to a homeostasis region (e.g., an Fc region of an immunoglobulin sequence). For example, in some embodiments, the PD-1 binding antagonist is an Fc fusion protein. In some embodiments, the PD-1 binding antagonist is AMP-224. AMP-224, also known as B7-DCIg, is a PD-L2-Fc fused soluble receptor described in WO 2010/027827 and WO 2011/066342. In some embodiments, the PD-1 binding antagonist is a peptide or a small molecule compound. In some embodiments, the PD-1 binding antagonist is AUNP-12 (PierreFabre/Aurigene). See, e.g., WO 2012/168944, WO 2015/036927, WO 2015/044900, WO 2015/033303, WO 2013/144704, WO 2013/132317, and WO 2011/161699. In some embodiments, the PD-1 binding antagonist is a small molecule that inhibits PD-1.

在一些實例中，PD-1 結合拮抗劑為抗 PD-1 抗體。多種抗 PD-1 抗體可用於本文所揭示之方法及用途。在本文之任意實例中，PD-1 抗體可以結合人 PD-1 或其變異體。在一些實例中，抗 PD-1 抗體為單株抗體。在一些實例中，抗 PD-1 拮抗劑抗體為選自由以下所組成之群組的抗體片段：Fab、Fab'、Fab'-SH、Fv、scFv 及 (Fab')₂片段。在一些實例中，抗 PD-1 抗體為人源化抗體。在其他實例中，抗 PD-1 抗體為人抗體。例示性抗 PD-1 拮抗劑抗體包括納武利尤單抗 (nivolumab)、帕博利珠單抗、MEDI-0680、PDR001 (spartalizumab)、REGN2810 (西米普利單抗，cemiplimab)、BGB-108、普羅格利單抗 (prolgolimab)、卡瑞利珠單抗 (camrelizumab)、信迪利單抗 (sintilimab)、替雷利珠單抗 (tislelizumab)、特瑞普利單抗 (toripalimab)、多塔利單抗 (dostarlimab)、瑞弗利單抗 (retifanlimab)、薩善利單抗 (sasanlimab)、派安普利單抗 (penpulimab)、CS1003、HLX10、SCT-I10A、賽帕利單抗 (zimberelimab)、巴替利單抗 (balstilimab)、杰諾單抗 (genolimzumab)、BI 754091、西利單抗 (cetrelimab)、YBL-006、BAT1306、HX008、布格利單抗 (budigalimab)、AMG 404、CX-188、JTX-4014、609A、Sym021、LZM009、F520、SG001、AM0001、ENUM 244C8、ENUM 388D4、STI-1110、AK-103 及 hAb21。In some examples, the PD-1 binding antagonist is an anti-PD-1 antibody. A variety of anti-PD-1 antibodies can be used for the methods and uses disclosed herein. In any example herein, the PD-1 antibody can bind to human PD-1 or a variant thereof. In some examples, the anti-PD-1 antibody is a monoclonal antibody. In some examples, the anti-PD-1 antagonist antibody is an antibody fragment selected from the group consisting of: Fab, Fab', Fab'-SH, Fv, scFv and (Fab')₂ fragments. In some examples, the anti-PD-1 antibody is a humanized antibody. In other examples, the anti-PD-1 antibody is a human antibody. Exemplary anti-PD-1 antagonist antibodies include nivolumab, pembrolizumab, MEDI-0680, PDR001 (spartalizumab), REGN2810 (cemiplimab), BGB-108, prolgolimab, camrelizumab, sintilimab, tislelizumab, toripalimab, dostarlimab, retifanlimab, sasanlimab, penpulimab, CS1003, HLX10, SCT-I10A, zimberelimab, balstilimab, genolimzumab, BI 754091, cetrelimab, YBL-006, BAT1306, HX008, budigalimab, AMG 404, CX-188, JTX-4014, 609A, Sym021, LZM009, F520, SG001, AM0001, ENUM 244C8, ENUM 388D4, STI-1110, AK-103, and hAb21.

在一些實例中，抗 PD-1 抗體為納武利尤單抗 (CAS 登錄號：946414-94-4)。納武利尤單抗 (Bristol-Myers Squibb/Ono)，亦稱為 MDX-1106-04、MDX-1106、ONO-4538、BMS-936558 及 OPDIVO®，為 WO 2006/121168 中所述之抗 PD-1 抗體。In some instances, the anti-PD-1 antibody is nivolumab (CAS Registry No.: 946414-94-4). Nivolumab (Bristol-Myers Squibb/Ono), also known as MDX-1106-04, MDX-1106, ONO-4538, BMS-936558, and OPDIVO®, is an anti-PD-1 antibody described in WO 2006/121168.

在一些實例中，抗 PD-1 抗體為帕博利珠單抗 (CAS 登錄號：1374853-91-4)。帕博利珠單抗 (Merck)，亦稱為 MK-3475、Merck 3475、蘭洛利珠、SCH-900475 及 KEYTRUDA®，為 WO 2009/114335 所述之抗 PD-1 抗體。In some embodiments, the anti-PD-1 antibody is pembrolizumab (CAS Registry No.: 1374853-91-4). Pembrolizumab (Merck), also known as MK-3475, Merck 3475, lanlorizumab, SCH-900475, and KEYTRUDA®, is an anti-PD-1 antibody described in WO 2009/114335.

在一些實例中，抗 PD-1 抗體為 MEDI-0680 (AMP-514; AstraZeneca)。MEDI-0680 為人源化 IgG4 抗 PD-1 抗體。In some embodiments, the anti-PD-1 antibody is MEDI-0680 (AMP-514; AstraZeneca). MEDI-0680 is a humanized IgG4 anti-PD-1 antibody.

在一些實例中，抗 PD-1 抗體為 PDR001 (CAS 註冊號 1859072-53-9；Novartis)。PDR001 為人源化 IgG4 抗 PD-1 抗體，可阻斷 PD-L1 及 PD-L2 與 PD-1 之結合。In some embodiments, the anti-PD-1 antibody is PDR001 (CAS Reg. No. 1859072-53-9; Novartis). PDR001 is a humanized IgG4 anti-PD-1 antibody that blocks the binding of PD-L1 and PD-L2 to PD-1.

在一些實例中，抗 PD-1 抗體為 REGN2810 (Regeneron)。REGN2810 為人抗 PD-1 抗體。In some instances, the anti-PD-1 antibody is REGN2810 (Regeneron). REGN2810 is a human anti-PD-1 antibody.

在一些實例中，抗 PD-1 抗體為 BGB-108 (BeiGene)。In some instances, the anti-PD-1 antibody is BGB-108 (BeiGene).

在一些實例中，抗 PD-1 抗體為 BGB-A317 (BeiGene)。In some instances, the anti-PD-1 antibody is BGB-A317 (BeiGene).

在一些實例中，抗 PD-1 抗體為 JS-001 (Shanghai Junshi)。JS-001 為人源化抗 PD-1 抗體。In some embodiments, the anti-PD-1 antibody is JS-001 (Shanghai Junshi). JS-001 is a humanized anti-PD-1 antibody.

在一些實例中，抗 PD-1 抗體為 STI-A1110 (Sorrento)。STI-A1110 為人抗 PD-1 抗體。In some instances, the anti-PD-1 antibody is STI-A1110 (Sorrento). STI-A1110 is a human anti-PD-1 antibody.

在一些實例中，抗 PD-1 抗體為 INCSHR-1210 (Incyte)。INCSHR-1210 為人 IgG4 抗 PD-1 抗體。In some embodiments, the anti-PD-1 antibody is INCSHR-1210 (Incyte). INCSHR-1210 is a human IgG4 anti-PD-1 antibody.

在一些實例中，抗 PD-1 抗體為 PF-06801591 (Pfizer)。In some instances, the anti-PD-1 antibody is PF-06801591 (Pfizer).

在一些實例中，抗 PD-1 抗體為 TSR-042 (亦稱為 ANB011；Tesaro/AnaptysBio)。In some instances, the anti-PD-1 antibody is TSR-042 (also known as ANB011; Tesaro/AnaptysBio).

在一些實例中，抗 PD-1 抗體為 AM0001 (ARMO Biosciences)。In some instances, the anti-PD-1 antibody is AM0001 (ARMO Biosciences).

在一些實例中，抗 PD-1 抗體為 ENUM 244C8 (Enumeral Biomedical Holdings)。ENUM 244C8 為抗 PD-1 抗體，可抑制 PD-1 功能而不阻斷 PD-L1 與 PD-1 之結合。In some embodiments, the anti-PD-1 antibody is ENUM 244C8 (Enumeral Biomedical Holdings). ENUM 244C8 is an anti-PD-1 antibody that inhibits the function of PD-1 without blocking the binding of PD-L1 to PD-1.

在一些實例中，抗 PD-1 抗體為 ENUM 388D4 (Enumeral Biomedical Holdings)。ENUM 388D4 為抗 PD-1 抗體，可競爭性抑制 PD-L1 與 PD-1 之結合。In some embodiments, the anti-PD-1 antibody is ENUM 388D4 (Enumeral Biomedical Holdings). ENUM 388D4 is an anti-PD-1 antibody that competitively inhibits the binding of PD-L1 to PD-1.

在一些實例中，抗 PD-1 抗體包含 WO 2015/112800、WO 2015/112805、WO 2015/112900、US 20150210769、WO2016/089873、WO 2015/035606、WO 2015/085847、WO 2014/206107、WO 2012/145493、US 9,205,148、WO 2015/119930、WO 2015/119923、WO 2016/032927、WO 2014/179664、WO 2016/106160 及 WO 2014/194302 所述之抗 PD-1 抗體的六個 HVR 序列 (例如，三個重鏈 HVR 及三個輕鏈 HVR) 及/或重鏈可變域及輕鏈可變域。In some embodiments, the anti-PD-1 antibody comprises the anti-PD-1 described in WO 2015/112800, WO 2015/112805, WO 2015/112900, US 20150210769, WO2016/089873, WO 2015/035606, WO 2015/085847, WO 2014/206107, WO 2012/145493, US 9,205,148, WO 2015/119930, WO 2015/119923, WO 2016/032927, WO 2014/179664, WO 2016/106160 and WO 2014/194302. The six HVR sequences (e.g., three heavy chain HVRs and three light chain HVRs) and/or the heavy chain variable domains and light chain variable domains of an antibody.

在還一具體態樣中，抗 PD-1 抗體具有降低的或最小的效應功能。在還一具體態樣中，最小的效應功能來自「較少效應子 Fc 突變」或去醣基化突變。在還一實例下，較少效應子 Fc 突變為恆定區中的 N297A 或 D265A/N297A 取代。在一些實例下，分離的抗 PD-1 抗體為無醣基化的。C. PD-L2結合拮抗劑In yet another embodiment, the anti-PD-1 antibody has reduced or minimal effector function. In yet another embodiment, the minimal effector function is derived from a "less effector Fc mutation" or a deglycosylation mutation. In yet another embodiment, the less effector Fc mutation is a N297A or D265A/N297A substitution in the constant region. In some embodiments, the isolated anti-PD-1 antibody is aglycosylated.C. PD-L2Binding Antagonist

在一些實例中，PD-1 軸結合拮抗劑為 PD-L2 結合拮抗劑。在一些實例中，PD-L2 結合拮抗劑為抑制 PD-L2 與其配體結合配偶體之結合的分子。在具體態樣中，PD-L2 結合配體配偶體為 PD-1。PD-L2 結合拮抗劑可以是但不限於抗體、其抗原結合片段、免疫黏附素、融合蛋白、寡肽或小分子。In some examples, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some examples, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its ligand binding partner. In a specific aspect, the PD-L2 binding ligand partner is PD-1. PD-L2 binding antagonists may be, but are not limited to, antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, or small molecules.

在一些實例中，PD-L2 結合拮抗劑為抗 PD-L2 抗體。在本文之任意實例中，抗 PD-L2 抗體可以結合人 PD-L2 或其變異體。在一些實例中，抗 PD-L2 抗體為單株抗體。在一些實例中，抗 PD-L2 拮抗劑抗體為選自由以下所組成之群組的抗體片段：Fab、Fab'、Fab'-SH、Fv、scFv 及 (Fab')₂片段。在一些實例中，抗 PD-L2 抗體為人源化抗體。在其他實例中，抗 PD-L2 抗體為人抗體。 在還一具體態樣中，抗 PD-L2 抗體具有降低的或最小的效應功能。在還一具體態樣中，最小的效應功能來自「較少效應子 Fc 突變」或去醣基化突變。在還一實例下，較少效應子 Fc 突變為恆定區中的 N297A 或 D265A/N297A 取代。在一些實例中，分離的抗 PD-L2 抗體為無醣基化的。D. PD-1軸結合拮抗劑之給藥In some examples, the PD-L2 binding antagonist is an anti-PD-L2 antibody. In any example herein, the anti-PD-L2 antibody can bind to human PD-L2 or a variant thereof. In some examples, the anti-PD-L2 antibody is a monoclonal antibody. In some examples, the anti-PD-L2 antagonist antibody is an antibody fragment selected from the group consisting of: Fab, Fab', Fab'-SH, Fv, scFv and (Fab')₂ fragments. In some examples, the anti-PD-L2 antibody is a humanized antibody. In other examples, the anti-PD-L2 antibody is a human antibody. In another specific aspect, the anti-PD-L2 antibody has a reduced or minimal effector function. In another embodiment, the minimal effector function is derived from a "less effector Fc mutation" or a deglycosylation mutation. In another embodiment, the less effector Fc mutation is a N297A or D265A/N297A substitution in the constant region. In some embodiments, the isolated anti-PD-L2 antibody is aglycosylated. D.Administration ofPD-1 axis binding antagonists

作為一般性建議，向患有癌症 (例如，非小細胞肺癌 (NSCLC)) 的個體投予的治療有效量之 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 在約 0.01 至約 50 mg/kg 個體體重的範圍內，無論藉由一次投予亦是多次投予。As a general rule, a therapeutically effective amount of a PD-1 axis binding antagonist (e.g., atezolizumab) administered to an individual having cancer (e.g., non-small cell lung cancer (NSCLC)) is in the range of about 0.01 to about 50 mg/kg of the individual's body weight, whether by a single administration or multiple administrations.

例如，在 PCT 申請公開號 WO 2021/154761 中提供了 PD-1 軸結合拮抗劑的示例性劑量及給藥方案，該 PCT 申請公開以全文引用的方式併入本文。For example, exemplary dosages and dosing regimens for PD-1 axis binding antagonists are provided in PCT Application Publication No. WO 2021/154761, which is incorporated herein by reference in its entirety.

在一些實例中，PD-1 軸結合拮抗劑 (例如，如本文所揭示的 PD-1 軸結合拮抗劑，例如，阿替利珠單抗) 在給藥週期之約第 1 天 (例如，第 -3 天、第 -2 天、第 -1 天、第 1 天、第 2 天或第 3 天) 投予。In some examples, a PD-1 axis binding antagonist (e.g., a PD-1 axis binding antagonist as disclosed herein, e.g., atezolizumab) is administered on about day 1 (e.g., day -3, day -2, day -1, day 1, day 2, or day 3) of a dosing cycle.

在一些實例中，PD-1 軸結合拮抗劑為阿替利珠單抗，且阿替利珠單抗每 2 週以約 840 mg 的劑量、每 3 週以約 1200 mg 的劑量或每 4 週以約 1680 mg 的劑量向個體靜脈內投予。在一些態樣中，阿替利珠單抗每 4 週以 1680 mg 的劑量向個體靜脈內投予。例如，在一些態樣中，阿替利珠單抗每 3 週以 1200 mg 的劑量向個體靜脈內投予。在一些態樣中，阿替利珠單抗每 2 週以 840 mg 的劑量向個體靜脈內投予。In some embodiments, the PD-1 axis binding antagonist is atezolizumab, and atezolizumab is administered intravenously to a subject at a dose of about 840 mg every 2 weeks, at a dose of about 1200 mg every 3 weeks, or at a dose of about 1680 mg every 4 weeks. In some embodiments, atezolizumab is administered intravenously to a subject at a dose of 1680 mg every 4 weeks. For example, in some embodiments, atezolizumab is administered intravenously to a subject at a dose of 1200 mg every 3 weeks. In some embodiments, atezolizumab is administered intravenously to a subject at a dose of 840 mg every 2 weeks.

在一些實例中，向個體投予抗 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 總共 1 至 60 劑，例如，1 至 60 劑、1 至 55 劑、1 至 50 劑、1 至 45 劑、1 至 40 劑、1 至 35 劑、1 至 30 劑、1 至 25 劑、1 至 20 劑、1 至 15 劑、1 至 10 劑、1 至 5 劑、2 至 60 劑、2 至 55 劑、2 至 50 劑、2 至 45 劑、2 至 40 劑、2 至 35 劑、2 至 30 劑、2 至 25 劑、2 至 20 劑、2 至 15 劑、2 至 10 劑、2 至 5 劑、3 至 60 劑、3 至 55 劑、3 至 50 劑、3 至 45 劑、3 至 40 劑、3 至 35 劑、3 至 30 劑、3 至 25 劑、3 至 20 劑、3 至 15 劑、3 至 10 劑、3 至 5 劑、4 至 60 劑、4 至 55 劑、4 至 50 劑、4 至 45 劑、4 至 40 劑、4 至 35 劑、4 至 30 劑、4 至 25 劑、4 至 20 劑、4 至 15 劑、4 至 10 劑、4 至 5 劑、5 至 60 劑、5 至 55 劑、5 至 50 劑、5 至 45 劑、5 至 40 劑、5 至 35 劑、5 至 30 劑、5 至 25 劑、5 至 20 劑、5 至 15 劑、5 至 10 劑、10 至 60 劑、10 至 55 劑、10 至 50 劑、10 至 45 劑、10 至 40 劑、10 至 35 劑、10 至 30 劑、10 至 25 劑、10 至 20 劑、10 至 15 劑、15 至 60 劑、15 至 55 劑、15 至 50 劑、15 至 45 劑、15 至 40 劑、15 至 35 劑、15 至 30 劑、15 至 25 劑、15 至 20 劑、20 至 60 劑、20 至 55 劑、20 至 50 劑、20 至 45 劑、20 至 40 劑、20 至 35 劑、20 至 30 劑、20 至 25 劑、25 至 50 劑、25 至 45 劑、25 至 40 劑、25 至 35 劑、25 至 30 劑、30 至 60 劑、30 至 55 劑、30 至 50 劑、30 至 45 劑、30 至 40 劑、30 至 35 劑、35 至 60 劑、35 至 55 劑、35 至 50 劑、35 至 45 劑、35 至 40 劑、40 至 60 劑、40 至 55 劑、40 至 50 劑、40 至 45 劑、45 至 50 劑、50 至 60 劑或 55 至 60 劑。在特定實例中，劑量可係靜脈內投予。In some examples, an anti-PD-1 axis binding antagonist (e.g., atezolizumab) is administered to a subject for a total of 1 to 60 doses, e.g., 1 to 60 doses, 1 to 55 doses, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 60 doses, 2 to 55 doses, 2 to 50 doses, 2 to 45 doses, 2 to 40 doses, 2 to 35 doses, dose, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 60 doses, 3 to 55 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 60 doses, 4 to 55 doses, 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses, 4 to 10 doses, 4 to 5 doses, 5 to 60 doses, 5 to 55 doses, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 30 doses, 5 to 25 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 60 doses, 10 to 55 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 60 doses, 15 to 55 doses, 15 to 50 doses, 15 to 45 doses, 15 to 40 doses, 15 to 35 doses, 15 to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 to 60 doses, 20 to 55 doses, 20 to 50 doses, 20 to 45 doses, 20 to 40 dose, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 50 doses, 25 to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 to 30 doses, 30 to 60 doses, 30 to 55 doses, 30 to 50 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 60 doses, 35 to 55 doses, 35 to 50 doses, 35 to 45 doses, 35 to 40 doses, 40 to 60 dose, 40 to 55 doses, 40 to 50 doses, 40 to 45 doses, 45 to 50 doses, 50 to 60 doses, or 55 to 60 doses. In certain examples, the dose may be administered intravenously.

PD-1 軸結合拮抗劑及/或任何額外治療劑可以本領域已知的任何合適方式投予。例如，PD-1 軸結合拮抗劑及/或任何額外治療劑可依序 (在不同天) 或同時地 (在同一天或在同一治療週期內) 投予。在一些實例中，PD-1 軸結合拮抗劑在額外治療劑之前投予。在其他實例中，PD-1 軸結合拮抗劑在額外治療劑之後投予。在一些實例中，PD-1 軸結合拮抗劑及/或任何額外治療劑可在同一天投予。在一些實例中，PD-1 軸結合拮抗劑可先於在同一天投予的額外治療劑投予。例如，PD-1 軸結合拮抗劑可在同一天在化學療法之前投予。在另一個實例中，PD-1 軸結合拮抗劑可在同一天在化學療法及另一種藥物兩者之前投予。在其他實例中，PD-1 軸結合拮抗劑可在同一天投予的額外治療劑之後投予。在又一其他實例中，PD-1 軸結合拮抗劑與額外治療劑同時投予。在一些實例中，PD-1 軸結合拮抗劑與額外治療劑處於單獨的組成物中。在一些實例中，PD-1 軸結合拮抗劑與額外治療劑處於同一組成物中。在一些實例中，PD-1 軸結合拮抗劑藉由單獨於在同一天向個體投予的任何其他治療劑的靜脈管路投予。The PD-1 axis binding antagonist and/or any additional therapeutic agent may be administered in any suitable manner known in the art. For example, the PD-1 axis binding antagonist and/or any additional therapeutic agent may be administered sequentially (on different days) or simultaneously (on the same day or within the same treatment cycle). In some examples, the PD-1 axis binding antagonist is administered before the additional therapeutic agent. In other examples, the PD-1 axis binding antagonist is administered after the additional therapeutic agent. In some examples, the PD-1 axis binding antagonist and/or any additional therapeutic agent may be administered on the same day. In some examples, the PD-1 axis binding antagonist may be administered prior to an additional therapeutic agent administered on the same day. For example, the PD-1 axis binding antagonist may be administered on the same day before chemotherapy. In another example, the PD-1 axis binding antagonist may be administered on the same day before both chemotherapy and another drug. In other examples, the PD-1 axis binding antagonist may be administered after an additional therapeutic agent administered on the same day. In yet other examples, the PD-1 axis binding antagonist and the additional therapeutic agent are administered at the same time. In some examples, the PD-1 axis binding antagonist and the additional therapeutic agent are in separate compositions. In some instances, the PD-1 axis binding antagonist is in the same composition as the additional therapeutic agent. In some instances, the PD-1 axis binding antagonist is administered via an intravenous line separate from any other therapeutic agent administered to the individual on the same day.

可藉由相同投予途徑或藉由不同投予途徑來投予 PD-1 軸結合拮抗劑及任何額外治療劑。在一些實例中，PD-1 軸結合拮抗劑靜脈內、肌內、皮下、局部、口服、經皮、腹膜內、眶內、藉由植入、藉由吸入、鞘內腔、心室內或鼻內投予。在一些實例中，額外治療劑係靜脈內、肌內、皮下、局部、口服、經皮、腹膜內、眶內、藉由植入、藉由吸入、鞘內腔、心室內或鼻內投予。The PD-1 axis binding antagonist and any additional therapeutic agent may be administered by the same route of administration or by different routes of administration. In some instances, the PD-1 axis binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecal cavity, intraventricularly, or intranasally. In some instances, the additional therapeutic agent is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecal cavity, intraventricularly, or intranasally.

在一個較佳之實施例中，PD-1 軸結合拮抗劑係靜脈內投予。在一個實例中，阿替利珠單抗可以靜脈內投予超過 60 分鐘；如果可以耐受第一輸注，則所有後續輸注可以遞送超過 30 分鐘。在一些實例中，PD-1 軸結合拮抗劑不以靜脈內推注或團注投予。E.抗TIGIT拮抗劑抗體及PD-1軸結合拮抗劑之共同投予In a preferred embodiment, the PD-1 axis binding antagonist is administered intravenously. In one embodiment, atezolizumab can be administered intravenously over 60 minutes; if the first infusion can be tolerated, all subsequent infusions can be delivered over 30 minutes. In some embodiments, the PD-1 axis binding antagonist is not administered as an intravenous push or bolus.E. Co-administration ofanti-TIGITantagonist antibodies andPD-1axis binding antagonists

在一些態樣中，抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 及 PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 係共同投予。例如，在一些態樣中，替瑞利尤單抗及阿替利珠單抗係靜脈內共同投予。在一些態樣中，共同輸注的替瑞利尤單抗及阿替利珠單抗在輸注之前混合 (例如，單獨調配並由投予藥物的醫師混合)，例如，在投予之前在 IV 袋中組合。在其他態樣中，將共同輸注的替瑞利尤單抗及阿替利珠單抗調配在一起 (亦即，不由投予藥物的醫師混合) 並且作為 IV 投予的固定劑量組合 (FDC) 投予。在一些態樣中，IV 投予的替瑞利尤單抗及阿替利珠單抗 (例如，FDC) 的共同輸注包含劑量為 1680 mg 的阿替利珠單抗及劑量為 840 mg 的替瑞利尤單抗。在一些態樣中，替瑞利尤單抗及阿替利珠單抗係每四週 (Q4W) 以 1680 mg 阿替利珠單抗的劑量及 840 mg 替瑞利尤單抗的劑量靜脈內共同輸注。在一些態樣中，IV 投予的替瑞利尤單抗及阿替利珠單抗 (例如，FDC) 的共同輸注包含劑量為 1200 mg 的阿替利珠單抗及劑量為 600 mg 的替瑞利尤單抗。在一些態樣中，替瑞利尤單抗及阿替利珠單抗係每三週 (Q3W) 以 1200 mg 阿替古魯單抗的劑量及 600 mg 替瑞利尤單抗的劑量靜脈內共同輸注。In some aspects, an anti-TIGIT antagonist antibody (e.g., tisleliumab) and a PD-1 axis binding antagonist (e.g., atezolizumab) are co-administered. For example, in some aspects, tisleliumab and atezolizumab are co-administered intravenously. In some aspects, the co-infused tisleliumab and atezolizumab are mixed prior to infusion (e.g., separately formulated and mixed by a physician administering the medications), e.g., combined in an IV bag prior to administration. In other aspects, the co-infused tisleliumab and atezolizumab are formulated together (i.e., not mixed by a physician administering the medications) and administered as a fixed dose combination (FDC) for IV administration. In some aspects, the IV-administered co-infusion of tisleliumab and atezolizumab (e.g., FDC) comprises a dose of 1680 mg of atezolizumab and a dose of 840 mg of tisleliumab. In some aspects, tisleliumab and atezolizumab are co-infused intravenously every four weeks (Q4W) at a dose of 1680 mg of atezolizumab and a dose of 840 mg of tislelizumab. In some aspects, the IV-administered co-infusion of tisleliumab and atezolizumab (e.g., FDC) comprises a dose of 1200 mg of atezolizumab and a dose of 600 mg of tisleliumab. In some aspects, tisleliumab and atezolizumab are co-infused intravenously every three weeks (Q3W) at a dose of 1200 mg atezolizumab and 600 mg tisleliumab.

在一些態樣中，替瑞利尤單抗及阿替利珠單抗係靜脈內共同輸注。在一些態樣中，共同輸注的替瑞利尤單抗及阿替利珠單抗在輸注之前混合 (例如，單獨調配並由投予藥物的醫師混合)。在其他態樣中，將共同輸注的替瑞利尤單抗及阿替利珠單抗調配在一起 (亦即，不由投予藥物的醫師混合) 並且作為 SC 投予的 FDC 投予。在一些態樣中，SC 投予的替瑞利尤單抗及阿替利珠單抗 (例如，FDC) 的共同輸注包含劑量為 1875 mg 或 2000 mg 的阿替利珠單抗及劑量為 880 mg 的替瑞利尤單抗。在其他態樣中，SC 投予的替瑞利尤單抗及阿替利珠單抗 (例如，FDC) 的共同輸注包含劑量為 1875 mg 或 2000 mg 的阿替利珠單抗及劑量為 1000 mg 的替瑞利尤單抗。In some aspects, tisleliumab and atezolizumab are co-infused intravenously. In some aspects, the tisleliumab and atezolizumab co-infused are mixed prior to infusion (e.g., separately formulated and mixed by the physician administering the medication). In other aspects, the tisleliumab and atezolizumab co-infused are formulated together (i.e., not mixed by the physician administering the medication) and administered as a SC-administered FDC. In some aspects, the co-infusion of tisleliumab and atezolizumab administered SC (e.g., FDC) comprises a dose of 1875 mg or 2000 mg of atezolizumab and a dose of 880 mg of tisleliumab. In other aspects, the co-infusion of tisleliumab and atezolizumab (e.g., FDC) administered SC comprises a dose of 1875 mg or 2000 mg of atezolizumab and a dose of 1000 mg of tisleliumab.

在一些態樣中，該方法包含替瑞利尤單抗及/或阿替利珠單抗之 IV 及 SC 投予兩者，例如，包含一個或多個 IV 投予劑量及一個或多個 SC 投予劑量之替瑞利尤單抗及/或阿替利珠單抗。例如，在一些態樣中，該方法包含投予至少一劑之替瑞利尤單抗及阿替利珠單抗作為 IV 投予的 FDC 並且包含投予至少一劑之替瑞利尤單抗及阿替利珠單抗作為 SC 投予的 FDC。In some aspects, the method comprises both IV and SC administration of tisleliumab and/or atezolizumab, e.g., comprises one or more IV administered doses and one or more SC administered doses of tisleliumab and/or atezolizumab. For example, in some aspects, the method comprises administering at least one dose of tisleliumab and atezolizumab as an IV administered FDC and comprises administering at least one dose of tisleliumab and atezolizumab as a SC administered FDC.

替瑞利尤單抗及阿替利珠單抗的示例性 IV 及 SC FDC 劑量及調配物提供於 PCT 申請公開號 WO 2023/122665 以及美國臨時專利申請號 63/493,691 (2023 年 3 月 31 日提交) 及 63/494,983 (2023 年 4 月 7 日提交) (均標題為“用抗 TIGIT 抗體治療腫瘤之方法”)，它們中之各者以全文引用的方式併入本文。IV.抗TIGIT拮抗劑抗體Exemplary IV and SC FDC dosages and formulations of tisleliumab and atezolizumab are provided in PCT Application Publication No. WO 2023/122665 and U.S. Provisional Patent Application Nos. 63/493,691 (filed March 31, 2023) and 63/494,983 (filed April 7, 2023) (both entitled “Methods of Treating Tumors with Anti-TIGIT Antibodies”), each of which is incorporated herein by reference in its entirety.IV.Anti-TIGITAntagonist Antibodies

本發明提供可用於治療患有癌症 (例如，NSCLC，例如，可切除 NSCLC) 的個體 (例如，人類) 中的癌症的抗 TIGIT 拮抗劑抗體。The present invention provides anti-TIGIT antagonist antibodies that are useful for treating cancer in an individual (e.g., a human) having cancer (e.g., NSCLC, e.g., resectable NSCLC).

在一些實例中，抗 TIGIT 拮抗劑抗體為替瑞利尤單抗 (CAS 登錄號：1918185-84-8)。替瑞利尤單抗 (Genentech) 也稱為 MTIG7192A。In some embodiments, the anti-TIGIT antagonist antibody is tisleliumab (CAS Registry Number: 1918185-84-8). Tisleliumab (Genentech) is also known as MTIG7192A.

在某些實例中，抗 TIGIT 拮抗劑抗體包括選自以下項之至少一個、兩個、三個、四個、五個或六個 HVR：(a) HVR-H1，其包含 SNSAAWN (SEQ ID NO: 11) 之胺基酸序列；(b) HVR-H2，其包含 KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12) 之胺基酸序列；(c) HVR-H3，其包含 ESTTYDLLAGPFDY (SEQ ID NO: 13) 之胺基酸序列；(d) HVR-L1，其包含 KSSQTVLYSSNNKKYLA (SEQ ID NO: 14) 之胺基酸序列，(e) HVR-L2，其包含 WASTRES (SEQ ID NO: 15) 之胺基酸序列；及/或 (f) HVR-L3，其包含 QQYYSTPFT (SEQ ID NO: 16) 之胺基酸序列，或上述 HVR 中之一者或多者的組合及其一種或多種與 SEQ ID NO: 11 至 16 中之任一者具有至少約 90% 序列同一性 (例如，90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性) 的變異體。In certain embodiments, the anti-TIGIT antagonist antibody comprises at least one, two, three, four, five or six HVRs selected from: (a) HVR-H1 comprising an amino acid sequence of SNSAAWN (SEQ ID NO: 11); (b) HVR-H2 comprising an amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12); (c) HVR-H3 comprising an amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 13); (d) HVR-L1 comprising an amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 14), (e) HVR-L2 comprising an amino acid sequence of WASTRES (SEQ ID NO: 15); and/or (f) HVR-L3 comprising an amino acid sequence of QQYYSTPFT (SEQ ID NO: 16), or a combination of one or more of the above HVRs and one or more variants thereof having at least about 90% sequence identity (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity) to any one of SEQ ID NOs: 11 to 16.

在一些實例中，抗 TIGIT 拮抗劑抗體可包括：(a) HVR-H1，其包含 SNSAAWN (SEQ ID NO: 11) 之胺基酸序列；(b) HVR-H2，其包含 KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12) 之胺基酸序列；(c) HVR-H3，其包含 ESTTYDLLAGPFDY (SEQ ID NO: 13) 之胺基酸序列；(d) HVR-L1，其包含 KSSQTVLYSSNNKKYLA (SEQ ID NO: 14) 之胺基酸序列；(e) HVR-L2，其包含 WASTRES (SEQ ID NO: 15) 之胺基酸序列；及 (f) HVR-L3，其包含 QQYYSTPFT (SEQ ID NO: 16) 之胺基酸序列。在一些實例中，抗 TIGIT 拮抗劑抗體具有：VH 域，其包含胺基酸序列，該胺基酸序列與以下之序列具有至少 90% 序列同一性 (例如，至少 91%、92%、93%、94%、95%、96%、97%、98% 或 99% 序列同一性) 或具有以下之序列：EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 27)，或胺基酸序列，該胺基酸序列與以下之序列具有至少 90% 序列同一性 (例如，至少 91%、92%、93%、94%、95%、96%、97%、98% 或 99% 序列同一性) 或具有以下之序列：QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO:28)；及/或 VL 域，其包含胺基酸序列，該胺基酸序列與以下之序列具有至少 90% 序列同一性 (例如，至少 91%、92%、93%、94%、95%、96%、97%、98% 或 99% 序列同一性) 或具有以下之序列：DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO: 29)。在一些實例中，抗 TIGIT 拮抗劑抗體具有：包含胺基酸序列之 VH 域，該胺基酸序列與以下之序列具有至少 90% 序列同一性 (例如，至少 91%、92%、93%、94%、95%、96%、97%、98% 或 99% 序列同一性) 或具有以下之序列：SEQ ID NO: 27；及/或包含胺基酸序列之 VL 域，該胺基酸序列與以下之序列具有至少 90% 序列同一性 (例如，至少 91%、92%、93%、94%、95%、96%、97%、98% 或 99% 序列同一性) 或具有以下之序列：SEQ ID NO: 29。在一些實例中，抗 TIGIT 拮抗劑抗體具有：VH 域，其包含 SEQ ID NO: 27 之胺基酸序列，及 VL 域，其包含 SEQ ID NO: 29 之胺基酸序列。在一些實例中，抗 TIGIT 拮抗劑抗體具有：包含胺基酸序列之 VH 域，該胺基酸序列與以下之序列具有至少 90% 序列同一性 (例如，至少 91%、92%、93%、94%、95%、96%、97%、98% 或 99% 序列同一性) 或具有以下之序列：SEQ ID NO: 28；及/或包含胺基酸序列之 VL 域，該胺基酸序列與以下之序列具有至少 90% 序列同一性 (例如，至少 91%、92%、93%、94%、95%、96%、97%、98% 或 99% 序列同一性) 或具有以下之序列：SEQ ID NO: 29。在一些實例中，抗 TIGIT 拮抗劑抗體具有：VH 域，其包含 SEQ ID NO: 28 之胺基酸序列，及 VL 域，其包含 SEQ ID NO: 29。In some examples, the anti-TIGIT antagonist antibody may include: (a) HVR-H1 comprising an amino acid sequence of SNSAAWN (SEQ ID NO: 11); (b) HVR-H2 comprising an amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12); (c) HVR-H3 comprising an amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 13); (d) HVR-L1 comprising an amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 14); (e) HVR-L2 comprising an amino acid sequence of WASTRES (SEQ ID NO: 15); and (f) HVR-L3 comprising an amino acid sequence of QQYYSTPFT (SEQ ID NO: 16). In some examples, the anti-TIGIT antagonist antibody has: a VH domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the following sequence or having the following sequence: EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO: 27), or an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the following sequence. sequence identity) or having the following sequence: QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSS (SEQ ID NO:28); and/or a VL domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity) to the following sequence or having the following sequence: DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIK (SEQ ID NO:29); ID NO: 29). In some examples, the anti-TIGIT antagonist antibody has: a VH domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or has the sequence of, SEQ ID NO: 27; and/or a VL domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or has the sequence of, SEQ ID NO: 29. In some examples, the anti-TIGIT antagonist antibody has: a VH domain comprising the amino acid sequence of SEQ ID NO: 27, and a VL domain comprising the amino acid sequence of SEQ ID NO: 29. In some examples, the anti-TIGIT antagonist antibody has: a VH domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or has the sequence of, SEQ ID NO: 28; and/or a VL domain comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or has the sequence of, SEQ ID NO: 29. In some examples, the anti-TIGIT antagonist antibody has: a VH domain comprising the amino acid sequence of SEQ ID NO: 28, and a VL domain comprising SEQ ID NO: 29.

在一些實例中，抗 TIGIT 拮抗劑抗體包括重鏈及輕鏈序列，其中：(a) 重鏈包含胺基酸序列： EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33)；並且 (b) 輕鏈包含胺基酸序列： DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 34)。In some embodiments, the anti-TIGIT antagonist antibody comprises a heavy chain and a light chain sequence, wherein: (a) the heavy chain comprises the amino acid sequence: EVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGKTYYRFKWYSDYAVSVKGRITINPDTSKNQFSLQLNSVTPEDTAVFYCTRESTTYDLLAGPFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS CDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 33); and (b) the light chain contains an amino acid sequence: DIVMTQSPDSLAVSLGERATINCKSSQTVLYSSNNKKYLAWYQQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPFTFGPGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 34).

在一些實例中，抗 TIGIT 拮抗劑抗體進一步包含以下輕鏈可變區骨架區 (FR) 中的至少一個、兩個、三個或四個：FR-L1，其包含 DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 17) 之胺基酸序列；FR-L2，其包含 WYQQKPGQPPNLLIY (SEQ ID NO: 18) 之胺基酸序列；FR-L3，其包含 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 19) 之胺基酸序列；及/或 FR-L4，其包含 FGPGTKVEIK (SEQ ID NO: 20) 之胺基酸序列，或上述 FR 中之一者或多者的組合及其一種或多種與 SEQ ID NO: 17 至 20 中之任一者具有至少約 90% 序列同一性 (例如，90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性) 的變異體。在一些實例中，例如，該抗體進一步包含：FR-L1，其包含 DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 17) 之胺基酸序列；FR-L2，其包含 WYQQKPGQPPNLLIY (SEQ ID NO: 18) 之胺基酸序列；FR-L3，其包含 GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 19) 之胺基酸序列；及 FR-L4，其包含 FGPGTKVEIK (SEQ ID NO: 20) 之胺基酸序列。In some examples, the anti-TIGIT antagonist antibody further comprises at least one, two, three or four of the following light chain variable region framework regions (FRs): FR-L1 comprising an amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 17); FR-L2 comprising an amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 18); FR-L3 comprising an amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 19); and/or FR-L4 comprising an amino acid sequence of FGPGTKVEIK (SEQ ID NO: 20), or a combination of one or more of the above FRs and one or more of which have at least about 90% sequence identity to any one of SEQ ID NOs: 17 to 20. In some embodiments, the antibody further comprises: a FR-L1 comprising an amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 17); a FR-L2 comprising an amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 18); a FR-L3 comprising an amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 19); and a FR-L4 comprising an amino acid sequence of FGPGTKVEIK (SEQ ID NO: 20).

在一些實例中，抗 TIGIT 拮抗劑抗體進一步包含以下重鏈可變區 FR 中的至少一個、兩個、三個或四個：FR-H1，其包含 X₁VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 21) 之胺基酸序列，其中 X₁為 E 或 Q；FR-H2，其包含 WIRQSPSRGLEWLG (SEQ ID NO: 22) 之胺基酸序列；FR-H3，其包含 RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23) 之胺基酸序列；及/或 FR-H4，其包含 WGQGTLVTVSS (SEQ ID NO: 24) 之胺基酸序列，或上述 FR 中之一者或多者的組合及其一種或多種與 SEQ ID NO: 21 至 24 中之任一者具有至少約 90% 序列同一性 (例如，90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性) 的變異體。抗 TIGIT 拮抗劑抗體可進一步包括例如以下重鏈可變區 FR 中之至少一個、兩個、三個或四個：FR-H1，其包含 EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 25) 之胺基酸序列；FR-H2，其包含 WIRQSPSRGLEWLG (SEQ ID NO: 22) 之胺基酸序列；FR-H3，其包含 RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23) 之胺基酸序列；及/或 FR-H4，其包含 WGQGTLVTVSS (SEQ ID NO: 24) 之胺基酸序列，或上述 FR 中之一者或多者的組合及其一種或多種與 SEQ ID NO: 22 至 25 中之任一者具有至少約 90% 序列同一性 (例如，90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性) 的變異體。在一些實例中，抗 TIGIT 拮抗劑抗體包括：FR-H1，其包含 EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 25) 之胺基酸序列；FR-H2，其包含 WIRQSPSRGLEWLG (SEQ ID NO: 22) 之胺基酸序列；FR-H3，其包含 RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23) 之胺基酸序列；及 FR-H4，其包含 WGQGTLVTVSS (SEQ ID NO: 24) 之胺基酸序列。在另一實例中，例如，抗 TIGIT 拮抗劑抗體可進一步包括以下重鏈可變區 FR 中之至少一個、兩個、三個或四個：FR-H1，其包含 QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 26) 之胺基酸序列；FR-H2，其包含 WIRQSPSRGLEWLG (SEQ ID NO: 22) 之胺基酸序列；FR-H3，其包含 RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23) 之胺基酸序列；及/或 FR-H4，其包含 WGQGTLVTVSS (SEQ ID NO: 24) 之胺基酸序列，或上述 FR 中之一者或多者的組合及其一種或多種與 SEQ ID NO: 22 至 24 及 26 中之任一者具有至少約 90% 序列同一性 (例如，90%、91%、92%、93%、94%、95%、96%、97%、98% 或 99% 同一性) 的變異體。在一些實例中，抗 TIGIT 拮抗劑抗體包括：FR-H1，其包含 QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 26) 之胺基酸序列；FR-H2，其包含 WIRQSPSRGLEWLG (SEQ ID NO: 22) 之胺基酸序列；FR-H3，其包含 RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23) 之胺基酸序列；及 FR-H4，其包含 WGQGTLVTVSS (SEQ ID NO: 24) 之胺基酸序列。In some examples, the anti-TIGIT antagonist antibody further comprises at least one, two, three or four of the following heavy chain variable region FRs: FR-H1 comprising an amino acid sequence of_{X1VQLQQSGPGLVKPSQTLSLTCAISGDSVS} (SEQ ID NO: 21), wherein_X1 is E or Q; FR-H2 comprising an amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); FR-H3 comprising an amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and/or FR-H4 comprising an amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24), or a combination of one or more of the above FRs and one or more of which have at least about 90% affinity with any one of SEQ ID NOs: 21 to 24. Variants with 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity. The anti-TIGIT antagonist antibody may further include, for example, at least one, two, three or four of the following heavy chain variable region FRs: FR-H1 comprising an amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 25); FR-H2 comprising an amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); FR-H3 comprising an amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and/or FR-H4 comprising an amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24), or a combination of one or more of the above FRs and one or more of which have at least about 90% affinity with any one of SEQ ID NOs: 22 to 25. In some embodiments, the anti-TIGIT antagonist antibody comprises: FR-H1 comprising an amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 25); FR-H2 comprising an amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); FR-H3 comprising an amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and FR-H4 comprising an amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24). In another example, for example, the anti-TIGIT antagonist antibody may further include at least one, two, three or four of the following heavy chain variable region FRs: FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 26); FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and/or FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24), or a combination of one or more of the above FRs and one or more of which have at least about 90% affinity with any one of SEQ ID NOs: 22 to 24 and 26. In some embodiments, the anti-TIGIT antagonist antibody comprises: FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 26); FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 22); FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 23); and FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 24).

在另一態樣中，提供了抗 TIGIT 拮抗劑抗體，其中，抗體包含如上文所提供之實例中之任一者的 VH 以及如上文所提供之實例中之任一者的 VL，其中，可變域序列中的一者或兩者包括轉譯後修飾。In another aspect, an anti-TIGIT antagonist antibody is provided, wherein the antibody comprises a VH as any of the examples provided above and a VL as any of the examples provided above, wherein one or both of the variable domain sequences include a post-translational modification.

在一些實例中，上述抗 TIGIT 拮抗劑抗體中之任一者除人 TIGIT 外還能夠與兔 TIGIT 結合。在一些實例中，上述抗 TIGIT 拮抗劑抗體中之任一者能夠與人 TIGIT 及食蟹獼猴 (cyno) TIGIT 兩者結合。在一些實例中，上述抗 TIGIT 拮抗劑抗體中之任一者能夠與人 TIGIT、cyno TIGIT 及兔 TIGIT 結合。在一些實例中，上述抗 TIGIT 拮抗劑抗體中之任一者能夠與人 TIGIT、cyno TIGIT 及兔 TIGIT 結合，但不與鼠 TIGIT 結合。In some instances, any of the above anti-TIGIT antagonist antibodies can bind to rabbit TIGIT in addition to human TIGIT. In some instances, any of the above anti-TIGIT antagonist antibodies can bind to both human TIGIT and cynomolgus monkey (cyno) TIGIT. In some instances, any of the above anti-TIGIT antagonist antibodies can bind to human TIGIT, cyno TIGIT, and rabbit TIGIT. In some instances, any of the above anti-TIGIT antagonist antibodies can bind to human TIGIT, cyno TIGIT, and rabbit TIGIT, but not mouse TIGIT.

在一些實例中，抗 TIGIT 拮抗劑抗體以約 10 nM 或更低的 KD 結合人類 TIGIT 並且以約 10 nM 或更低的 KD 結合犬 TIGIT (例如，以約 0.1 nM 至約 1 nM 的 KD 結合人類 TIGIT 並且以約 0.5 nM 至約 1 nM的 KD 結合犬 TIGIT，例如，以約 0.1 nM 或更低的 KD 結合人類 TIGIT 並且以約 0.5 nM 或更低的 KD 結合犬 TIGIT)。In some examples, the anti-TIGIT antagonist antibody binds human TIGIT with a KD of about 10 nM or less and binds canine TIGIT with a KD of about 10 nM or less (e.g., binds human TIGIT with a KD of about 0.1 nM to about 1 nM and binds canine TIGIT with a KD of about 0.5 nM to about 1 nM, e.g., binds human TIGIT with a KD of about 0.1 nM or less and binds canine TIGIT with a KD of about 0.5 nM or less).

在一些實例中，抗 TIGIT 拮抗劑抗體特異性結合 TIGIT 並抑制或阻斷 TIGIT 與脊髓灰質炎病毒受體 (PVR) 之交互作用 (例如，拮抗劑抗體抑制 TIGIT 與 PVR 結合所介導之細胞內信號傳導)。在一些實例中，拮抗劑抗體抑制或阻斷人 TIGIT 與人 PVR 之結合，其 IC50 值為 10 nM 或更低 (例如，1 nM 至約 10 nM)。在一些實例中，抗 TIGIT 拮抗劑抗體特異性結合 TIGIT 並抑制或阻斷 TIGIT 與 PVR 之交互作用，而不影響 PVR-CD226 交互作用。在一些實例中，拮抗劑抗體抑制或阻斷 cyno TIGIT 與 cyno PVR 之結合，其 IC50 值為 50 nM 或更低 (例如，1 nM 至約 50 nM，例如，1 nM 至約 5 nM)。在一些實例中，抗 TIGIT 拮抗劑抗體抑制及/或阻斷 CD226 與 TIGIT 之交互作用。在一些實例中，抗 TIGIT 拮抗劑抗體抑制及/或阻斷 TIGIT 破壞 CD226 同源二聚化的能力。In some instances, the anti-TIGIT antagonist antibody specifically binds to TIGIT and inhibits or blocks the interaction of TIGIT with the poliovirus receptor (PVR) (e.g., the antagonist antibody inhibits intracellular signaling mediated by the binding of TIGIT to PVR). In some instances, the antagonist antibody inhibits or blocks the binding of human TIGIT to human PVR with an IC50 value of 10 nM or less (e.g., 1 nM to about 10 nM). In some instances, the anti-TIGIT antagonist antibody specifically binds to TIGIT and inhibits or blocks the interaction of TIGIT with PVR without affecting the PVR-CD226 interaction. In some instances, the antagonist antibody inhibits or blocks the binding of cyno TIGIT to cyno PVR with an IC50 value of 50 nM or less (e.g., 1 nM to about 50 nM, e.g., 1 nM to about 5 nM). In some instances, the anti-TIGIT antagonist antibody inhibits and/or blocks the interaction of CD226 and TIGIT. In some instances, the anti-TIGIT antagonist antibody inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization.

在一些實例中，本文所述之方法或用途可包括使用或投予經分離之抗 TIGIT 拮抗劑抗體，該抗體與上述抗 TIGIT 拮抗劑抗體中之任一者競爭與 TIGIT 之結合。例如，該方法可包括投予經分離之抗 TIGIT 拮抗劑抗體，該抗體與具有以下六個 HVR 之抗 TIGIT 拮抗劑抗體競爭與 TIGIT 之結合：(a) HVR-H1，其包含 SNSAAWN (SEQ ID NO: 11) 之胺基酸序列；(b) HVR-H2，其包含 KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12) 之胺基酸序列；(c) HVR-H3，其包含 ESTTYDLLAGPFDY (SEQ ID NO: 13) 之胺基酸序列；(d) HVR-L1，其包含 KSSQTVLYSSNNKKYLA (SEQ ID NO: 14) 之胺基酸序列，(e) HVR-L2，其包含 WASTRES (SEQ ID NO: 15) 之胺基酸序列；及 (f) HVR-L3，其包含 QQYYSTPFT (SEQ ID NO: 16) 之胺基酸序列。本文所述之方法還可包括投予經分離之抗 TIGIT 拮抗劑抗體，該抗體與上述抗 TIGIT 拮抗劑抗體結合相同的表位。In some examples, the methods or uses described herein may include using or administering an isolated anti-TIGIT antagonist antibody that competes with any of the above anti-TIGIT antagonist antibodies for binding to TIGIT. For example, the method may comprise administering an isolated anti-TIGIT antagonist antibody that competes for binding to TIGIT with an anti-TIGIT antagonist antibody having the following six HVRs: (a) HVR-H1 comprising an amino acid sequence of SNSAAWN (SEQ ID NO: 11); (b) HVR-H2 comprising an amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 12); (c) HVR-H3 comprising an amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 13); (d) HVR-L1 comprising an amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 14), (e) HVR-L2 comprising an amino acid sequence of WASTRES (SEQ ID NO: 15); and (f) HVR-L3 comprises an amino acid sequence of QQYYSTPFT (SEQ ID NO: 16). The methods described herein may also include administering an isolated anti-TIGIT antagonist antibody that binds to the same epitope as the anti-TIGIT antagonist antibody described above.

在一些態樣中，抗 TIGIT 拮抗劑抗體表現出 Fc 介導的效應子功能，例如，參與抗體依賴性細胞毒性 (ADCC)。在一些態樣中，抗 TIGIT 拮抗劑抗體為具有完整 Fc 媒介的效應功能的抗體 (例如，替瑞利尤單抗、維博利單抗、依替利單抗、EOS084448 或 TJ-T6) 或增強的效應子功能 (例如，SGN-TGT)。In some aspects, the anti-TIGIT antagonist antibody exhibits Fc-mediated effector function, e.g., participates in antibody-dependent cellular cytotoxicity (ADCC). In some aspects, the anti-TIGIT antagonist antibody is an antibody with intact Fc-mediated effector function (e.g., tisleliumab, vimbrinumab, eptilizumab, EOS084448, or TJ-T6) or enhanced effector function (e.g., SGN-TGT).

在其他態樣中，抗 TIGIT 拮抗劑抗體為缺乏 Fc 媒介的效應功能的抗體 (例如，東瓦納利單抗、BMS-986207、ASP8374 或 COM902)。In other aspects, the anti-TIGIT antagonist antibody is an antibody that lacks Fc-mediated effector function (e.g., donarumab, BMS-986207, ASP8374, or COM902).

在一些態樣中，抗 TIGIT 拮抗劑抗體為 IgG 類抗體。在一些態樣中，抗 TIGIT 拮抗劑抗體為 IgG1 類抗體，例如，替瑞利尤單抗、維博利單抗、東瓦納利單抗、BMS-986207、依替利單抗、BGB-A1217、SGN-TGT、EOS084448 (EOS-448)、TJ-T6 或 AB308。在一些態樣中，抗體係包含 Fc 區的人類單株全長 IgG1 類抗體。In some aspects, the anti-TIGIT antagonist antibody is an IgG class antibody. In some aspects, the anti-TIGIT antagonist antibody is an IgG1 class antibody, for example, tisleliumab, vibriolimab, donvarizumab, BMS-986207, etanercept, BGB-A1217, SGN-TGT, EOS084448 (EOS-448), TJ-T6, or AB308. In some aspects, the antibody is a human monoclonal full-length IgG1 class antibody comprising an Fc region.

在一些態樣中，抗 TIGIT 拮抗劑抗體為人類單株全長 IgG1 亞類抗體，其包含人類 IgG1 Fc 區、包含 SEQ ID NO: 27 之胺基酸序列的重鏈可變區 (VH)，及包含 SEQ ID NO: 29 之胺基酸序列輕鏈可變區 (VL)。In some aspects, the anti-TIGIT antagonist antibody is a human monoclonal full-length IgG1 subclass antibody comprising a human IgG1 Fc region, a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 27, and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 29.

在其他態樣中，抗 TIGIT 拮抗劑抗體為 IgG4 類抗體，例如，ASP8374 或 COM902。In other aspects, the anti-TIGIT antagonist antibody is an IgG4 class antibody, e.g., ASP8374 or COM902.

可用於本發明的抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)，包括含有此類抗體之組成物，可以與 PD-1 軸結合拮抗劑 (例如，PD-L1 結合拮抗劑 (例如，抗 PD-L1 拮抗劑抗體，例如，阿替利珠單抗)、PD-1 結合拮抗劑 (例如，抗 PD-1 拮抗劑抗體，例如，帕博利珠單抗) 及 PD-L2 結合拮抗劑 (例如，抗 PD-L2 拮抗劑抗體)) 聯合使用，如本文所述。Anti-TIGIT antagonist antibodies useful in the present invention (e.g., tisleliumab), including compositions containing such antibodies, can be used in combination with PD-1 axis binding antagonists (e.g., PD-L1 binding antagonists (e.g., anti-PD-L1 antagonist antibodies, e.g., atezolizumab), PD-1 binding antagonists (e.g., anti-PD-1 antagonist antibodies, e.g., pembrolizumab), and PD-L2 binding antagonists (e.g., anti-PD-L2 antagonist antibodies)), as described herein.

在一些實施例中，抗 TIGIT 拮抗劑抗體起到抑制 TIGIT 傳訊的作用。在一些實施例中，抗 TIGIT 拮抗劑抗體抑制 TIGIT 與其結合配偶體之結合。例示性 TIGIT 結合配偶體 包括 CD155 (PVR)、CD112 (PVRL2 或 Nectin-2) 及 CD113 (PVRL3 或 Nectin‑3)。在一些實施例中，抗 TIGIT 拮抗劑抗體能夠抑制 TIGIT 與 CD155 之間的結合。在一些實施例中，抗 TIGIT 拮抗劑抗體可抑制 TIGIT 與 CD112 之間的結合。在一些實施例中，抗 TIGIT 拮抗劑抗體抑制 TIGIT 與 CD113 之間的結合。在一些實施例中，抗 TIGIT 拮抗劑抗體抑制免疫細胞中 TIGIT 介導的細胞信號傳導。在一些實施例中，抗 TIGIT 拮抗劑抗體藉由消耗調節性 T 細胞 (例如，參與 FcγR 時) 抑制 TIGIT。In some embodiments, the anti-TIGIT antagonist antibody acts to inhibit TIGIT signaling. In some embodiments, the anti-TIGIT antagonist antibody inhibits the binding of TIGIT to its binding partner. Exemplary TIGIT binding partners include CD155 (PVR), CD112 (PVRL2 or Nectin-2), and CD113 (PVRL3 or Nectin-3). In some embodiments, the anti-TIGIT antagonist antibody is capable of inhibiting the binding between TIGIT and CD155. In some embodiments, the anti-TIGIT antagonist antibody can inhibit the binding between TIGIT and CD112. In some embodiments, the anti-TIGIT antagonist antibody inhibits the binding between TIGIT and CD113. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT-mediated cell signaling in an immune cell. In some embodiments, the anti-TIGIT antagonist antibody inhibits TIGIT by depleting regulatory T cells (e.g., when FcγR is engaged).

在一些實施例中，抗 TIGIT 抗體為單株抗體。在一些實施例中，抗 TIGIT 抗體為抗體片段，其選自由以下所組成之群組：Fab、Fab'-SH、Fv、scFv 及 (Fab')₂片段。在一些實施例中，抗 TIGIT 抗體為人源化抗體。在一些實施例中，抗 TIGIT 抗體為人抗體。在一些實施例中，本文所述之抗 TIGIT 抗體與人 TIGIT 結合。在一些實施例中，抗 TIGIT 抗體為 Fc 融合蛋白。In some embodiments, the anti-TIGIT antibody is a monoclonal antibody. In some embodiments, the anti-TIGIT antibody is an antibody fragment selected from the group consisting of: Fab, Fab'-SH, Fv, scFv and (Fab')₂ fragments. In some embodiments, the anti-TIGIT antibody is a humanized antibody. In some embodiments, the anti-TIGIT antibody is a human antibody. In some embodiments, the anti-TIGIT antibody described herein binds to human TIGIT. In some embodiments, the anti-TIGIT antibody is an Fc fusion protein.

在一些實施例中，抗 TIGIT 抗體選自由以下所組成之群組：替瑞利尤單抗 (MTIG7192A、RG6058 或 RO7092284)、維博利單抗 (MK-7684)、ASP8374 (PTZ-201)、EOS884448 (EOS-448)、SEA-TGT (SGN-TGT)、BGB-A1217、BMS-986207 (ONO-4686)、COM902 (CGEN-15137)、IBI939、domvanalimab (AB154)、M6223、AB308、AB154、TJ-T6、MG1131、NB6253、HLX301、HLX53、SL-9258 (TIGIT-Fc-LIGHT)、STW264 及 YBL-012。在一些實施例中，抗 TIGIT 抗體選自由以下所組成之群組：替瑞利尤單抗 (MTIG7192A、RG6058 或 RO7092284)、維博利單抗 (MK-7684)、ASP8374 (PTZ-201)、EOS-448 及 SEA-TGT (SGN-TGT)。抗 TIGIT 抗體可以是替瑞利尤單抗 (MTIG7192A、RG6058 或 RO7092284)。In some embodiments, the anti-TIGIT antibody is selected from the group consisting of tisleliumab (MTIG7192A, RG6058, or RO7092284), vibriolimab (MK-7684), ASP8374 (PTZ-201), EOS884448 (EOS-448), SEA-TGT (SGN-TGT), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), IBI939, domvanalimab (AB154), M6223, AB308, AB154, TJ-T6, MG1131, NB6253, HLX301, HLX53, SL-9258 (TIGIT-Fc-LIGHT), STW264, and YBL-012. In some embodiments, the anti-TIGIT antibody is selected from the group consisting of: tisleliumab (MTIG7192A, RG6058 or RO7092284), vibriostat (MK-7684), ASP8374 (PTZ-201), EOS-448 and SEA-TGT (SGN-TGT). The anti-TIGIT antibody may be tisleliumab (MTIG7192A, RG6058 or RO7092284).

在一些實施例中，抗 TIGIT 抗體包含本文所揭示之抗 TIGIT 抗體中之任一者的至少一個、兩個、三個、四個、五個或六個高度可變區 (HVR)。在一些實施例中，抗 TIGIT 抗體包含本文所揭示之抗 TIGIT 抗體中之任一者的六個 HVR。在一些實施例中，抗 TIGIT 抗體包含選自由以下所組成之群組的抗體中之任一者的六個 HVR：替瑞利尤單抗、ASP8374 (PTZ-201)、BGB-A1217、BMS-986207 (ONO-4686)、COM902 (CGEN-15137)、M6223、IBI939、EOS884448 (EOS-448)、domvanalimab (AB154)、維博利單抗 (MK-7684) 及 SEA-TGT (SGN-TGT)。In some embodiments, the anti-TIGIT antibody comprises at least one, two, three, four, five, or six highly variable regions (HVRs) of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises six HVRs of any of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises six HVRs of any one of the antibodies selected from the group consisting of tisleliumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibriolimab (MK-7684), and SEA-TGT (SGN-TGT).

在一些實施例中，抗 TIGIT 抗體包含重鏈和輕鏈，其中，重鏈包含本文所揭示之抗 TIGIT 抗體中之任一者的重鏈可變區 (VH) 序列，並且輕鏈包含相同抗體的輕鏈可變區 (VL)。在一些實施例中，抗 TIGIT 抗體包含選自由以下所組成之群組的抗 TIGIT 抗體的 VH 及 VL：替瑞利尤單抗、ASP8374 (PTZ-201)、BGB-A1217、BMS-986207 (ONO-4686)、COM902 (CGEN-15137)、M6223、IBI939、EOS884448 (EOS-448)、domvanalimab (AB154)、維博利單抗 (MK-7684) 及 SEA-TGT (SGN-TGT)。In some embodiments, the anti-TIGIT antibody comprises a heavy chain and a light chain, wherein the heavy chain comprises a heavy chain variable region (VH) sequence of any of the anti-TIGIT antibodies disclosed herein, and the light chain comprises a light chain variable region (VL) of the same antibody. In some embodiments, the anti-TIGIT antibody comprises the VH and VL of an anti-TIGIT antibody selected from the group consisting of tisleliumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vibriolimab (MK-7684), and SEA-TGT (SGN-TGT).

在一些實施例中，抗 TIGIT 抗體包含本文揭示的抗 TIGIT 抗體中之任一者的重鏈及輕鏈。在一些實施例中，抗 TIGIT 抗體包含選自由以下所組成之群組的抗 TIGIT 抗體的重鏈及輕鏈：替瑞利尤單抗、ASP8374 (PTZ-201)、BGB-A1217、BMS-986207 (ONO-4686)、COM902 (CGEN-15137)、M6223、IBI939、EOS884448 (EOS-448)、domvanalimab (AB154)、維博利單抗 (MK-7684) 及 SEA-TGT (SGN-TGT)。A.抗TIGIT拮抗劑抗體之給藥In some embodiments, the anti-TIGIT antibody comprises the heavy chain and light chain of any one of the anti-TIGIT antibodies disclosed herein. In some embodiments, the anti-TIGIT antibody comprises the heavy chain and light chain of an anti-TIGIT antibody selected from the group consisting of tisleliumab, ASP8374 (PTZ-201), BGB-A1217, BMS-986207 (ONO-4686), COM902 (CGEN-15137), M6223, IBI939, EOS884448 (EOS-448), domvanalimab (AB154), vilbotrinumab (MK-7684) and SEA-TGT (SGN-TGT).A. Administration ofanti-TIGITantagonist antibodies

作為一般性建議，向患有癌症 (例如，NSCLC) 的個體投予的治療有效量之抗 TIGIT 拮抗劑抗體 (例如，本文所揭露之抗 TIGIT 拮抗劑抗體，例如，替瑞利尤單抗) 在約 0.01 至約 50 mg/kg 個體體重的範圍內，無論藉由一次投予亦是多次投予。在一些實施例中，向個體投予的治療有效量之抗 TIGIT 拮抗劑抗體 (例如，本文所揭露之抗 TIGIT 拮抗劑抗體，例如，替瑞利尤單抗) 在 0.01 至 50 mg/kg 個體體重範圍內，無論藉由一次投予亦是多次投予。As a general proposition, a therapeutically effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tisleliumab) administered to an individual having cancer (e.g., NSCLC) is in the range of about 0.01 to about 50 mg/kg of the individual's body weight, either by a single administration or by multiple administrations. In some embodiments, a therapeutically effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tisleliumab) administered to an individual is in the range of 0.01 to 50 mg/kg of the individual's body weight, either by a single administration or by multiple administrations.

例如，在 PCT 申請公開號 WO 2021/154761 中提供了抗 TIGIT 拮抗劑抗體的示例性劑量及給藥方案，該 PCT 申請公開以全文引用的方式併入本文。For example, exemplary dosages and dosing regimens for anti-TIGIT antagonist antibodies are provided in PCT Application Publication No. WO 2021/154761, which is incorporated herein by reference in its entirety.

在一些實例中，抗 TIGIT 拮抗劑抗體 (例如，如本文所揭示的抗 TIGIT 拮抗劑抗體，例如，替瑞利尤單抗) 在給藥週期之約第 1 天 (例如，第 -3 天、第 -2 天、第 -1 天、第 1 天、第 2 天或第 3 天) 投予。In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tisleliumab) is administered on about day 1 (e.g., day -3, day -2, day -1, day 1, day 2, or day 3) of a dosing cycle.

在一些實例中，有效量之抗 TIGIT 拮抗劑抗體 (例如，如本文所揭示之抗 TIGIT 拮抗劑抗體，例如替瑞利尤單抗) 為每四週約 840 mg 的固定劑量 (例如，每四週 840 mg ± 10 mg，例如 840 ± 6 mg、例如 840 ± 5 mg、例如 840 ± 3 mg、例如 840 ± 1 mg、例如 840 ± 0.5 mg、例如 840 mg)。In some examples, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tisleliumab) is a fixed dose of about 840 mg every four weeks (e.g., 840 mg ± 10 mg, e.g., 840 ± 6 mg, e.g., 840 ± 5 mg, e.g., 840 ± 3 mg, e.g., 840 ± 1 mg, e.g., 840 ± 0.5 mg, e.g., 840 mg every four weeks).

在一些實例中，有效量之抗 TIGIT 拮抗劑抗體 (例如，如本文所揭示之抗 TIGIT 拮抗劑抗體，例如替瑞利尤單抗) 為每三週約 600 mg 的固定劑量。在一些實例中，有效量之抗 TIGIT 拮抗劑抗體 (例如，如本文所揭示之抗 TIGIT 拮抗劑抗體，例如替瑞利尤單抗) 為每三週 600 mg 的固定劑量。In some instances, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tisleliumab) is a fixed dose of about 600 mg every three weeks. In some instances, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tisleliumab) is a fixed dose of 600 mg every three weeks.

在一些實例中，有效量之抗 TIGIT 拮抗劑抗體 (例如，如本文所揭示之抗 TIGIT 拮抗劑抗體，例如替瑞利尤單抗) 為每兩週約 420 mg 的固定劑量 (例如，每兩週 420 mg ± 10 mg，例如 420 ± 6 mg、例如 420 ± 5 mg、例如 420 ± 3 mg、例如 420 ± 1 mg、例如 420 ± 0.5 mg、例如 420 mg)。In some instances, an effective amount of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tisleliumab) is a fixed dose of about 420 mg every two weeks (e.g., 420 mg ± 10 mg, e.g., 420 ± 6 mg, e.g., 420 ± 5 mg, e.g., 420 ± 3 mg, e.g., 420 ± 1 mg, e.g., 420 ± 0.5 mg, e.g., 420 mg every two weeks).

在一些實例中，抗 TIGIT 拮抗劑抗體 (例如，如本文揭示的抗 TIGIT 拮抗劑抗體，例如，替瑞利尤單抗) 係靜脈內投予。可替代地，在一些實施例中，抗 TIGIT 拮抗劑抗體 (例如，本文所揭示之抗 TIGIT 拮抗劑抗體，例如，替瑞利尤單抗) 經皮下投予。在一些實例中，替瑞利尤單抗係每 2 週以約 420 mg 的劑量、每 3 週以約 600 mg 的劑量或每 4 週以約 840 mg 的劑量向個體靜脈內投予。在一些實例中，替瑞利尤單抗係每 2 週以 420 mg 的劑量、每 3 週以 600 mg 的劑量或每 4 週以 840 mg 的劑量向個體靜脈內投予。In some examples, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tisleliumab) is administered intravenously. Alternatively, in some embodiments, an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody disclosed herein, e.g., tisleliumab) is administered subcutaneously. In some examples, tisleliumab is administered intravenously to a subject at a dose of about 420 mg every 2 weeks, at a dose of about 600 mg every 3 weeks, or at a dose of about 840 mg every 4 weeks. In some instances, tisleliumab is administered intravenously to a subject at a dose of 420 mg every 2 weeks, at a dose of 600 mg every 3 weeks, or at a dose of 840 mg every 4 weeks.

在一些實例中，向個體投予抗 TIGIT 拮抗劑抗體 (例如，如本文所揭示之抗 TIGIT 拮抗劑抗體，例如，替瑞利尤單抗) 的總共 1 至 60 劑，例如，1、2、3、4，5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、36、37、38、39、40、41、42、43、44、45、46、47、48、49、50、51、52、53、54、55、56、57、58、59 或 60 劑。在一些實例中，向個體投予抗 TIGIT 拮抗劑抗體 (例如，如本文所揭示之抗 TIGIT 拮抗劑抗體，例如，替瑞利尤單抗) 的總共 1 至 60 劑，例如，1 至 60 劑、1 至 55 劑、1 至 50 劑、1 至 45 劑、1 至 40 劑、1 至 35 劑、1 至 30 劑、1 至 25 劑、1 至 20 劑、1 至 15 劑、1 至 10 劑、1 至 5 劑、2 至 60 劑、2 至 55 劑、2 至 50 劑、2 至 45 劑、2 至 40 劑、2 至 35 劑、2 至 30 劑、2 至 25 劑、2 至 20 劑、2 至 15 劑、2 至 10 劑、2 至 5 劑、3 至 60 劑、3 至 55 劑、3 至 50 劑、3 至 45 劑、3 至 40 劑、3 至 35 劑、3 至 30 劑、3 至 25 劑、3 至 20 劑、3 至 15 劑、3 至 10 劑、3 至 5 劑、4 至 60 劑、4 至 55 劑、4 至 50 劑、4 至 45 劑、4 至 40 劑、4 至 35 劑、4 至 30 劑、4 至 25 劑、4 至 20 劑、4 至 15 劑、4 至 10 劑、4 至 5 劑、5 至 60 劑、5 至 55 劑、5 至 50 劑、5 至 45 劑、5 至 40 劑、5 至 35 劑、5 至 30 劑、5 至 25 劑、5 至 20 劑、5 至 15 劑、5 至 10 劑、10 至 60 劑、10 至 55 劑、10 至 50 劑、10 至 45 劑、10 至 40 劑、10 至 35 劑、10 至 30 劑、10 至 25 劑、10 至 20 劑、10 至 15 劑、15 至 60 劑、15 至 55 劑、15 至 50 劑、15 至 45 劑、15 至 40 劑、15 至 35 劑、15 至 30 劑、15 至 25 劑、15 至 20 劑、20 至 60 劑、20 至 55 劑、20 至 50 劑、20 至 45 劑、20 至 40 劑、20 至 35 劑、20 至 30 劑、20 至 25 劑、25 至 60 劑、25 至 55 劑、25 至 50 劑、25 至 45 劑、25 至 40 劑、25 至 35 劑、25 至 30 劑、30 至 60 劑、30 至 55 劑、30 至 50 劑、30 至 45 劑、30 至 40 劑、30 至 35 劑、35 至 60 劑、35 至 55 劑、35 至 50 劑、35 至 45 劑、35 至 40 劑、40 至 60 劑、40 至 55 劑、40 至 50 劑、40 至 45 劑、45 至 50 劑、50 至 60 劑或 55 至 60 劑。在特定實例中，劑量可係靜脈內投予。In some instances, a total of 1 to 60 doses of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tisleliumab) is administered to a subject, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 In some examples, a total of 1 to 60 doses of an anti-TIGIT antagonist antibody (e.g., an anti-TIGIT antagonist antibody as disclosed herein, e.g., tisleliumab) is administered to a subject, e.g., 1 to 60 doses, 1 to 55 doses, 1 to 50 doses, 1 to 45 doses, 1 to 40 doses, 1 to 35 doses, 1 to 30 doses, 1 to 25 doses, 1 to 20 doses, 1 to 15 doses, 1 to 10 doses, 1 to 5 doses, 2 to 60 doses, 2 to 55 doses, 2 to 50 doses, 2 to 45 doses dose, 2 to 40 doses, 2 to 35 doses, 2 to 30 doses, 2 to 25 doses, 2 to 20 doses, 2 to 15 doses, 2 to 10 doses, 2 to 5 doses, 3 to 60 doses, 3 to 55 doses, 3 to 50 doses, 3 to 45 doses, 3 to 40 doses, 3 to 35 doses, 3 to 30 doses, 3 to 25 doses, 3 to 20 doses, 3 to 15 doses, 3 to 10 doses, 3 to 5 doses, 4 to 60 doses, 4 to 55 doses, 4 4 to 50 doses, 4 to 45 doses, 4 to 40 doses, 4 to 35 doses, 4 to 30 doses, 4 to 25 doses, 4 to 20 doses, 4 to 15 doses, 4 to 10 doses, 4 to 5 doses, 5 to 60 doses, 5 to 55 doses, 5 to 50 doses, 5 to 45 doses, 5 to 40 doses, 5 to 35 doses, 5 to 30 doses, 5 to 25 doses, 5 to 20 doses, 5 to 15 doses, 5 to 10 doses, 10 to 60 doses, 10 to 55 doses, 10 to 50 doses, 10 to 45 doses, 10 to 40 doses, 10 to 35 doses, 10 to 30 doses, 10 to 25 doses, 10 to 20 doses, 10 to 15 doses, 15 to 60 doses, 15 to 55 doses, 15 to 50 doses, 15 to 45 doses, 15 to 40 doses, 15 to 35 doses, 15 to 30 doses, 15 to 25 doses, 15 to 20 doses, 20 to 60 doses, 20 to 55 doses, 20 to 50 dose, 20 to 45 doses, 20 to 40 doses, 20 to 35 doses, 20 to 30 doses, 20 to 25 doses, 25 to 60 doses, 25 to 55 doses, 25 to 50 doses, 25 to 45 doses, 25 to 40 doses, 25 to 35 doses, 25 to 30 doses, 30 to 60 doses, 30 to 55 doses, 30 to 50 doses, 30 to 45 doses, 30 to 40 doses, 30 to 35 doses, 35 to 60 doses, 35 to 55 doses dose, 35 to 50 doses, 35 to 45 doses, 35 to 40 doses, 40 to 60 doses, 40 to 55 doses, 40 to 50 doses, 40 to 45 doses, 45 to 50 doses, 50 to 60 doses, or 55 to 60 doses. In certain examples, the dose may be administered intravenously.

抗 TIGIT 拮抗劑抗體可以本領域已知的任何合適方式投予。在一些實例中，抗 TIGIT 拮抗劑抗體在給藥週期之約第 1 天 (例如，第 -3 天、第 -2 天、第 -1 天、第 1 天、第 2 天或第 3 天) 投予。在一些實例中，抗 TIGIT 拮抗劑抗體可以在同一天投予。在一些實例中，PD-1 軸結合拮抗劑靜脈內、肌內、皮下、局部、口服、經皮、腹膜內、眶內、藉由植入、藉由吸入、鞘內腔、心室內或鼻內投予。在一些實例中，抗 TIGIT 拮抗劑抗體係靜脈內投予。在一些實例中，抗 TIGIT 拮抗劑抗體係靜脈內、肌內、皮下、局部、口服、經皮、腹膜內、眶內、藉由植入、藉由吸入、鞘內腔、心室內或鼻內投予。在一些實例中，抗 TIGIT 拮抗劑抗體係靜脈內投予。在一些實例中，在投予抗 TIGIT 拮抗劑抗體之後存在第一觀察期。在一些實例中，該觀察期的長度介於約 30 分鐘至約 60 分鐘之間。在一些實例中，抗 TIGIT 拮抗劑抗體係靜脈內或皮下投予。The anti-TIGIT antagonist antibody can be administered in any suitable manner known in the art. In some instances, the anti-TIGIT antagonist antibody is administered on about day 1 (e.g., day -3, day -2, day -1, day 1, day 2, or day 3) of the dosing cycle. In some instances, the anti-TIGIT antagonist antibody can be administered on the same day. In some instances, the PD-1 axis binding antagonist is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the anti-TIGIT antagonist antibody is administered intravenously. In some instances, the anti-TIGIT antagonist antibody is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. In some instances, the anti-TIGIT antagonist antibody is administered intravenously. In some instances, there is a first observation period following administration of the anti-TIGIT antagonist antibody. In some instances, the length of the observation period is between about 30 minutes and about 60 minutes. In some instances, the anti-TIGIT antagonist antibody is administered intravenously or subcutaneously.

在一個實例中，替瑞利尤單抗可以靜脈內投予超過 60 分鐘；如果可以耐受第一輸注，則所有後續輸注可以遞送超過 30 分鐘。In one example, tisleliumab can be administered intravenously over 60 minutes; if the first infusion can be tolerated, all subsequent infusions can be delivered over 30 minutes.

在前述實例中之任一者中，各給藥週期可具有任何合適的長度，例如，約 7 天 (約 5、6、7、8 或 9 天)、約 14 天 (例如，約 12、13、14、15 或 16 天)、約 21 天 (例如，約 18、19、20、21、22、23 或 24 天)、約 28 天 (約 25、26、27、28、29、30 或 31 天) 或更長時間。在一些實例中，各給藥週期為約 21 天。V.醫藥組成物、調配物及套組In any of the foregoing examples, each dosing cycle can have any suitable length, for example, about 7 days (about 5, 6, 7, 8 or 9 days), about 14 days (e.g., about 12, 13, 14, 15 or 16 days), about 21 days (e.g., about 18, 19, 20, 21, 22, 23 or 24 days), about 28 days (about 25, 26, 27, 28, 29, 30 or 31 days) or longer. In some examples, each dosing cycle is about 21 days.V.Pharmaceutical Compositions, Formulations and Kits

本文所述的抗癌劑中之任一者 (例如，PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及/或抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗)) 可用於醫藥組成物及調配物。PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及/或抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 之醫藥組成物及調配物可藉由將具有所需純度之一種或兩種藥劑與一種或多種視情況之醫藥上可接受之載劑混合來製備 (Remington's Pharmaceutical Sciences第 16 版，Osol, A. 編輯 (1980))，呈凍乾調配物或水溶液的形式。醫藥上可接受之載劑在採用的劑量及濃度下通常對受體無毒，其包括但不限於：緩衝劑，諸如磷酸鹽、檸檬酸鹽及其他有機酸；抗氧化劑，包括抗壞血酸及甲硫胺酸；防腐劑 (諸如十八烷基二甲基芐基氯化銨；氯化六甲雙銨；氯化苯銨；氯化本索寧；苯酚、丁醇或芐醇；對羥基苯甲酸烷基酯諸如對羥基苯甲酸甲酯或對羥基苯甲酸丙酯；兒茶酚；間苯二酚；環己醇；3-戊醇及間甲酚)；低分子量 (小於約 10 個殘基) 多肽；蛋白質，諸如血清白蛋白、明膠或免疫球蛋白；親水性聚合物，諸如聚乙烯吡咯啶酮；胺基酸，諸如甘胺酸、麩醯胺酸、天冬醯胺酸、組胺酸、精胺酸或離胺酸；單醣、二醣及其他碳水化合物，包括葡萄糖、甘露糖或糊精；螯合劑，諸如 EDTA；糖，諸如蔗糖、甘露醇、海藻糖或山梨糖醇；成鹽相對離子，諸如鈉；金屬錯合物 (例如，鋅蛋白錯合物)；及/或非離子界面活性劑，諸如聚乙二醇 (PEG)。本文中示例性醫藥上可接受之載劑進一步包括間質藥物分散劑，例如可溶性中性活性透明質酸酶糖蛋白 (sHASEGP)，例如人類可溶性 PH-20 透明質酸酶糖蛋白，諸如 rHuPH20 (HYLENEX^®，Baxter International, Inc.)。某些例示性 sHASEGP 及使用方法 (包括 rHuPH20) 描述於美國專利公開號 2005/0260186 及 2006/0104968 中。在一個態樣中，sHASEGP 與一種或多種額外的糖胺聚醣酶諸如軟骨素酶結合在一起。Any of the anticancer agents described herein (e.g., PD-1 axis binding antagonists (e.g., atezolizumab) and/or anti-TIGIT antagonist antibodies (e.g., tisleliumab)) can be used in pharmaceutical compositions and formulations. Pharmaceutical compositions and formulations of PD-1 axis binding antagonists (e.g., atezolizumab) and/or anti-TIGIT antagonist antibodies (e.g., tisleliumab) can be prepared by mixing one or both agents having the desired purity with one or more pharmaceutically acceptable carriers as appropriate (Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed. (1980)), in the form of a lyophilized formulation or an aqueous solution. Pharmaceutically acceptable carriers are generally nontoxic to the recipient at the dosages and concentrations employed and include, but are not limited to: buffers such as phosphates, citrates and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzylammonium chloride; hexadecene diammonium chloride; benzoammonium chloride; benzathonine chloride; phenol, butyl alcohol or benzyl alcohol; alkyl parabens such as methyl paraben or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspartic acid, histidine, arginine or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter ions such as sodium; metal complexes (e.g., zinc protein complexes); and/or non-ionic surfactants such as polyethylene glycol (PEG). Exemplary pharmaceutically acceptable carriers herein further include interstitial drug dispersions, such as soluble neutral active hyaluronidase glycoproteins (sHASEGP), such as human soluble PH-20 hyaluronidase glycoproteins, such as rHuPH20 (^HYLENEX® , Baxter International, Inc.). Certain exemplary sHASEGPs and methods of use (including rHuPH20) are described in U.S. Patent Publication Nos. 2005/0260186 and 2006/0104968. In one aspect, sHASEGP is conjugated to one or more additional glycosaminoglycans, such as chondroitinase.

例示性凍乾抗體調配物如美國專利號 6,267,958 所述。水性抗體調配物包括美國專利第 6,171,586 號及 PCT 申請公開號 WO 2006/044908 中所述之調配物，後者調配物包括組胺酸-乙酸鹽緩衝液。Exemplary lyophilized antibody formulations are described in U.S. Patent No. 6,267,958. Aqueous antibody formulations include those described in U.S. Patent No. 6,171,586 and PCT Application Publication No. WO 2006/044908, the latter formulation comprising a histidine-acetate buffer.

示例性阿替利珠單抗調配物包含冰醋酸、L-組胺酸、聚山梨酯 20 及蔗糖，其 pH 值為 5.8。例如，阿替利珠單抗可在包含 1200 mg 阿替利珠單抗的 20 mL 小瓶中提供，該阿替利珠單抗係經調配於冰乙酸 (16.5 mg)、L-組胺酸 (62 mg)、聚山梨酸酯 20 (8 mg) 及蔗糖 (821.6 mg) 中，其 pH 為 5.8。在另一實例中，阿替利珠單抗可在包含 840mg 阿替利珠單抗的 14 mL 小瓶中提供，該阿替利珠單抗係經調配於冰醋酸 (11.5mg)、L-組胺酸 (43.4mg)、聚山梨酸酯 20 (5.6mg) 及蔗糖 (575.1mg) 中，其 pH 為 5.8。Exemplary atezolizumab formulations include glacial acetic acid, L-histidine, polysorbate 20, and sucrose at a pH of 5.8. For example, atezolizumab can be provided in a 20 mL vial containing 1200 mg of atezolizumab formulated in glacial acetic acid (16.5 mg), L-histidine (62 mg), polysorbate 20 (8 mg), and sucrose (821.6 mg) at a pH of 5.8. In another example, atezolizumab can be provided in a 14 mL vial containing 840 mg of atezolizumab formulated in glacial acetic acid (11.5 mg), L-histidine (43.4 mg), polysorbate 20 (5.6 mg), and sucrose (575.1 mg) at a pH of 5.8.

例示性替瑞利尤單抗調配物包含含有聚山梨酸酯 20、蔗糖、L-甲硫胺酸及 WFI 的組胺酸溶液。替瑞利尤單抗可以在 15 mL 小瓶中提供，該小瓶包含 10 mL 替瑞利尤單抗藥品，替瑞利尤單抗抗體的近似濃度為 60 mg/mL。An exemplary tisleliumab formulation comprises a histidine solution containing polysorbate 20, sucrose, L-methionine, and WFI. Tisleliumab can be provided in a 15 mL vial containing 10 mL of tisleliumab drug product, with an approximate concentration of tisleliumab antibody of 60 mg/mL.

本文所述之調配物還可含有適合於所治療的特定適應症的多於一種活性成分，較佳地，為那些相互無不利影響的具有互補活性成分。例如，可能需要進一步提供額外治療劑。此等活性成分適宜地以對預期目的有效的量組合存在。The formulations described herein may also contain more than one active ingredient suitable for the specific indication to be treated, preferably, those having complementary active ingredients that do not adversely affect each other. For example, it may be necessary to further provide an additional therapeutic agent. These active ingredients are suitably present in combination in an amount effective for the intended purpose.

活性成分可以包載在例如藉由凝聚技術或藉由介面聚合製備的微囊 (例如，分別為羥甲基纖維素微囊或明膠微囊及聚(甲基丙烯酸甲酯)微囊) 中、膠體藥物遞送系統 (例如脂質體、白蛋白微球、微乳、奈米顆粒及奈米囊 (nanocapsule)) 中或粗滴乳狀液中。此等技術揭示於Remington's Pharmaceutical Sciences(第 16 版，Osol, A. 主編，1980)。The active ingredient can be entrapped in microcapsules (e.g., hydroxymethylcellulose microcapsules or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively) prepared, for example, by coacervation techniques or by interfacial polymerization, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles and nanocapsules), or in macroemulsions. Such techniques are disclosed inRemington's Pharmaceutical Sciences (16th edition, Osol, A. ed., 1980).

可以製備緩釋製劑。持續釋放製劑的適宜的實例包括含有抗體的固體疏水聚合物的半透性基質，該基質是成形物品的形式，例如，膜或微囊。欲用於活體內投予之調配物通常係無菌的。無菌性可以易於例如藉由透過無菌濾膜過濾來實現。Sustained release formulations can be prepared. Suitable examples of sustained release formulations include semipermeable matrices of solid hydrophobic polymers containing the antibody, which are in the form of shaped articles, e.g., films or microcapsules. Formulations intended forintravital administration are generally sterile. Sterility can be readily achieved, for example, by filtration through a sterile filter membrane.

在一些態樣中，本發明提供套組，其包括 (a) PD-1 軸結合拮抗劑，其使用於與抗 TIGIT 拮抗劑抗體組合，(b) 抗 TIGIT 拮抗劑抗體，其使用於與 PD-1 軸結合拮抗劑組合，或 (c) PD-1 軸結合拮抗劑及抗 TIGIT 拮抗劑抗體，其用於根據本文所述的方法中之任一者治療患有癌症 (例如，非小細胞肺癌 (NSCLC)) 的個體。在一些實例中，製品或套組進一步包含包裝插頁，該包裝插頁包含使用以下的說明：(a) PD-1 軸結合拮抗劑，其與抗 TIGIT 拮抗劑抗體組合，(b) 抗 TIGIT 拮抗劑抗體，其與 PD-1 軸結合拮抗劑組合，或 (c) PD-1 軸結合拮抗劑及抗 TIGIT 拮抗劑抗體，其用於治療患者的癌症 (例如，NSCLC) 或延遲其進展。In some embodiments, the present invention provides a kit comprising (a) a PD-1 axis binding antagonist for use in combination with an anti-TIGIT antagonist antibody, (b) an anti-TIGIT antagonist antibody for use in combination with a PD-1 axis binding antagonist, or (c) a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody for use in treating an individual having cancer (e.g., non-small cell lung cancer (NSCLC)) according to any of the methods described herein. In some examples, the article of manufacture or kit further comprises a package insert comprising instructions for using: (a) a PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody, (b) an anti-TIGIT antagonist antibody in combination with a PD-1 axis binding antagonist, or (c) a PD-1 axis binding antagonist and an anti-TIGIT antagonist antibody for treating or delaying the progression of cancer (e.g., NSCLC) in a patient.

因此，在一些態樣中，本發明提供了套組，其包括 (a) 阿替利珠單抗，其使用於與替瑞利尤單抗組合，(b) 替瑞利尤單抗，其使用於與阿替利珠單抗組合，或 (c) 阿替利珠單抗及替瑞利尤單抗，其用於根據本文所述的方法中之任一者治療患有癌症 (例如，NSCLC) 的個體。在一些實例中，製品或套組進一步包含包裝插頁，該包裝插頁包含使用以下的說明：(a) 阿替利珠單抗，其與替瑞利尤單抗組合，(b) 替瑞利尤單抗，其與阿替利珠單抗組合，或 (c) 阿替利珠單抗及替瑞利尤單抗，其用於治療患者的癌症 (例如，NSCLC) 或延遲其進展。Thus, in some aspects, the invention provides a kit comprising (a) atezolizumab for use in combination with tisleliumab, (b) tisleliumab for use in combination with atezolizumab, or (c) atezolizumab and tisleliumab for use in treating an individual having cancer (e.g., NSCLC) according to any of the methods described herein. In some instances, the article of manufacture or kit further comprises a package insert comprising instructions for use of (a) atezolizumab in combination with tisleliumab, (b) tisleliumab in combination with atezolizumab, or (c) atezolizumab and tisleliumab for use in treating or delaying the progression of cancer (e.g., NSCLC) in a patient.

在一些實例中，PD-1 軸結合拮抗劑 (例如，阿替利珠單抗) 及抗 TIGIT 拮抗劑抗體 (例如，替瑞利尤單抗) 在同一容器或單獨的容器中。適合的容器包括例如瓶、小瓶、袋及注射器。容器可由多種材料形成，諸如玻璃、塑膠 (諸如聚氯乙烯或聚烯烴) 或金屬合金 (諸如不鏽鋼或赫史特合金 (hastelloy))。在一些實例中，容器保持調配物，並且在容器上或與容器相關聯的標籤可指示使用方向。製品或套組可進一步包括自商業及使用者角度來看需要之其他材料，包括其他緩衝劑、稀釋劑、過濾器、針、注射器及具有使用說明之藥品仿單。在一些實例中，製品還包括一種或多種其他試劑 (例如，額外化學治療劑或抗腫瘤劑)。用於一種或多種藥劑之適合容器包括例如瓶、小瓶、袋及注射器。VI.實例實例1：一項在具有完全切除的IIB期、IIIA期或選定的IIIB期PD-L1陽性非小細胞肺癌且已接受輔助鉑類化學療法的參與者中替瑞利尤單抗加阿替利珠單抗與安慰劑加阿替利珠單抗相比的III期、隨機、雙盲研究In some instances, the PD-1 axis binding antagonist (e.g., atezolizumab) and the anti-TIGIT antagonist antibody (e.g., tisleliumab) are in the same container or in separate containers. Suitable containers include, for example, bottles, vials, bags, and syringes. The container may be formed from a variety of materials, such as glass, plastics (such as polyvinyl chloride or polyolefins) or metal alloys (such as stainless steel or hastelloy). In some instances, the container holds the formulation, and a label on or associated with the container may indicate directions for use. The article or kit may further include other materials desirable from a commercial and user perspective, including other buffers, diluents, filters, needles, syringes, and a drug leaflet with instructions for use. In some examples, the article of manufacture also includes one or more other agents (e.g., additional chemotherapeutic agents or anti-neoplastic agents). Suitable containers for one or more agents include, for example, bottles, vials, bags, and syringes.VI.ExamplesExample1: A Phase III, randomized, double-blind study of tisleliumab plus atezolizumab versus placebo plus atezolizumab in participants with completely resected stageIIB, stageIIIA ,or selectedstageIIIBPD-L1 -positive non-smallcell lungcancerwho had received adjuvant platinum-based chemotherapy

GO45006 係一項 III 期、隨機、雙盲、全球、多中心研究，旨在評估在切除及輔助鉑類化學療法後向參與者投予的替瑞利尤單抗加阿替利珠單抗與安慰劑加阿替利珠單抗相比的療效、安全性及藥物動力學，該參與者具有 PD-L1 陽性 (使用研究性 VENTANA PD-L1 (SP263) CDx 測定法判定的任何膜染色高於背景的腫瘤細胞百分比 ≥1% (≥1% TC)) 的 IIB 期、IIIA 期或選定的 IIIB 期 (僅 T3N2) 非小細胞肺癌 (NSCLC)。GO45006 is a Phase III, randomized, double-blind, global, multicenter study designed to evaluate the efficacy, safety, and pharmacokinetics of tisleliumab plus atezolizumab compared with placebo plus atezolizumab administered after resection and adjuvant platinum-based chemotherapy in participants with Stage IIB, IIIA, or selected Stage IIIB (T3N2 only) non-small cell lung cancer (NSCLC) that is PD-L1 positive (any percentage of tumor cells with membrane staining ≥1% above background (≥1% TC) as determined using the investigational VENTANA PD-L1 (SP263) CDx assay).

NSCLC 分期依據美國癌症聯合委員會 (AJCC)/國際抗癌聯盟 (UICC) 非小細胞肺癌 (NSCLC) 分期，第 8 版 (AJCC 第 8 版 (Detterbeck 等人,Chest, 151: 193-203, 2017) 確定；參見例如本文表 4)。T3N2 IIIB 期 NSCLC 係其中原發性腫瘤為 T3 (亦即，最大尺寸 ＞ 5 cm 但 ≤ 7 cm，或伴隨與原發性腫瘤位於同一肺葉中的單獨腫瘤結節，或直接侵犯以下結構中之任一者：胸壁 (包括壁層胸膜及上溝腫瘤)、膈神經及壁層心包) 且淋巴結狀態為 N2 (亦即，區域淋巴結累及的特徵係同側縱隔及/或隆突下淋巴結轉移) 之 NSCLC。表4.AJCC/UICC非小細胞肺癌分期，第8版T：原發性腫瘤Tx原發性腫瘤無法評定，或腫瘤藉由痰或支氣管沖洗液中存在惡性細胞來證明，但無法藉由影像或支氣管鏡檢查來觀察。T0無原發性腫瘤證據。Tis原位癌T1 T1a(mi) T1a T1b T1c腫瘤最大尺寸 ≤ 3 cm，被肺或臟層胸膜包圍，沒有支氣管鏡檢查證據顯示比肺葉支氣管更近端的侵犯 (亦即不在主支氣管中^a微創腺癌^b腫瘤最大尺寸 ≤ 1 cm^a腫瘤最大尺寸 ＞ 1 cm 但 ≤ 2 cm^a腫瘤最大尺寸 ＞ 2 cm 但 ≤ 3 cm^aT2 T2a T2b腫瘤 ＞ 3 cm 但 ≤ 5 cm 且有以下特徵中之任一者^c： •  涉及主支氣管，無論與隆突的距離如何，但不累及隆突 •  侵犯髒層胸膜 •  伴隨延伸至肺門區，涉及部分或全部肺的肺不張或阻塞性肺炎 腫瘤最大尺寸 ＞ 3 cm 但 ≤ 4 cm 腫瘤最大尺寸 ＞ 4 cm 但 ≤ 5 cmT3腫瘤最大尺寸 ＞ 5 cm 但 ≤ 7 cm，或伴隨與原發性腫瘤位於同一肺葉內的單獨腫瘤結節，或直接侵犯以下結構中之任一者：胸壁 (包括壁層胸膜及上溝腫瘤)，膈神經、壁層心包。T4腫瘤最大尺寸 ＞ 7 cm，或伴隨與原發性腫瘤不同的同側肺葉中的單獨腫瘤結節，或侵犯以下結構中之任一者：橫膈膜、縱膈、心臟、大血管、氣管、喉返神經、食道、椎體及隆突N：區域淋巴結累及Nx無法評定區域淋巴結N0無區域淋巴結轉移N1同側支氣管周圍及/或同側肺門淋巴結及肺內淋巴結轉移，包括直接延伸累及N2同側縱膈及/或隆突下淋巴結轉移N3對側縱膈、對側肺門、同側或對側斜角肌或鎖骨上淋巴結轉移M：遠端轉移M0無遠端轉移M1 M1a M1b M1c存在遠端轉移 對側肺葉中的單獨腫瘤結節；腫瘤伴隨胸膜或心包結節或惡性胸膜或心包積液^d單發胸外轉移瘤^e一個或多個器官的多發性胸外轉移^a任何大小的罕見淺表擴散腫瘤，其侵襲成分限於支氣管壁，可能延伸至主支氣管近端，亦被歸類為 T1a。^b孤立性腺癌，≤ 3 cm，主要呈鱗屑狀，且任一病灶侵犯 ≤ 5 mm。^c如果最大尺寸 ≤ 4 cm 或大小無法判定，則具有這些特徵的 T2 腫瘤分類為 T2a；且如果最大尺寸 ＞ 4 cm 但 ≤ 5 cm，則分類為 T2b。^d大多數肺癌胸腔 (心包) 積液是由腫瘤引起的。然而，在少數患者中，胸腔 (心包膜) 積液的多次顯微鏡檢查對腫瘤呈陰性，且流體不是含血的且不是滲出液。當這些要素及臨床判斷顯示積液與腫瘤無關時，應將積液作為分期描述符排除。^e這包括單一遠端 (非區域) 淋巴結累及。N 類總分期第 7 版描述符建議的 T/MN0N1N2N3T1 ≤ 1 cmT1aIA1(IA)IIB(IIA)IIIAIIIBT1 ＞ 1-2 cmT1bIA2(IA)IIB(IIA)IIIAIIIBT1 ＞ 2-3 cmT1cIA3(IA)IIB(IIA)IIIAIIIBT2 ＞ 3-4 cmT2aIBIIB(IIA)IIIAIIIBT2 ＞ 4-5 cmT2bIIA(IB)IIB(IIA)IIIAIIIBT2 ＞ 5-7 cmT3IIB(IIA)IIIA(IIB)IIIB(IIIA)IIIC(IIIB)T3 結構T3IIBIIIAIIIB(IIIA)IIIC(IIIB)T3 ＞ 7 cmT4IIIA(IIB)IIIAIIIB(IIIA)IIIC(IIIB)T3 橫膈膜T4IIIA(IIB)IIIAIIIB(IIIA)IIIC(IIIB)T3 支氣管內：位置/肺不張 3-4 cmT2aIB(IIB)IIB(IIIA)IIIAIIIBT3 支氣管內：位置/肺不張 4-5 cmT2bIIA(IIB)IIB(IIIA)IIIAIIIBT4T4IIIAIIIAIIIBIIIC(IIIB)M1aM1aIVA(IV)IVA(IV)IVA(IV)IVA(IV)M1b 單病灶M1bIVA(IV)IVA(IV)IVA(IV)IVA(IV)M1c 多發性病灶M1cIVB(IV)IVB(IV)IVB(IV)IVB(IV)當有變化時，第八版提議的最終階段分組為粗體，且第七版的分期在括號內給出。NSCLC staging is determined according to the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) non-small cell lung cancer (NSCLC) staging, 8th edition (AJCC 8th edition (Detterbeck et al.,Chest , 151: 193-203, 2017); see, e.g., Table 4 herein). T3N2 Stage IIIB NSCLC is NSCLC in which the primary tumor is T3 (i.e., > 5 cm but ≤ 7 cm in greatest dimension, or is associated with a separate tumor nodule in the same lobe as the primary tumor, or directly invades any of the following structures: chest wall (including parietal pleura and superior sulcus tumor), phrenic nerve, and parietal pericardium) and the lymph node status is N2 (i.e., regional lymph node involvement is characterized by metastasis to the ipsilateral diaphragmatic and/or subcarinal lymph nodes).Table4. AJCC/UICCStaging of Non-Small Cell Lung Cancer,8thEdition T: primary tumor Tx The primary tumor cannot be assessed or the tumor is evidenced by the presence of malignant cells in sputum or bronchial washings but cannot be seen by imaging or bronchoscopy. T0 There was no evidence of primary tumor. Tis Carcinoma in situ T1 T1a(mi) T1a T1b T1c Tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura, with no bronchoscopic evidence of invasion more proximally than^a lobar bronchus (i.e., not in a mainstem bronchus)aMinimally invasive^{adenocarcinomabTumor} ≤ 1 cm in greatest dimension^aTumor > 1 cm but ≤ 2 cm in greatest dimension^aTumor > 2 cm but ≤ 3 cm in greatest dimension^a T2 T2a T2b Tumor > 3 cm but ≤ 5 cm with any of the following featuresc^: • Involvement of a mainstem bronchus, regardless of distance from the carina, but not the carina • Invasion of the pleura • Accompanied by atelectasis or obstructive pneumonia extending to the hilar region, involving part or all of the lung Tumor > 3 cm but ≤ 4 cm in greatest dimension Tumor > 4 cm but ≤ 5 cm in greatest dimension T3 The tumor is greater than 5 cm but less than 7 cm in its greatest dimension, or is associated with a separate tumor nodule in the same lobe as the primary tumor, or directly invades any of the following structures: chest wall (including parietal pleura and superior sulcus tumor), phrenic nerve, or parietal pericardium. T4 Tumor > 7 cm in greatest dimension, or associated with a separate tumor nodule in a different ipsilateral lobe from the primary tumor, or invasion of any of the following structures: diaphragm, diaphragm, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, and carina N: Regional lymph node involvement Nx Unable to assess regional lymph nodes N0 No regional lymph node metastasis N1 Metastasis to ipsilateral peribronchial and/or ipsilateral hilar and intrapulmonary lymph nodes, including direct extension N2 Ipsilateral diaphragmatic and/or subcarinal lymph node metastasis N3 Metastasis to the contralateral diaphragmatic, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph nodes M: Remote transfer M0 No remote transfer M1 M1a M1b M1c Presence of distant metastasis: a single tumor nodule in the opposite lobe; tumor with associated pleural or pericardial nodules or malignant pleural or pericardial effusions;^d single extrathoracic metastasis^{; e} multiple extrathoracic metastases to one or more organs^aRare superficial spreading tumors of any size with an invasive component limited to the bronchial wall and possibly extending proximally to a mainstem bronchus are also classified as T1a.^bSolitary adenocarcinoma, ≤ 3 cm, predominantly squamous, with any one focus invading ≤ 5 mm.^cT2 tumors with these features are classified as T2a if ≤ 4 cm in greatest dimension or if size cannot be determined, and as T2b if > 4 cm but ≤ 5 cm in greatest dimension.^dMost pleural (pericardial) effusions with lung cancer are caused by tumor. However, in a minority of patients, multiple microscopic examinations of the pleural (pericardial) effusion are negative for tumor, and the fluid is not bloody and is not an exudate. When these factors and clinical judgment indicate that the effusion is not related to the tumor, the presence of an effusion should be excluded as a stage descriptor.^eThis includes involvement of a single distal (nonregional) lymph node. N Type Total installment Version 7 Descriptors Recommended T/M N0 N1 N2 N3 T1 ≤ 1 cm T1aIA1 (IA)IIB (IIA) IIIA IIIB T1 ＞ 1-2 cm T1bIA2 (IA)IIB (IIA) IIIA IIIB T1 ＞ 2-3 cm T1cIA3 (IA)IIB (IIA) IIIA IIIB T2 ＞ 3-4 cm T2a IBIIB (IIA) IIIA IIIB T2 ＞ 4-5 cm T2bIIA (IB)IIB (IIA) IIIA IIIB T2 ＞ 5-7 cm T3IIB (IIA)IIIA (IIB)IIIB (IIIA)IIIC (IIIB) T3 Structure T3 IIB IIIAIIIB (IIIA)IIIC (IIIB) T3 ＞ 7 cm T4IIIA (IIB) IIIAIIIB (IIIA)IIIC (IIIB) T3 Diaphragm T4IIIA (IIB) IIIAIIIB (IIIA)IIIC (IIIB) T3 Endobronchial: Location/atelectasis 3-4 cm T2aIB (IIB)IIB (IIIA) IIIA IIIB T3 Endobronchial: Location/atelectasis 4-5 cm T2bIIA (IIB)IIB (IIIA) IIIA IIIB T4 T4 IIIA IIIA IIIBIIIC (IIIB) M1a M1aIVA (IV)IVA (IV)IVA (IV)IVA (IV) M1b Single lesion M1bIVA (IV)IVA (IV)IVA (IV)IVA (IV) M1c Multiple lesions M1cIVB (IV)IVB (IV)IVB (IV)IVB (IV) When there are changes, the final stage groupings proposed in the Eighth Edition are in bold, and the Seventh Edition periodizations are given in brackets.

PD-L1 陽性個體的 TC ≥ 1%，如使用研究性 VENTANA PD-L1 (SP263) CDx 測定法判定的)。PD-L1 高個體的 TC ≥ 50%，如使用研究性 VENTANA PD-L1 (SP263) CDx 測定法判定的。TC ≥ 1% for PD-L1 positive individuals as determined using the investigational VENTANA PD-L1 (SP263) CDx assay). TC ≥ 50% for PD-L1 high individuals as determined using the investigational VENTANA PD-L1 (SP263) CDx assay.

表 5 給出了根據國際協調理事會 (ICH) E9(R1) 臨床試驗統計原則 (ICH 2020) 使用被估量框架表示的研究主要目標，以及選定的次要目標及相應的終點。表 6 列出了進一步的次要及探索性目標以及相應的終點。表5.主要及次要目標以及相應的被估量/終點主要目標被估量定義• 評估與安慰劑加阿替利珠單抗相比的替瑞利尤單抗加阿替利珠單抗在 PD-L1 ≥ 50% TC 及 PD-L1 ≥ 1% TC 群體中的療效。•由研究者評定的 PD-L1 ≥ 50% TC 群體中的無疾病存活 (DFS)。研究者評估的 DFS 的被估量定義如下： -群體：完全切除 IIB 期、IIIA 期或選定的 IIIB 期 NSCLC 腫瘤 (PD‑L150% TC，藉由研究性 VENTANA PD-L1 (SP263) CDx 測定法確定) 的已接受輔助化學療法的參與者。 -變量：由研究者判定的從隨機分組到發生 NSCLC 局部/區域或遠端復發、新的原發性 NSCLC 或任何原因導致的死亡 (以先發生者為準) 的時間。 -治療： •替瑞利尤單抗加阿替利珠單抗：替瑞利尤單抗 840 mg 加阿替利珠單抗 1680 mg，在各 28 天週期的第 1 天藉由靜脈內 (IV) 共同輸注投予，持續最多 13 個週期，大約 1 年。 •安慰劑加阿替利珠單抗：安慰劑加阿替利珠單抗 1680 mg，在各 28 天週期的第 1 天藉由 IV 共同輸注投予，持續最多 13 個週期，大約一年。 -併發事件： •任何原因提前中止研究治療：使用治療政策策略。 •在相應的感興趣事件之前開始非方案抗癌療法：使用治療政策策略。 -群體水平的總結：DFS 的風險比。 •由研究者評定的 PD-L1 ≥ 1% TC 群體中的 DFS。被估量的定義方式與 PD-L1 ≥ 50% TC 群體中研究者評定的 DFS 的定義方式相同，但以下情況除外： -群體：完全切除 PDL1 ≥ 1% TC (藉由研究性 VENTANA PD-L1 (SP263) CDx 測定法確定) IIB 期、IIIA 期或選定的 IIIB 期 NSCLC 的已接受輔助化學療法的參與者。次要目標終點定義•評估與安慰劑加阿替利珠單抗相比的替瑞利尤單抗加阿替利珠單抗的安全性。•不良事件之發生率及嚴重度，其嚴重度根據美國國家癌症研究所 (NCI) 不良事件通用術語標準 (CTCAE) 版本 5.0 (NCI CTCAE v5.0) 判定。•評估與安慰劑加阿替利珠單抗相比的替瑞利尤單抗加阿替利珠單抗的療效。•總存活 (OS)。 •3 年、5 年及 7 年 DFS 率。•評估與安慰劑相比用替瑞利尤單抗加阿替利珠單抗治療的參與者的健康相關生活質量。•健康相關生活品質 (HRQoL) 係基於在治療過程中在患者報告的角色、情緒及身體功能以及整體健康狀況/生活品質方面相對於基線保持或具有有意義的改善的參與者比例。•評估與安慰劑加阿替利珠單抗相比的替瑞利尤單抗加阿替利珠單抗的安全性。•不良事件之發生率及嚴重度，其嚴重度根據美國國家癌症研究所 (NCI) 不良事件通用術語標準 (CTCAE) 版本 5.0 (NCI CTCAE v5.0) 判定。表6.其他次要及探索性目標及終點其他次要目標相應終點•從參與者的角度評估與安慰劑加阿替利珠單抗相比的替瑞利尤單抗加阿替利珠單抗的參與者報告耐受性。•如透過研究治療期間使用 NCI 參與者報告的不良事件結果通用術語標準 (PRO-CTCAE) (選定項目) 所評定，對症治療毒性的存在、發生頻率、嚴重性及/或對日常功能的干擾程度。 •如透過使用 PRO-CTCAE (選定項目) 所評定，對症治療毒性之相對於基線的變化。 •如透過使用單項目 EORTC IL-46 所評定，參與者對治療症狀困擾程度的反應頻率。•表徵替瑞利尤單抗加阿替利珠單抗之藥物動力學 (PK)。•指定時間點的替瑞利尤單抗血清濃度。 •指定時間點的阿替利珠單抗血清濃度。•評估對替瑞利尤單抗及阿替利珠單抗之免疫反應。•基線時對於替瑞利尤單抗之抗藥物抗體 (ADA) 發生率及研究期間對於替瑞利尤單抗之 ADA 發生率。 •基線時對於阿替利珠單抗的 ADA 發生率及研究期間對於阿替利珠單抗的 ADA 發生率。探索性目標相應終點•評估與安慰劑加阿替利珠單抗相比的替瑞利尤單抗加阿替利珠單抗的參與者報告的 HRQoL、功能及症狀。•如在研究期間透過使用 EORTC QLQ-C30 及 QLQ-LC13 評定，參與者報告的 HRQoL、功能及症狀之實際評分及相對於基線的變化。•從參與者的角度評估與安慰劑加阿替利珠單抗相比的替瑞利尤單抗加阿替利珠單抗的參與者報告耐受性。•如透過研究治療期間使用 NCI 參與者報告的不良事件結果通用術語標準 (PRO-CTCAE) (選定項目) 所評定，對症治療毒性的存在、發生頻率、嚴重性及/或對日常功能的干擾程度。 •如透過使用 PRO-CTCAE (選定項目) 所評定，對症治療毒性之相對於基線的變化。 •如透過使用單項目 EORTC IL-46 所評定，參與者對治療症狀困擾程度的反應頻率。•評估 ADA 的潛在效應。•替瑞利尤單抗 ADA 狀態及/或阿替利珠單抗 ADA 狀態與療效、安全性或 PK 終點之間的關係。•識別及/或評估生物標記 (即預測性生物標記)，其可能與替瑞利尤單抗加阿替利珠單抗與安慰劑加阿替利珠單抗相比的臨床獲益相關，係療效的早期替代指標，與進展為更嚴重的疾病狀態相關 (亦即，預後生物標記)，與替瑞利尤單抗加阿替利珠單抗與安慰劑加阿替利珠單抗相比的獲得性抗性相關，可提供替瑞利尤單抗加阿替利珠單抗與安慰劑加阿替利珠單抗活性相比的證據 (亦即，藥效生物標記)，或可增加對疾病生物學及藥物安全性的知識及理解。•腫瘤組織及血液中生物標記與療效、安全性、PK、免疫原性或其他生物標記終點之間的關係。•評估與阿替利珠單抗相比的用替瑞利尤單抗加阿替利珠單抗治療的參與者的健康狀態效用評分。•研究期間指定時間點的基於 EQ-5D-5L 指數的評分及視覺模擬量表 (VAS) 評分之實際評分以及相對於基線的變化。實例2：研究設計Table 5 presents the primary objectives of the study expressed using the estimand framework according to the International Council for Harmonisation (ICH) E9(R1) Principles of Clinical Trial Statistics (ICH 2020), as well as selected secondary objectives and corresponding endpoints. Table 6 lists further secondary and exploratory objectives and corresponding endpoints.Table5.Primary and secondary objectives and corresponding estimands/endpointsMain objectivesEstimated Definition • To assess the efficacy of tislelizumab plus atezolizumab compared with placebo plus atezolizumab in the PD-L1 ≥ 50% TC and PD-L1 ≥ 1% TC populations. •Disease-free survival (DFS) in the PD-L1 ≥ 50% TC population as assessed by the investigator. The estimator for investigator-assessed DFS was defined as follows: - Population: Completely resected stage IIB, IIIA, or selected stage IIIB NSCLC tumors (PD-L1 50% TC, as determined by the investigational VENTANA PD-L1 (SP263) CDx assay) who had received adjuvant chemotherapy. -Variables: Time from randomization to development of local/regional or distant recurrence of NSCLC, new primary NSCLC, or death from any cause, whichever occurred first, as assessed by the investigator. -Treatment: • Tisrelizumab plus atezolizumab: Tisrelizumab 840 mg plus atezolizumab 1680 mg, administered by co-infusion via intravenous (IV) on Day 1 of each 28-day cycle for up to 13 cycles, approximately 1 year. • Placebo plus atezolizumab: Placebo plus atezolizumab 1680 mg, administered by IV co-infusion on Day 1 of each 28-day cycle for up to 13 cycles, approximately one year. - Complications: • Early discontinuation of study treatment for any reason: Use treatment policy strategy. • Initiation of non-protocol anticancer therapy prior to corresponding event of interest: Use treatment policy strategy. - Population-level summary: Hazard ratio for DFS. • DFS in the PD-L1 ≥ 1% TC population assessed by investigator. The measure was defined in the same manner as investigator-assessed DFS in the PD-L1 ≥ 50% TC population, with the following exceptions: - Population: Participants with completely resected PDL1 ≥ 1% TC (determined by the investigational VENTANA PD-L1 (SP263) CDx assay) Stage IIB, IIIA, or selected Stage IIIB NSCLC who received adjuvant chemotherapy.Secondary GoalsEnd point definition •To assess the safety of tisleliumab plus atezolizumab compared with placebo plus atezolizumab. • The incidence and severity of adverse events were determined according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (NCI CTCAE v5.0). •To assess the efficacy of tisleliumab plus atezolizumab compared with placebo plus atezolizumab. •Overall survival (OS). •3-year, 5-year and 7-year DFS rates. • To assess health-related quality of life in participants treated with tisleliumab plus atezolizumab compared with placebo. • Health-related quality of life (HRQoL) was based on the proportion of participants who maintained or had meaningful improvements over baseline in patient-reported role, emotional and physical functioning, and global health status/quality of life during treatment. •To assess the safety of tisleliumab plus atezolizumab compared with placebo plus atezolizumab. • The incidence and severity of adverse events were determined according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (NCI CTCAE v5.0).Table6.Other secondary and exploratory objectives and endpointsOther secondary goalsCorresponding endpoint • To assess the participant-reported tolerability of tisleliumab plus atezolizumab compared with placebo plus atezolizumab from the participant's perspective. • The presence, frequency, severity, and/or interference with daily functioning of symptomatic treatment toxicity as assessed using the NCI Participant-Reported Common Terminology Criteria for Adverse Events (PRO-CTCAE) (selected items) during study treatment. • The change from baseline in symptomatic treatment toxicity as assessed using PRO-CTCAE (selected items). • The frequency of participant responses regarding the degree of bothersomeness of treatment symptoms as assessed using the single-item EORTC IL-46. • Characterize the pharmacokinetics (PK) of tisleliumab plus atezolizumab. • Serum concentrations of tisleliumab at the indicated time points. • Serum concentrations of atezolizumab at the indicated time points. •Assess the immune response to tisleliumab and atezolizumab. • The incidence of anti-drug antibodies (ADA) for tisleliumab at baseline and during the study. • The incidence of ADA for atezolizumab at baseline and during the study.Exploratory goalsCorresponding endpoint • To assess participant-reported HRQoL, function, and symptoms of tisleliumab plus atezolizumab compared with placebo plus atezolizumab. • Participant-reported actual scores and changes from baseline in HRQoL, functioning, and symptoms during the study period as assessed using the EORTC QLQ-C30 and QLQ-LC13. • To assess the participant-reported tolerability of tisleliumab plus atezolizumab compared with placebo plus atezolizumab from the participant's perspective. • The presence, frequency, severity, and/or interference with daily functioning of symptomatic treatment toxicity as assessed using the NCI Participant-Reported Common Terminology Criteria for Adverse Events (PRO-CTCAE) (selected items) during study treatment. • The change from baseline in symptomatic treatment toxicity as assessed using PRO-CTCAE (selected items). • The frequency of participant responses regarding the degree of bothersomeness of treatment symptoms as assessed using the single-item EORTC IL-46. •Assess the potential effects of ADA. •Relationship between tisleliumab ADA status and/or atezolizumab ADA status and efficacy, safety, or PK endpoints. • Identify and/or assess biomarkers (i.e., predictive biomarkers) that may be associated with clinical benefit of tisleliumab plus atezolizumab compared with placebo plus atezolizumab, are early surrogate markers of efficacy, are associated with progression to more severe disease states (i.e., prognostic biomarkers), are associated with acquired resistance to tisleliumab plus atezolizumab compared with placebo plus atezolizumab, may provide evidence of activity of tisleliumab plus atezolizumab compared with placebo plus atezolizumab (i.e., pharmacodynamic biomarkers), or may increase knowledge and understanding of disease biology and drug safety. •Relationship between biomarkers in tumor tissue and blood and efficacy, safety, PK, immunogenicity or other biomarker endpoints. • To assess health status utility scores in participants treated with tisleliumab plus atezolizumab compared with atezolizumab. • Actual scores and changes from baseline based on EQ-5D-5L index and visual analog scale (VAS) scores at designated time points during the study.Example2: Research Design

圖 1 提供了 GO45006 研究的研究方案。Figure 1 provides the study plan for the GO45006 study.

年齡 ≥ 18 歲且東部腫瘤協作組 (ECOG) 體能狀態為 0 或 1 的已完全手術切除 IIB 期、IIIA 期或選定的 IIIB 期 (僅 T3N2) NSCLC (PD-L1 表現 ≥ 1% TC) 隨後進行輔助鉑類化學療法且沒有疾病復發證據的男性及女性參與者有資格參與研究。Male and female participants aged ≥ 18 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with completely surgically resected stage IIB, IIIA, or selected stage IIIB (T3N2 only) NSCLC (PD-L1 expression ≥ 1% TC) followed by adjuvant platinum-based chemotherapy without evidence of disease recurrence were eligible for the study.

除中心 PD-L1 組織測試 (及/或 EGFR 或 ALK (如適用)) 外，篩選測試及評估必須在最後一劑化學療法後且隨機分組後 28 天內進行。在預篩選或篩選期間，中心實驗室使用研究性 VENTANA PD-L1 (SP263) CDx 測定法對來自各潛在有資格參與者的腫瘤組織進行 PD-L1 表現檢測。只有藉由研究性 VENTANA PD-L1 (SP263) CDx 測定法判定的 PD L1 表現 ≥ 1% TC 的參與者才有資格入組。Screening testing and assessments, in addition to central PD-L1 tissue testing (and/or EGFR or ALK, as applicable), must be performed after the last dose of chemotherapy and within 28 days of randomization. During the prescreening or screening period, tumor tissue from each potentially eligible participant will be tested for PD-L1 expression using the investigational VENTANA PD-L1 (SP263) CDx assay in the central laboratory. Only participants with PD L1 expression ≥ 1% TC as determined by the investigational VENTANA PD-L1 (SP263) CDx assay will be eligible.

其腫瘤具有已知上皮生長因子受體 (EGFR) 突變或者退行性淋巴瘤激酶 (ALK) 重排的參與者被排除在研究入組之外。EGFR 或 ALK 狀態未知的非鱗狀 NSCLC 參與者需要在篩選時進行測試。EGFR 或 ALK 狀態未知的鱗狀 NSCLC 參與者係有資格的，且無需在預篩選或篩選時進行測試。EGFR 及/或 ALK 狀態可在本地或在中心實驗室評定。Participants whose tumors had known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements were excluded from study enrollment. Participants with non-squamous NSCLC with unknown EGFR or ALK status were required to be tested at screening. Participants with squamous NSCLC with unknown EGFR or ALK status were eligible and did not need to be tested prescreening or at screening. EGFR and/or ALK status may be assessed locally or at a central laboratory.

約 1150 名參與者 (約 700 名參與者 (約 60%) 的 PD-L1 ≥ 50% TC，且約 450 名參與者 (約 40%) 的 PD-L1 ≥ 1% 且 ＜ 50% TC) 入組該研究。一旦達到指定目標，則具體 PD-L1 群體的入組就會受到限制。過早中止研究治療的參與者不會被替代。Approximately 1150 participants (approximately 700 participants (approximately 60%) with PD-L1 ≥ 50% TC and approximately 450 participants (approximately 40%) with PD-L1 ≥ 1% and < 50% TC) will be enrolled in the study. Enrollment in specific PD-L1 groups will be restricted once the specified goals are met. Participants who prematurely discontinue study treatment will not be replaced.

隨機分組最晚必須在最後一劑化學療法後 70 天完成。有資格的參與者按 1:1 的比例隨機分組以接受替瑞利尤單抗加阿替利珠單抗或安慰劑加阿替利珠單抗。如果可能，則參與者在隨機分組當天接受其第一劑研究治療。如果不可能，則應在隨機分組後 5 天內進行第一劑。Randomization must be completed no later than 70 days after the last dose of chemotherapy. Eligible participants were randomized in a 1:1 ratio to receive either tisleliumab plus atezolizumab or placebo plus atezolizumab. Participants received their first dose of study treatment on the day of randomization, if possible. If not possible, the first dose should be given within 5 days of randomization.

有資格的參與者根據腫瘤組織學 (鱗狀細胞與非鱗狀細胞)、疾病分期 (IIB 期與 IIIA 期 + 選定的 IIIB 期 (僅 T3N2)) 及 PD-L1 狀態 (≥1% 且 ＜50% TC 與 ≥ 50% TC) 進行分層。入組 PD-L1 ≥1% 且 ＜50% TC 亞組的上限為約 450 名參與者 (約佔參與者的 40%)，且入組 PD-L1 ≥ 50% TC 亞組的上限為約 700 名參與者 (約佔參與者的 60%)。Eligible participants were stratified by tumor histology (squamous vs. nonsquamous), disease stage (stage IIB vs. stage IIIA + selected stage IIIB (T3N2 only)), and PD-L1 status (≥1% and <50% TC vs. ≥50% TC). Enrollment in the PD-L1 ≥1% and <50% TC subgroup was capped at approximately 450 participants (approximately 40% of participants), and enrollment in the PD-L1 ≥50% TC subgroup was capped at approximately 700 participants (approximately 60% of participants).

在實驗臂中，在各 28 天週期的第 1 天，藉由 IV 共同輸注投予 840 mg 劑量的替瑞利尤單抗加 1680 mg 劑量的阿替利珠單抗 (將替瑞利尤單抗及阿替利珠單抗混合併在一個 IV 袋中投予)，持續總共 13 個週期 (約 1 年)。在比較臂中，在各 28 天週期的第 1 天，藉由 IV 共同輸注投予安慰劑加 1680 mg 劑量的阿替利珠單抗，持續最多 13 個週期。In the experimental arm, tisleliumab at a dose of 840 mg plus atezolizumab at a dose of 1680 mg (tisleliumab and atezolizumab were mixed and administered in one IV bag) was administered by IV co-infusion on Day 1 of each 28-day cycle for a total of 13 cycles (approximately 1 year). In the comparator arm, placebo plus atezolizumab at a dose of 1680 mg was administered by IV co-infusion on Day 1 of each 28-day cycle for up to 13 cycles.

不允許從安慰劑加阿替利珠單抗臂交叉到替瑞利尤單抗加阿替利珠單抗臂。Crossover from the placebo plus atezolizumab arm to the tislelizumab plus atezolizumab arm was not permitted.

在沒有疾病復發或不可接受的毒性的情況下，治療最多持續 13 個週期 (約 1 年)。Treatment was continued for up to 13 cycles (approximately 1 year) in the absence of disease recurrence or unacceptable toxicity.

所有參與者在篩選時以及從第一年第 1 週期第 1 天開始每 16 週 (± 2 週)，在第 2 至 5 年每 26 週 (± 4 週)，且此後每年 (5 年後建議的低劑量非增強 CT)，接受預定的藉由電腦斷層攝影 (CT) 進行的疾病評定掃描。無論研究治療是完成或暫停還是中止 (出於任何原因)，疾病評定都會按照預定繼續進行，直到疾病復發、撤回同意、死亡或研究終止 (以先發生者為準)。疾病復發必須藉由放射學判定，如局部/區域復發、遠端轉移或第二原發性 NSCLC 所證明的。如果疾病評定顯示疾病復發，則必須藉由病理學證實，除非臨床上不可行。All participants underwent scheduled disease assessment scans by computed tomography (CT) at screening and every 16 weeks (± 2 weeks) starting on Cycle 1 Day 1 in Year 1, every 26 weeks (± 4 weeks) in Years 2 to 5, and annually thereafter (low-dose non-enhanced CT recommended after Year 5). Disease assessments continued as scheduled, regardless of whether study treatment was completed or paused or discontinued (for any reason), until disease recurrence, withdrawal of consent, death, or study termination, whichever occurred first. Disease recurrence must be determined radiologically as evidenced by locoregional/regional recurrence, distant metastases, or second primary NSCLC. If disease assessment indicates disease recurrence, this must be confirmed by pathology unless clinically impractical.

安全性評定包括不良事件之發生率、特性及嚴重程度，其根據美國國家癌症研究所不良事件通用術語標準 (NCI CTCAE) 5.0 版來進行分級。Safety assessment included the incidence, nature, and severity of adverse events, which were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.

請參與者在研究治療期間、治療中止/完成時以及治療後追蹤期間的疾病評定時間點完成參與者報告的結果 (PRO) 問卷。Participants were asked to complete participant-reported outcomes (PRO) questionnaires at disease assessment time points during study treatment, at treatment discontinuation/completion, and during post-treatment follow-up.

在研究期間，採集血清樣品以監測阿替利珠單抗及替瑞利尤單抗的藥物動力學，並檢測是否存在針對阿替利珠單抗及替瑞利尤單抗的抗體。亦收集參與者樣品 (包括存檔及新鮮腫瘤組織、血清、血漿及血液樣品) 以進行探索性生物標記評定。During the study, serum samples were collected to monitor the pharmacokinetics of atezolizumab and tisleliumab and to detect the presence of antibodies against atezolizumab and tisleliumab. Participant samples (including archival and fresh tumor tissue, serum, plasma, and blood samples) were also collected for exploratory biomarker assessments.

在開始研究治療後，所有不良事件都被記錄直到最後一劑研究治療後 30 天或直到開始另一全身性抗癌療法，以先發生者為準。將繼續報告嚴重不良事件直到最後一劑研究治療後 90 天或直到開始新的全身性抗癌療法，以先發生者為準。此外，無論是否開始新的抗癌療法，都繼續報告特別關注的不良事件，直至最後一劑研究治療後 90 天。在該時期之後，研究者報告據信與先前使用研究藥物的治療有關的嚴重不良事件。研究者應追蹤各不良事件，直到事件消退至基線級或更高級、事件被研究者評定為穩定、患者失訪或患者撤回同意為止。After initiation of study treatment, all adverse events are recorded until 30 days after the last dose of study treatment or until another systemic anticancer therapy is started, whichever occurs first. Serious adverse events will continue to be reported until 90 days after the last dose of study treatment or until a new systemic anticancer therapy is started, whichever occurs first. In addition, adverse events of special concern continue to be reported until 90 days after the last dose of study treatment, regardless of whether a new anticancer therapy is started. After this period, serious adverse events believed to be related to previous treatment with study drug are reported by the investigator. The investigator should follow each adverse event until the event resolves to baseline grade or higher, the event is assessed by the investigator as stable, the patient is lost to follow-up, or the patient withdraws consent.

中止治療後，參與者進入研究的治療‑後追蹤期。治療‑後追蹤由如上所述的持續評定組成。收集追蹤資訊直至死亡、失訪或研究終止 (以先發生者為準)。A.研究設計的依據研究群體的依據After discontinuation of treatment, participants entered the treatment-post follow-up phase of the study. Treatment-post follow-up consisted of ongoing assessments as described above. Follow-up information was collected until death, loss to follow-up, or study termination (whichever occurred first).A.Basis of Study DesignBasis of Study Population

研究入組 PD-L1 ≥ 1% TC 的 IIB 期、IIIA 期或選定的 IIIB 期 (T3N2) NSCLC 參與者。隨著癌症免疫療法 (CIT) 及標靶療法可用於可切除的 NSCLC，一些患者的治療選擇與基於化學療法的方案相比有所改善。儘管如此，很大一部分患者仍會出現疾病復發並死於其疾病，這凸顯了在最近成功的基礎上繼續努力的必要性。主要終點的依據The study enrolled participants with stage IIB, IIIA, or selected stage IIIB (T3N2) NSCLC with PD-L1 ≥ 1% TC. As cancer immunotherapy (CIT) and targeted therapies become available for resectable NSCLC, treatment options have improved for some patients compared with chemotherapy-based regimens. Despite this, a significant proportion of patients will experience disease recurrence and die from their disease, highlighting the need for continued efforts to build on recent successes.Rationale for the Primary Endpoint

雖然 OS 係在腫瘤學臨床試驗中確定獲益的黃金標準，但在輔助 NSCLC 治療中讀取 OS 所需的時間可能會導致向參與者提供新的有效療法時出現不可接受的延遲。DFS (本研究中的主要療效終點) 係一個有意義且可靠的療效終點，與 OS 相比，評估時間更早。正如幾項化學療法薈萃分析所證明的，在輔助 NSCLC 治療中，DFS 似乎與 OS 密切相關 (Michiels 等人,Journal of Clinical Oncology, 29(15): 7004, 2011；Mauguen 等人,Lancet Oncol,14: 619-626, 2013)。此外，FDA 建議 DFS 作為加速核准及傳統核准兩者的替代終點，並因此將其用作核准多種適應症的輔助療法的主要依據，包括 NSCLC 的輔助 CIT (FDA 行業指南，2018；及 KEYTRUDA® 美國包裝插頁)。Although OS is the gold standard for determining benefit in oncology clinical trials, the time required to read out OS in adjuvant NSCLC therapy may result in unacceptable delays in providing new effective therapies to participants. DFS, the primary efficacy endpoint in this study, is a meaningful and reliable efficacy endpoint that can be assessed earlier than OS. As demonstrated in several chemotherapy meta-analyses, DFS appears to be closely associated with OS in the adjuvant setting of NSCLC (Michiels et al.,Journal of Clinical Oncology , 29(15): 7004, 2011; Mauguen et al.,Lancet Oncol, 14: 619-626, 2013). In addition, the FDA recommends DFS as a surrogate endpoint for both accelerated and traditional approvals and, therefore, uses it as the primary basis for approval of adjuvant therapies for multiple indications, including adjuvant CIT in NSCLC (FDA Guidance for Industry, 2018; and KEYTRUDA® U.S. Package Insert).

次要療效終點，包括特定時間點的 DFS 率及 OS，提供了療效的支持性量度。B.研究結束及參與持續時間Secondary efficacy endpoints, including DFS rate and OS at specific time points, provided supportive measures of efficacy.B.Study Completion and Participation Duration

研究結束在最後一位患者進行最後一次訪視時或自最後一位參與者接收到統計分析 (亦即，DFS 之最終分析) 或安全性追蹤所需的最後資料點處的日期時發生 (以後發生者為準)。預計該研究的總長度 (自首位參與者隨機分組至研究結束) 為 15 年。Study closure occurs when the last patient has his or her last visit or the date from the last participant to the last data point required for statistical analysis (i.e., final analysis of DFS) or safety tracking, whichever occurs later. The total length of the study (from the first participant randomized to study closure) is expected to be 15 years.

參與持續到退出或因任何原因死亡為止。實例3：研究群體Participation continued until withdrawal or death for any reason.Example3: Study population

約 1150 名 (藉由研究性 VENTANA PD-L1 (SP263) CDx 測定法確定的約 700 名 PD-L1 ≥ 50% TC 的參與者及約 450 名 PD-L1 ≥1% 且 ＜50% TC 的參與者) 完全切除 IIB 期、IIIA 期或選定的 IIIB 期 (T3N2) NSCLC 的已接受輔助鉑類雙效化學療法的參與者入組 GO45006 研究。A.入選標準Approximately 1,150 participants (approximately 700 participants with PD-L1 ≥ 50% TC and approximately 450 participants with PD-L1 ≥1% and <50% TC as determined by the investigational VENTANA PD-L1 (SP263) CDx assay) with completely resected Stage IIB, Stage IIIA, or selected Stage IIIB (T3N2) NSCLC who had received adjuvant platinum-doublet chemotherapy were enrolled in the GO45006 study.A.Inclusion Criteria

僅當適用以下所有標準時，潛在參與者才有資格被納入研究： • 簽署知情同意書時的年齡 ≥ 18 歲。 •東部腫瘤協作組 (ECOG) 體能狀態為 0 或 1。 •非鱗狀或鱗狀組織學之 IIB 期、IIIA 期或選定的 IIIB 期 (T3N2) NSCLC 的組織學或細胞學診斷 (根據 UICC/AJCC 分期系統，第 8 版；Detterbeck 等人,Chest, 151: 193-203, 2017)。 • NSCLC 組織學混合型腫瘤參與者必須根據主要組織學成分分為非鱗狀或鱗狀。 •同時患有 NSCLC 及小細胞肺癌兩者的混合組織學腫瘤參與者沒有資格。 •未明確說明大細胞神經內分泌癌、肉瘤樣癌或 NSCLC 的組織學的 NSCLC 沒有資格。 •參與者必須完全切除 NSCLC (無殘留腫瘤且所有手術切緣對侵襲性癌均呈陰性)。 •接受的切除類型包括以下中任一者：肺葉切除術、袖式肺葉切除術、雙肺葉切除術或肺切除術。僅進行過肺段切除術或楔形切除術的參與者沒有本研究的資格。 •至少，必須進行縱隔淋巴結系統取樣，但完整縱膈淋巴結清除術 (MLND) 係較佳的。系統取樣被定義為去除指定水平的至少一個代表性淋巴結。MLND 需要切除該等同一站的所有淋巴結。需要在至少 2 個淋巴結 N2 站進行取樣或 MLND。以下情況可獲例外： •如果術前進行了縱膈鏡檢查或支氣管內超音波 (EBUS)，則可使用診斷性縱膈淋巴結取樣來滿足至少 2 個淋巴結 N2 站。 •如果手術報告或外科醫生單獨提交的附錄明確記載對所需淋巴結區域的探索，並且如果在該等區域沒有發現淋巴結，則參與者被認為係有資格的。 •參與者必須接受介於一個週期與四個週期之間 (較佳地為四個) 的輔助基於組織學的鉑雙效化學療法：順鉑 (較佳) 或卡鉑，以及培美曲塞 (非鱗狀)、吉西他濱、多西紫杉醇、長春瑞濱、依托泊苷或紫杉醇。可接受的輔助化學療法方案描述於 NCCN/ESMO 指南 (National Comprehensive Cancer Network.NCCN Guidelines® Insights: Non–Small Cell Lung Cancer, 2023) 及表 1 中。 •參與者必須已從手術及輔助化學療法中充分恢復 (沒有 ＞ 2 級未消退的毒性)。可包括具有受控且預期不會因研究藥物治療而加重的不可逆毒性的患者 (例如，聽力喪失)。 •患者必須在其手術日期後 12 週內開始輔助化學療法。 •患者之隨機分組必須距最後一劑化學療法 (最後一個週期的第 1 天) 不超過 70 天 (10 週)。 •腫瘤 PD-L1 表現，亦即由研究性 VENTANA PD-L1 (SP263) CDx 測定法判定的任何膜染色高於背景的腫瘤細胞百分比 ≥ 1% (≥ 1% TC)，透過代表性腫瘤組織標本的中心測試來記錄。 •在研究入組前，將石蠟塊中福馬林固定石蠟包埋 (FFPE) 的現存切除腫瘤標本 (較佳) 或至少 15 至 20 個含未染色的、新切的連續切片的載玻片連同相關的病理報告一起提交。如果需要對 EGFR 突變及/或 ALK 易位進行中心測試，則另外提供五個未染色的載玻片。 •在隨機分組之前 14 天內獲得了以下實驗室測試結果所定義的足夠的血液學及終末器官功能： •無顆粒性白血球群落刺激因子支持之嗜中性白血球絕對計數 (ANC) ≥ 1.5 x 10⁹/L (≥ 1500/µL)，但一種情況除外：以下患有良性種族嗜中性白血球減少症 (BEN) 之參與者係有資格的：ANC ≥ 1.3 x 10⁹/L (≥ 1300/µL)。BEN (亦稱為體質性嗜中性白血球減少症) 為輕度或中度嗜中性白血球減少症之遺傳原因，與任何增加之感染風險或其他臨床表現無關 (Atallah-Yunes 等人,Blood Rev, 37: 100586, 2019)。BEN 被稱為種族嗜中性白血球減少症，因為其在非洲後裔及其他特定種族群體中之盛行率增加。 •淋巴球計數 ≥ 0.5 x 10⁹/L (≥ 500/µL)。 •在不輸血的情況下，血小板計數 ≥ 100 x 10⁹/L (≥ 100,000/µL)。 •血紅素 ≥ 90 g/L (≥ 9 g/dL)。可以向參與者輸血以滿足該標準。 • AST、ALT 及 ALP ≤ 2.5 x 正常值上限 (ULN)。 •總膽紅素 ≤ 1.5 x ULN，但下列情況除外：患有已知 Gilbert 氏病的參與者：總膽紅素 ≤ 3 x ULN。 •肌酐清除率 ≥30 mL/min (藉由機構標準或透過使用 Cockcroft-Gault 公式計算)。 •白蛋白 ≥ 25 g/L (≥ 2.5 g/dL)。 •對於未接受抗凝治療的參與者：INR 及 aPTT ≤ 1.5 x ULN。對於接受抗凝治療的參與者：穩定的抗凝方案。 •篩選時 HIV 測試呈陰性，但下列情況除外：篩選時 HIV 測試呈陽性的參與者係有資格的，前提條件是他們在抗逆轉錄病毒療法期間穩定，CD4 計數 ≥ 200/µL，且具有不可檢測的病毒負荷。 •參與者必須符合以下乙型肝炎病毒 (HBV) 標準中之一者： •篩選時乙型肝炎表面抗原 (HBsAg) 測試呈陰性，並伴隨以下情況中之任一者： 乙型肝炎表面抗體 (HBsAb) 陽性或 HBsAb 陰性且乙型肝炎核心抗體 (HBcAb) 陰性。 •對於總 HBcAb 測試呈陽性且 HBsAb 測試呈陰性的參與者，篩選時 HBV DNA ＜ 500 IU/mL。具有可檢測之 HBV DNA 的參與者應按照機構指南進行管理。 •篩選時丙型肝炎病毒 (HCV) 抗體測試呈陰性，或篩選時 HCV 抗體測試呈陽性然後 HCV RNA 測試呈陰性。對於 HCV 抗體測試呈陽性之參與者，必須進行 HCV RNA 測試。 •對於有生育能力的女性：同意禁欲 (避免異性性交) 或使用避孕措施。 •對於男性參與者：同意保持禁慾 (避免異性性交) 或使用避孕套，並且同意不捐贈精子。B.排除標準Potential participants were eligible for inclusion in the study only if all of the following criteria applied: • Age ≥ 18 years at the time of signing the informed consent. • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. • Histologic or cytologic diagnosis of stage IIB, stage IIIA, or selected stage IIIB (T3N2) NSCLC with non-squamous or squamous histology (according to the UICC/AJCC staging system, 8th edition; Detterbeck et al.,Chest , 151: 193-203, 2017). • Participants with mixed NSCLC histologic tumors must be classified as non-squamous or squamous based on the predominant histologic component. • Participants with mixed tumor histologies of both NSCLC and small cell lung cancer were not eligible. • NSCLC with unspecified histology of large cell neuroendocrine carcinoma, sarcomatoid carcinoma, or NSCLC were not eligible. • Participants must have had a completely resected NSCLC (no residual tumor and all surgical margins were negative for invasive cancer). • Type of resection received included any of the following: lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy. Participants who had only a segmentectomy or wedge resection were not eligible for this study. • At a minimum, systematic sampling of the diaphragmatic lymph nodes must be performed, but complete diaphragmatic lymph node dissection (MLND) is preferred. Systematic sampling is defined as removal of at least one representative lymph node at the specified level. MLND requires removal of all lymph nodes in those same stations. Sampling or MLND is required in at least 2 lymph node N2 stations. Exceptions are available for the following: • If a preoperative transdiaphragmatic examination or endobronchial ultrasound (EBUS) was performed, diagnostic transdiaphragmatic lymph node sampling may be used to satisfy at least 2 lymph node N2 stations. • Participants are considered eligible if the surgical report or a separate appendix submitted by the surgeon clearly states the exploration of the required lymph node regions and if no lymph nodes are found in those regions. • Participants must have received between one and four cycles (preferably four) of adjuvant tissue-based platinum doublet chemotherapy: cisplatin (preferably) or carboplatin, and pemetrexed (non-squamous), gemcitabine, docetaxel, vinorelbine, etoposide, or paclitaxel. Acceptable adjuvant chemotherapy regimens are described in the NCCN/ESMO Guidelines (National Comprehensive Cancer Network. NCCN Guidelines® Insights: Non–Small Cell Lung Cancer, 2023) and Table 1. • Participants must have adequately recovered from surgery and adjuvant chemotherapy (no > grade 2 unresolved toxicity). Patients with irreversible toxicities that are manageable and not expected to be exacerbated by study drug treatment (e.g., hearing loss) may be included. • Patients must have started adjuvant chemotherapy within 12 weeks of their surgery date. • Patients must have been randomized no more than 70 days (10 weeks) from the last dose of chemotherapy (Day 1 of the last cycle). • Tumor PD-L1 expression, defined as any percentage of tumor cells with membrane staining ≥ 1% above background (≥ 1% TC) as determined by the investigational VENTANA PD-L1 (SP263) CDx assay, was documented by central testing of representative tumor tissue specimens. •Existing resected tumor specimen in formalin-fixed paraffin-embedded (FFPE) paraffin block (preferably) or at least 15 to 20 slides with unstained, freshly cut serial sections, along with the relevant pathology report, will be submitted prior to study enrollment. Five additional unstained slides will be provided if central testing for EGFR mutations and/or ALK translocations is required. • Adequate hematologic and end-organ function as defined by the following laboratory test results obtained within 14 days prior to randomization: • Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹ /L (≥ 1500/µL) without granulocyte colony-stimulating factor support, with one exception: Participants with benign ethnic neutropenia (BEN) were eligible as follows: ANC ≥ 1.3 x 10⁹ /L (≥ 1300/µL). BEN (also called constitutional neutropenia) is a hereditary cause of mild or moderate neutropenia that is not associated with any increased risk of infection or other clinical manifestations (Atallah-Yunes et al.,Blood Rev , 37: 100586, 2019). BEN is called ethnic neutropenia because of its increased prevalence in people of African descent and other specific ethnic groups. • Lymphocyte count ≥ 0.5 x¹⁰⁹ /L (≥ 500/µL). • Platelet count ≥ 100 x¹⁰⁹ /L (≥ 100,000/µL) without transfusion. • Hemoglobin ≥ 90 g/L (≥ 9 g/dL). Participants may be given a transfusion to meet this criterion. • AST, ALT, and ALP ≤ 2.5 x upper limit of normal (ULN). • Total bilirubin ≤ 1.5 x ULN, except for the following: Participants with known Gilbert's disease: Total bilirubin ≤ 3 x ULN. • Creatinine clearance ≥ 30 mL/min (by institutional criteria or by using the Cockcroft-Gault formula). • Albumin ≥ 25 g/L (≥ 2.5 g/dL). • For participants not receiving anticoagulation: INR and aPTT ≤ 1.5 x ULN. For participants receiving anticoagulation: stable anticoagulation regimen. • HIV test negative at screening, except for the following: Participants with a positive HIV test at screening are eligible provided they are stable on antiretroviral therapy, have a CD4 count ≥ 200/µL, and have an undetectable viral load. • Participants must meet one of the following Hepatitis B Virus (HBV) criteria: • Negative Hepatitis B Surface Antigen (HBsAg) test at screening, with either of the following: Hepatitis B Surface Antibody (HBsAb) positive or HBsAb negative and Hepatitis B Core Antibody (HBcAb) negative. •HBV DNA < 500 IU/mL at screening for participants with a positive total HBcAb test and a negative HBsAb test. Participants with detectable HBV DNA should be managed according to institutional guidelines. •Hepatitis C virus (HCV) antibody test negative at screening, or a positive HCV antibody test followed by a negative HCV RNA test at screening. HCV RNA testing is mandatory for participants with a positive HCV antibody test. •For females of childbearing potential: agree to abstinence (avoid heterosexual intercourse) or use contraception. •For male participants: agree to remain abstinent (avoid heterosexual intercourse) or use condoms, and agree not to donate sperm.B.Exclusion Criteria

若潛在參與者適用下列標準中之任一者，則將其排除在研究之外： •過去 5 年內有任何先前 NSCLC 病史。 •既往 NSCLC 必須僅用手術治療。 • NSCLC 手術切除後或輔助化學療法期間或之後殘留疾病或疾病復發的任何證據。 •已知具有 EGFR 基因中之突變或者 ALK 融合致癌基因的 NSCLC： • EGFR 或 ALK 狀態未知的非鱗狀 NSCLC 參與者需要在預篩選或篩選時進行測試。 • EGFR 或 ALK 狀態未知的鱗狀 NSCLC 參與者係有資格的，且無需在預篩選或篩選時進行測試。 • EGFR 及/或 ALK 狀態可在本地或在中心實驗室評定。局部評定的 EGFR 及或 ALK 狀態必須在組織上使用在臨床實驗室改進修正案 (CLIA) 或同等認證的實驗室中進行的經驗證的衛生當局核准的或經適當驗證的下一代定序 (NGS) 測試進行。EGFR 測試必須檢測外顯子 18 至 21 的突變。如果樣品被提交用於中心 EGFR 及/或 ALK 測試，則必須提供額外的五個載玻片。 •使用全身性療法 (例如，化學療法或免疫療法) 治療 NSCLC 的先前治療，但納入標準中概述的輔助鉑類化學療法除外。 •使用針對 NSCLC 之放射治療 (包括術後放射療法 (PORT)) 的先前治療，但手術切除前的局部症狀導向放射除外。 •自身免疫性疾病或免疫缺陷的活動或病史，包括但不限於重症肌無力、肌炎、自身免疫性肝炎、全身性紅斑性狼瘡、類風濕性關節炎、炎症性腸病、抗磷脂抗體症候群、肉芽腫性多血管炎、Sjögren 症候群、格林-巴雷症候群或多發性硬化症，但下列情況除外： •具有自身免疫相關甲狀腺機能減退之病史的正在服用甲狀腺替代激素之參與者有資格參與研究。 •接受胰島素治療的 1 型糖尿病受控參與者有資格參與研究。 •若滿足以下所有條件，則患有濕疹、乾癬病、慢性單純性苔蘚或僅具有皮膚病學表現的白癜風之參與者 (例如，銀屑病關節炎參與者被排除在外) 有資格參與研究：皮疹必須覆蓋小於 10% 的體表面積；疾病在基線時得到很好的控制，只需要低效局部皮質類固醇；在過去的 12 個月內，尚未發生需要補骨脂素加紫外線 A 輻射、胺甲蝶呤、維甲酸、生物製劑、口服鈣調神經磷酸酶抑制劑或高效或口服皮質類固醇的基礎疾病急性加重。 •篩選時 Epstein-Barr 二氏病毒 (EBV) 病毒殼抗原 IgM 測試呈陽性。EBV 聚合酶鏈反應 (PCR) 試驗應按照臨床指示進行，以篩選急性感染或疑似慢性活動性感染。EBV PCR 試驗呈陽性的參與者被排除。 •特發性肺纖維化病史，組織性肺炎 (例如，閉塞性細支氣管炎)，藥物性肺炎或特發性肺炎，或胸部 CT 掃描篩選為活動性肺炎的證據。 •允許有放射場中之放射性肺炎 (纖維化) 史。 •活動性結核病。 •在開始研究治療前 3 個月內出現嚴重的心血管疾病 (例如，紐約心臟協會 II 級或更高級別之心贓病、心肌梗塞或腦血管意外)，不穩定的心律失常或不穩定的心絞痛。 •在開始研究治療之前的 4 週內進行主要外科手術，或者預期研究治療期期間需要進行主要外科手術。 •在開始研究治療前 5 年內有惡性腫瘤病史 (但本研究中研究的癌症以及轉移或死亡風險可忽略不計 (例如 5 年 OS 率 ＞ 90%) 之惡性腫瘤除外，諸如已得到充分治療之子宮頸原位癌、非黑色素瘤皮膚癌、局部前列腺癌、原位導管癌或 I 期子宮癌)。 •在開始研究治療之前的 4 週內發生嚴重感染，包括但不限於因感染、菌血症或重度肺炎而住院，或者可能影響參與者安全性的任何活動性感染。 •開始研究治療前 2 週內治療性口服或 IV 抗生素治療。接受預防性抗生素 (例如，預防尿路感染或慢性阻塞性肺病 (COPD) 惡化) 之參與者符合研究的條件。 •既往同種異體幹細胞或實體器官移植。 •禁止使用研究性藥物、可能影響結果解釋或可能使參與者處於治療併發症高風險中的任何其他疾病、代謝功能障礙、體格檢查發現或臨床實驗室發現。 •在開始研究治療之前的 4 週內，或預期在研究治療期間需要此類疫苗的情況下，在最後一劑替瑞利尤單抗/安慰劑後 90 天內，以及在最後一劑阿替利珠單抗後 5 個月內，用減毒活疫苗進行治療。 •在開始研究治療之前的 28 天內，採用研究治療進行治療。 •使用 CD137 促效劑或免疫查核點阻斷療法進行的先前治療，包括抗 CTLA-4、抗 TIGIT、抗 PD-L1 及抗 PD-1 治療性抗體 •在開始研究治療之前的 4 週內或在 5 個藥物消除半衰期 (以較長者為準) 內，用全身性免疫刺激劑 (包括但不限於，干擾素及 IL-2) 進行治療。 •在開始研究治療前 2 週內用全身性免疫抑制用藥 (包括但不限於皮質類固醇、環磷醯胺、硫唑嘌呤、胺甲喋呤、沙利多邁 (thalidomide) 及抗腫瘤壞死因子 -α (TNF-α) 劑) 進行治療，或預期在研究治療期間需要進行全身性免疫抑制用藥，但下列情況除外： •接受急性小劑量全身性免疫抑制劑用藥或一次性脈沖劑量之全身性免疫抑制用藥 (例如，對對比劑過敏為 48 小時之皮質類固醇) 之參與者有資格參與研究。 •接受礦皮質素 (例如，氟可體松)，因 COPD 或哮喘而接受吸入或低劑量皮質類固醇、或因起立性低血壓或腎上腺功能不全而接受低劑量皮質類固醇之參與者有資格參與研究。 •對嵌合或人源化抗體或融合蛋白有嚴重過敏性變態反應史。 •已知對中國倉鼠卵巢細胞產品或阿替利珠單抗或替瑞利尤單抗調配物的任何組分過敏。 •在研究治療期間、在最後一劑替瑞利尤單抗/安慰劑後 90 天內，或在最後一劑阿替利珠單抗後 5 個月內，懷孕或哺乳或打算懷孕 •研究者認為會幹擾參與者安全參與及完成研究、研究藥物的評估或參與者安全性或研究結果的解釋的任何情況。實例4：研究治療及伴隨療法Potential participants were excluded from the study if they met any of the following criteria: • Any history of prior NSCLC within the past 5 years. • Prior NSCLC must have been treated exclusively with surgery. • Any evidence of residual disease or disease recurrence after surgical resection of NSCLC or during or after adjuvant chemotherapy. • NSCLC known to have a mutation in the EGFR gene or ALK fusion oncogene: • Non-squamous NSCLC participants with unknown EGFR or ALK status are required to be tested at prescreening or screening. • Squamous NSCLC participants with unknown EGFR or ALK status are eligible and do not need to be tested at prescreening or screening. • EGFR and/or ALK status can be assessed locally or at a central laboratory. Locally assessed EGFR and/or ALK status must be performed on tissue using a validated health authority-approved or appropriately validated next-generation sequencing (NGS) test performed in a Clinical Laboratory Improvement Amendments (CLIA) or equivalent accredited laboratory. The EGFR test must detect mutations in exons 18 to 21. If samples are submitted for central EGFR and/or ALK testing, an additional five slides must be provided. • Prior treatment for NSCLC with systemic therapy (e.g., chemotherapy or immunotherapy), except for adjuvant platinum-based chemotherapy as outlined in the inclusion criteria. •Prior treatment with radiation therapy for NSCLC, including postoperative radiation therapy (PORT), excluding local symptom-directed radiation prior to surgical resection. •Activity or history of autoimmune disease or immunodeficiency, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, granulomatosis with polyangiitis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions: •Participants taking thyroid replacement hormone with a history of autoimmune-related hypothyroidism were eligible. •Participants with controlled type 1 diabetes receiving insulin therapy were eligible. • Participants with eczema, pityriasis xeros, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis were excluded) were eligible if all of the following criteria were met: rash must cover less than 10% of body surface area; disease was well controlled at baseline requiring only low-potency topical corticosteroids; and there had been no acute exacerbations of underlying disease requiring psoralen plus ultraviolet A radiation, methotrexate, tretinoin, biologics, oral calcineurin inhibitors, or high-potency or oral corticosteroids in the past 12 months. • Positive Epstein-Barr virus (EBV) capsid antigen IgM test at screening. EBV polymerase chain reaction (PCR) testing should be performed as clinically indicated to screen for acute infection or suspected chronic active infection. Participants with a positive EBV PCR test were excluded. • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., obstructive bronchitis), drug-induced pneumonitis or idiopathic pneumonia, or evidence of active pneumonia as screened by chest CT scan. • History of radiation pneumonitis (fibrosis) in a radiation field is permitted. • Active tuberculosis. • Severe cardiovascular disease (e.g., New York Heart Association class II or higher heart disease, myocardial infarction, or cerebrovascular accident), unstable arrhythmias, or unstable angina within 3 months before the start of study treatment. • Major surgery within 4 weeks prior to the start of study treatment, or anticipated need for major surgery during the study treatment period. • History of malignancy within 5 years prior to the start of study treatment (except for cancers studied in this study and malignant tumors with negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated cervical carcinoma in situ, non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, or stage I uterine cancer). • Serious infection within 4 weeks prior to the start of study treatment, including but not limited to hospitalization for infection, bacteremia, or severe pneumonia, or any active infection that could affect the safety of the participant. •Therapeutic oral or IV antibiotic therapy within 2 weeks prior to initiation of study treatment. Participants receiving prophylactic antibiotics (e.g., to prevent urinary tract infection or exacerbation of chronic obstructive pulmonary disease (COPD)) were eligible for the study. •Prior allogeneic stem cell or solid organ transplantation. •Use of study medications, any other disease, metabolic disorder, physical examination finding, or clinical laboratory finding that may affect the interpretation of results or may place the participant at high risk for treatment complications were prohibited. • Treatment with live attenuated vaccines within 4 weeks prior to starting study treatment, or within 90 days after the last dose of tisleliumab/placebo, and within 5 months after the last dose of atezolizumab if such vaccines are anticipated during study treatment. • Treatment with study treatment within 28 days prior to starting study treatment. • Prior treatment with CD137 agonists or immune checkpoint blockade therapy, including anti-CTLA-4, anti-TIGIT, anti-PD-L1, and anti-PD-1 therapeutic antibodies • Treatment with systemic immune stimulants (including, but not limited to, interferons and IL-2) within 4 weeks or within 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment. • Participants who have been treated with systemic immunosuppressive medications (including but not limited to corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α (TNF-α) agents) within 2 weeks prior to the start of study treatment, or who anticipate the need for systemic immunosuppressive medications during study treatment, with the following exceptions: • Participants who have received acute low-dose systemic immunosuppressive medications or a one-time pulse dose of systemic immunosuppressive medications (e.g., 48-hour corticosteroids for comparator allergy) are eligible to participate in the study. • Participants receiving corticosteroids (e.g., fluocortisol), inhaled or low-dose corticosteroids for COPD or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency were eligible for the study. • History of severe allergic allergic reaction to chimeric or humanized antibodies or fusion proteins. • Known allergy to Chinese Hamster Ovary Cell products or any component of atezolizumab or tisleliumab formulations. • Pregnancy or breastfeeding, or attempts to become pregnant, during study treatment, within 90 days after the last dose of tisleliumab/placebo, or within 5 months after the last dose of atezolizumab • Any circumstances that the investigator believes would interfere with the participant's safe participation in and completion of the study, the assessment of study medication, or the participant's safety or the interpretation of study results.Example4: Study Treatment and Concomitant Therapy

表 7 提供針對 GO45006 研究的經分配之研究治療的描述。表7.研究治療描述替瑞利尤單抗替瑞利尤單抗安慰劑阿替利珠單抗用途實驗安慰劑實驗藥物形式液體濃縮物液體液體濃縮物單位劑量規格600 mg/10 mL不適用1200 mg/20 mL 或 840 mg/14 mL劑量水平840 mg Q4W840 mg1680 mg Q4W投予途徑IV 輸注。Q4W = 每 4 周。Table 7 provides a description of the assigned study treatments for Study GO45006.Table7.Study Treatment DescriptionTirelizumabTirelizumabplaceboAtezolizumabuse Experiment Placebo ExperimentDrug form Liquid concentrates Liquid Liquid concentratesUnit dosage specifications 600 mg/10 mL Not applicable 1200 mg/20 mL or 840 mg/14 mLDosage Level 840 mg Q4W 840 mg 1680 mg Q4WAdministration IV infusion. Q4W = every 4 weeks.

治療方案總結如下。如本文所用，「研究治療」係指作為研究的一部分分配給參與者的治療組合 (例如，阿替利珠單抗加替瑞利尤單抗)。The treatment regimens are summarized below. As used herein, "study treatment" refers to the treatment combination assigned to a participant as part of a study (e.g., atezolizumab plus tirizumab).

所有研究治療投予均在受監控的環境中進行，其中可立即獲得訓練有素的人員及足夠的設備及藥物以控制可能發生的嚴重反應。A.替瑞利尤單抗及阿替利珠單抗或者安慰劑及阿替利珠單抗All study treatment administrations were conducted in a monitored environment with immediate access to trained personnel and adequate equipment and medications to manage possible severe reactions.A.Tisrelizumab and atezolizumab or placebo and atezolizumab

按照表 8 中概述的說明投予替瑞利尤單抗/阿替利珠單抗以及安慰劑/阿替利珠單抗共同輸注液。Tisellimumab/atezolizumab and placebo/atezolizumab co-infusions were administered as outlined in Table 8.

在各 28 天週期的第 1 天，替瑞利尤單抗或安慰劑藉由 IV 輸注以固定劑量 840 mg 以及 1680 mg 阿替利珠單抗 (混合在同一 IV 袋中以進行共同輸注) 投予。On Day 1 of each 28-day cycle, tisleliumab or placebo was administered by IV infusion at a fixed dose of 840 mg along with 1680 mg of atezolizumab (mixed in the same IV bag for co-infusion).

除第 1 週期的第 1 天以及治療中止後的 6 個月及 12 個月 (或疾病復發後 6 個月) 外，治療期期間的所有其他研究訪視及評定均可在預定日期的 ± 3 天內進行。因此，替瑞利尤單抗/阿替利珠單抗及安慰劑/阿替利珠單抗共同輸注液可在各 28 天週期的第 1 天 ± 3 天投予，但第 1 週期除外。表8.與替瑞利尤單抗/安慰劑混合的阿替利珠單抗的首次及後續輸注之投予首次輸注後續輸注• 對於在同一個 IV 輸液袋中首次輸注替瑞利尤單抗/安慰劑及阿替利珠單抗，不允許術前用藥。 • 記錄開始輸注之前 60 分鐘內參與者的生命徵象 (脈搏數、呼吸頻率、血壓及體溫)。 • 初始劑量係歷經 90 (± 10) 分鐘投予。 • 若在臨床上指示，則在輸注期間每 15 (± 5) 分鐘記錄參與者的生命徵象。• 在開始輸注之前 60 分鐘內記錄參與者的生命徵象。 • 如果上次輸注耐受性良好，且未出現輸注相關反應 (IRR)，則下次輸注的遞送時間可縮短 30 分鐘，條件係輸注時間保持不少於 30 分鐘。 • 如果參與者在首次或任何後續輸注期間出現 IRR 或過敏反應，則研究者可酌情在後續輸注中投予抗組織胺及/或退燒藥物。如果上次輸注出現 IRR，則下次輸注的持續時間不應小於上次輸注的持續時間。 • 如果臨床上指示，則輸注期間每 15 (±5) 分鐘記錄生命徵象。B.治療分配及盲法治療分配All other study visits and assessments during the treatment period can be performed within ± 3 days of the scheduled date, except for Day 1 of Cycle 1 and 6 and 12 months after treatment discontinuation (or 6 months after disease relapse). Therefore, co-infusions of tisleliumab/atezolizumab and placebo/atezolizumab can be administered on Day 1 ± 3 days of each 28-day cycle, except Cycle 1.Table8.Administration of the First and Subsequent Infusions of Atezolizumab Mixedwith Tisleliumab/ Placebo First infusion Subsequent infusion • For the first infusion of tisleliumab/placebo and atezolizumab in the same IV bag, no premedication is allowed. • Record the participant’s vital signs (pulse rate, respiratory rate, blood pressure, and temperature) for 60 minutes prior to starting the infusion. • The initial dose is administered over 90 (± 10) minutes. • Record the participant’s vital signs every 15 (± 5) minutes during the infusion, if clinically indicated. • Record the participant’s vital signs for 60 minutes prior to the start of the infusion. • If the previous infusion was well tolerated and no infusion-related reactions (IRRs) occurred, the next infusion may be delivered 30 minutes shorter, provided the infusion duration is maintained at no less than 30 minutes. • If a participant experiences an IRR or allergic reaction during the first or any subsequent infusion, antihistamines and/or antipyretics may be administered with subsequent infusions at the investigator’s discretion. If an IRR occurred with the previous infusion, the duration of the next infusion should not be less than the duration of the previous infusion. • Record vital signs every 15 (±5) minutes during the infusion, if clinically indicated.B.Treatment Allocation and BlindedTreatment Allocation

該研究為一項隨機、雙盲研究。This study was a randomized, double-blind study.

隨機分組必須在最後一劑化學療法後 70 天 (10 周) 內完成。有資格的參與者按 1:1 的比例隨機分組以接受替瑞利尤單抗加阿替利珠單抗或安慰劑加阿替利珠單抗。如果可能，則參與者在隨機分組當天接受其第一劑研究治療。如果不可能，則應在隨機分組後 5 天內進行第一劑。Randomization must be completed within 70 days (10 weeks) of the last dose of chemotherapy. Eligible participants are randomized 1:1 to receive either tisleliumab plus atezolizumab or placebo plus atezolizumab. Participants receive their first dose of study treatment on the day of randomization, if possible. If not possible, the first dose should be given within 5 days of randomization.

有資格的參與者根據腫瘤組織學 (鱗狀與非鱗狀)、疾病分期 (II 期與 IIIA 期 + 選定的 IIIB 期 (T3N2)) 以及藉由研究性 VENTANA PD-L1 (SP263) CDx 測定法確定的 PD-L1 狀態 ((≥1% 且 ＜50% TC 與 ≥ 50% TC) 進行分層。應用置換區組隨機分組以確保在分層因素水準內平衡分配到各治療臂。C.聯合療法允許的療法Eligible participants were stratified based on tumor histology (squamous vs. nonsquamous), disease stage (stage II vs. stage IIIA + selected stage IIIB (T3N2)), and PD-L1 status as determined by the investigational VENTANA PD-L1 (SP263) CDx assay (≥1% and <50% TC vs. ≥50% TC). Permuted block randomization was applied to ensure balanced allocation to treatment arms within the levels of the stratified factors.C.Combination TherapiesPermitted Therapies

在研究期間，允許參與者使用以下療法： • 每年失敗率 ＜ 1% 的口服避孕藥。 • 激素替代療法。 • 預防性或治療性抗凝療法 (諸如穩定劑量的華法林或低分子量肝素)。 • 疫苗接種 (諸如流感，COVID-19)。不允許使用減毒活疫苗。 • 作為食慾刺激劑投予之乙酸甲地羥孕酮。 • 礦皮質素 (例如，氟可體松)。 • 因 COPD 或哮喘而投予皮質類固醇。 • 因體位性低血壓或腎上腺皮質功能不全而投予小劑量皮質類固醇。During the study, participants were allowed to use the following therapies:• Oral contraceptives with a failure rate of < 1% per year.• Hormone replacement therapy.• Prophylactic or therapeutic anticoagulation (eg, stable-dose warfarin or low molecular weight heparin).• Vaccinations (eg, influenza, COVID-19). Live attenuated vaccines were not allowed.• Megestrol acetate given as an appetite stimulant.• Mineralocorticoids (eg, fluocortisol).• Corticosteroids for COPD or asthma.• Low-dose corticosteroids for orthostatic hypotension or adrenocortical insufficiency.

根據研究者的判斷，可在第二次及後續輸注中投予抗組胺藥、退熱藥及/或止痛藥進行預防用藥。Antihistamines, antipyretics, and/or analgesics may be administered as prophylactic medication during the second and subsequent infusions at the investigator's discretion.

通常，研究者按照本地標準規範，採用臨床上指示的以下定義為慎用或禁用療法的支持療法以外的其他支持療法來管理參與者的護理 (包括原有疾病)。出現輸注相關症狀的參與者可用對乙醯胺酚、伊布洛芬 (ibuprofen)、苯海拉明、及/或​H₂受體拮抗劑 (例如，啡莫替定 (famotidine)、希美替定 (cimetidine)) 對症治療，或根據當地標準實踐投予同等用藥。表現為呼吸困難、低血壓、哮喘、支氣管痙攣、心動過速、血氧飽及度下降或呼吸窘迫的嚴重輸注相關事件用臨床上指示的支持療法 (例如，補充氧及 β2-腎上腺素促效劑) 進行控制。慎用療法In general, investigators managed participants’ care (including pre-existing conditions) using supportive therapies as clinically indicated, in accordance with local standard practices, other than those defined below as cautionary or contraindicated therapies. Participants who experienced infusion-related symptoms were treated symptomatically with acetaminophen, ibuprofen, diphenhydramine, and/or_H2 receptor antagonists (e.g., famotidine, cimetidine), or equivalent medications in accordance with local standard practices. Severe infusion-related events manifested by dyspnea, hypotension, asthma, bronchospasm, tachycardia, decreased oxygen saturation, orrespiratory distress are managed with supportive therapy (e.g., supplemental oxygen and beta-2-adrenaline agonists) as clinically indicated.

全身性皮質類固醇、免疫抑制藥物及 TNF-α 抑制劑可能減弱用替瑞利尤單抗及/或阿替利珠單抗進行治療的潛在有益免疫學效應。因此，在常規投予全身性皮質類固醇、免疫抑制藥物或 TNF-α 抑制劑的情況下，應考慮使用替代藥物，包括抗組織胺。若替代方案不可行，則可根據研究者的判斷投予全身性皮質類固醇、免疫抑制藥物及 TNF-α 抑制劑。Systemic corticosteroids, immunosuppressive drugs, and TNF-α inhibitors may attenuate the potential beneficial immunologic effects of treatment with tisleliumab and/or atezolizumab. Therefore, alternative agents, including antihistamines, should be considered in the setting of conventional administration of systemic corticosteroids, immunosuppressive drugs, or TNF-α inhibitors. If alternatives are not feasible, systemic corticosteroids, immunosuppressive drugs, and TNF-α inhibitors may be administered at the investigator's discretion.

根據研究者的決定，建議使用全身性皮質類固醇或免疫抑制藥物，以治療當與替瑞利尤單抗及/或阿替利珠單抗療法相關聯時的特定不良事件。Systemic corticosteroids or immunosuppressive drugs are recommended at the investigator's discretion for specific adverse events when associated with tisleliumab and/or atezolizumab therapy.

不建議同時使用草藥療法，因為它們的藥物動力學、安全性及潛在藥物交互作用通常為未知者。惟，於研究過程中，研究者可以酌情決定使用不旨在治療癌症的草藥療法。禁用療法Concomitant use of herbal therapies is not recommended because their pharmacokinetics, safety, and potential for drug interactions are generally unknown. However, during the course of a study, the investigator may, at their discretion, use herbaltherapies that are not intended to treat cancer.

如下所述，禁止使用以下伴隨療法： •旨在治療癌症的合併療法 (包括但不限於化學療法、激素療法、免疫療法、放射療法 (RT) 及草藥療法)，無論是經過衛生當局核准還是實驗性的，在開始研究治療之前的各種時間段內 (取決於藥劑)，以及在研究治療期間，直到記錄到疾病復發以及參與者中止研究治療。 •研究性療法，在開始研究治療之前的 28 天內及研究治療期間 •減毒活疫苗 (例如，FluMist®)，在開始研究治療之前的 4 週內，研究治療期間，最後一劑替瑞利尤單抗/安慰劑後 90 天內以及最後一劑阿替利珠單抗後 5 個月內。 •全身性免疫刺激劑 (包括但不限於 IFN 及 IL-2)，在開始研究治療之前的 4 週內或 5 個藥物消除半衰期 (以較長者為準) 內及研究治療期間，因為這些藥劑可能增加與研究治療組合給予時自身免疫病症的風險。實例5：研究評定及程序As described below, the following concomitant therapies are prohibited: • Concomitant therapies intended to treat cancer (including but not limited to chemotherapy, hormonal therapy, immunotherapy, radiation therapy (RT), and herbal therapies), whether approved by health authorities or experimental, for various periods of time prior to the start of study treatment (depending on the agent), and during study treatment until disease recurrence is documented and the participant discontinues study treatment. • Investigational therapies within 28 days prior to initiation of study treatment and during study treatment • Live attenuated vaccines (e.g., FluMist®) within 4 weeks prior to initiation of study treatment, during study treatment, within 90 days after the last dose of tisleliumab/placebo, and within 5 months after the last dose of atezolizumab. • Systemic immune stimulants (including but not limited to IFN and IL-2) within 4 weeks prior to initiation of study treatment or 5 drug elimination half-lives (whichever is longer) and during study treatment, as these agents may increase the risk of autoimmune disorders when given in combination with study treatment.Example5: Study Assessments and Procedures

在整個研究過程中，密切監測參與者的安全性。每劑前應對參與者進行毒性評定；只有在臨床評定及實驗室測試值均可接受的情況下才投予治療。A.功效評定The safety of participants was closely monitored throughout the study. Toxicity assessments were performed on participants before each dose; treatment was only given if clinical assessments and laboratory test values were acceptable.A.Efficacy Assessment

篩選及後續疾病評定包括胸部及腹部 (包括肝臟及腎上腺) 之使用造影劑的電腦斷層攝影 (CT) 掃描。如果使用造影劑的 CT 掃描係禁忌的 (例如，在腎清除率受損的參與者中)，則胸部非造影劑 CT 加腹部磁振造影 (MRI) 係較佳的，以及胸部/腹部 CT 非造影劑係可接受的。篩選時必須進行 MRI 掃描 (較佳) 或腦部造影劑 CT，以評估所有參與者的 CNS 轉移情況 (如果 CT 掃描係禁忌的，則必須進行 MRI 掃描)。如果 CT 掃描可疑，則需要進行腦部 MRI 掃描來確認或反駁基線時 CNS 轉移的診斷。如有臨床上指示，亦應進行頸部骨掃描及 CT 掃描。Screening and subsequent disease assessment included a computed tomography (CT) scan of the chest and abdomen (including the liver and adrenal glands) with contrast. If CT scan with contrast is contraindicated (e.g., in participants with impaired renal clearance), non-contrast CT of the chest plus magnetic resonance imaging (MRI) of the abdomen is preferred, and non-contrast CT of the chest/abdomen is acceptable. An MRI scan (preferably) or CT of the brain with contrast was mandatory at screening to assess for CNS metastases in all participants (MRI scan mandatory if CT scan is contraindicated). If the CT scan is equivocal, a brain MRI scan is indicated to confirm or refute the baseline diagnosis of CNS metastases. A cervical bone scan and CT scan should also be obtained if clinically indicated.

篩選時使用的相同的放射線照相方式 (例如，使用造影劑的 CT) 及程序 (例如，相同的 CT 掃描造影劑方案) 應該用於後續疾病評定。B.臨床結局評估The same radiographic modality (eg, CT with contrast) and procedure (eg, same CT scan contrast agent protocol) used for screening should be used for subsequent disease assessment.B.ClinicalOutcome Assessments

完成患者報告結果 (PRO) 工具，以評定患者報告的替瑞利尤單抗加阿替利珠單抗在選定劑量下的耐受性，並確認雙效組合的安全性概況。此外，PRO 工具使得能夠捕捉各參與者對替瑞利尤單抗加阿替利珠單抗的直接體驗。A patient-reported outcomes (PRO) tool was completed to assess patient-reported tolerability of tisleliumab plus atezolizumab at the selected doses and to confirm the safety profile of the dual-effect combination. In addition, the PRO tool enabled the capture of individual participants’ direct experience with tisleliumab plus atezolizumab.

PRO 資料透過使用以下工具收集：歐洲癌症研究與治療組織 (EORTC) QLQ-C30、EORTC QLQ-LC13、EORTC-IL46 及 PRO-CTCAE (選定項目) 及 EQ-5D-5L。PRO data were collected using the following instruments: European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-LC13, EORTC-IL46, and PRO-CTCAE (selected items) and EQ-5D-5L.

以下列順序投予 PRO：EORTC QLQ-C30、EORTC QLQ-LC13、EORTC-IL46、PRO-CTCAE (選定項目) 及 EQ-5D-5L。PROs were administered in the following order: EORTC QLQ-C30, EORTC QLQ-LC13, EORTC-IL46, PRO-CTCAE (selected items), and EQ-5D-5L.

QLQ-C30 係經驗證之可靠的自我報告量度 (參見 Aaronson 等人,J Natl Cancer Inst, 85: 365-376, 1993；Fitzsimmons 等人,Eur J Cancer, 35: 939-941, 1999)。The QLQ-C30 is a validated, reliable self-report measure (see Aaronson et al.,J Natl Cancer Inst , 85: 365-376, 1993; Fitzsimmons et al.,Eur J Cancer , 35: 939-941, 1999).

EORTC QLQ-LC13 是自我報告的 PRO 量度，其係 EORTC QLQ-C30 之肺癌特異性模組 (Bergman 等人,Eur J Cancer, 30A: 635-642, 1994)。The EORTC QLQ-LC13 is a self-reported PRO measure that is a lung cancer-specific module of the EORTC QLQ-C30 (Bergman et al.,Eur J Cancer , 30A: 635-642, 1994).

PRO-CTCAE 係經驗證之項目庫，用於表徵 78 種參與者可報告的對症治療毒性之存在、發生頻率、嚴重程度及/或對日常功能的干擾程度 (Basch 等人,J Natl Cancer Inst, 106: 1-11, 2014；Dueck 等人,JAMA Oncol, 1: 1051-1059, 2015)。PRO-CTCAE is a validated item bank that characterizes the presence, frequency, severity, and/or interference with daily functioning of 78 participant-reportable symptomatic treatment toxicities (Basch et al.,J Natl Cancer Inst , 106: 1-11, 2014; Dueck et al.,JAMA Oncol , 1: 1051-1059, 2015).

EORTC IL46 係 EORTC 項目庫中經驗證的單一項目，用於評定參與者因其治療副作用而困擾的程度。它採用 4 分制評分，範圍從“完全不”到“非常”。The EORTC IL46 is a validated single item from the EORTC item bank that assesses the extent to which participants are bothered by the side effects of their treatment. It is rated on a 4-point scale ranging from “not at all” to “very much”.

EQ-5D-5L 係經驗證的自我報告健康狀態問卷，其用於計算健康狀態效用評分以用於健康經濟分析 (EuroQol Group,Health Policy, 16: 199-208, 1990；Brooks,Health Policy, 37: 53-72, 1996；Herdman 等人,Qual Life Res,20: 1727-1736, 2011；Janssen 等人,Qual Life Res,22: 1717-1727, 2013)實例6：統計考量EQ-5D-5L is a validated self-report health status questionnaire that is used to calculate health status utility scores for use in health economic analysis (EuroQol Group,Health Policy , 16: 199-208, 1990; Brooks,Health Policy , 37: 53-72, 1996; Herdman et al.,Qual Life Res, 20: 1727-1736, 2011; Janssen et al.,Qual Life Res, 22: 1717-1727, 2013)Example6: Statistical considerations

正式測試關於與安慰劑加阿替利珠單抗相比的替瑞利尤單抗加阿替利珠單抗對 PD-L1 高分析集 (PHAS) (PD-L1 ≥ 50% TC，SP263) 及全分析集 (FAS) (PD-L1 ≥ 1% TC，SP263 CDx 測定法) 中研究者評定的無疾病存活 (DFS) 的影響的假設。關於 PHAS 及 FAS 中研究者評定的 DFS 的零假設 (H0) 及替代假設 (H1) 分別在 0.038 及 0.012 的雙側顯著性水準上進行檢驗，並且可用實驗臂與對照臂之間的群體風險比 λ 來表述： H0：λ = 1 與 H1：λ ≠1 除非另有說明，否則所有假設檢驗都係雙側的。A.樣品大小判定The hypothesis was formally tested regarding the effect of tisleliumab plus atezolizumab compared with placebo plus atezolizumab on investigator-assessed disease-free survival (DFS) in the PD-L1 High Analysis Set (PHAS) (PD-L1 ≥ 50% TC, SP263) and Full Analysis Set (FAS) (PD-L1 ≥ 1% TC, SP263 CDx assay). The null hypothesis (H0) and the alternative hypothesis (H1) regarding the investigator-rated DFS in PHAS and FAS were tested at two-sided significance levels of 0.038 and 0.012, respectively, and can be expressed by the population hazard ratio λ between the experimental arm and the control arm: H0: λ = 1 and H1: λ ≠1 Unless otherwise stated, all hypothesis tests are two-sided.A.Sample size determination

將總共約 1150 名參與者 (藉由研究性 VENTANA PD-L1 (SP263) CDx 測定法確定，約 700 名 PD-L1 ≥ 50% TC 的參與者及約 450 名 PD-L1 ≥1% 且 ＜50% TC 的參與者) 隨機分組到研究中。詳細的假設及計算如下所列。I類誤差控制A total of approximately 1150 participants (approximately 700 participants with PD-L1 ≥ 50% TC and approximately 450 participants with PD-L1 ≥1% and <50% TC as determined by the investigational VENTANA PD-L1 (SP263) CDx assay) were randomly assigned to the study. Detailed assumptions and calculations are listed below. TypeIError Control

該研究的總體 I 類誤差率為 0.05 (雙側)。PHAS 及 FAS 中研究者評定的 DFS 的主要終點分別在雙側 α 水準為 0.038 及 0.012 下進行檢驗。The study had an overall type I error rate of 0.05 (bilateral). The primary endpoint of investigator-assessed DFS in PHAS and FAS was tested at bilateral alpha levels of 0.038 and 0.012, respectively.

如果 DFS 在 PHAS 中具有統計顯著性，則將 0.038 的雙側 α 回收到 FAS，並在 0.05 的雙側 α 下檢驗 FAS。If DFS was statistically significant in PHAS, it was recycled to FAS at a two-sided α of 0.038 and tested in FAS at a two-sided α of 0.05.

如果 DFS 在 FAS 中具有統計顯著性，則將 0.012 的雙側 α 回收到 PHAS，以在 0.05 的雙側 α 水準下檢驗。If DFS was statistically significant in FAS, a two-sided α of 0.012 was carried back to PHAS to be tested at a two-sided α level of 0.05.

只要任何主要終點係陽性的，該研究就係陽性的。研究者評定之無疾病存活As long as any primary endpoint is positive, the study is positive.Investigator-rated disease-free survival

當已觀察到 PHAS 中約 322 個 DFS 事件及 FAS 中約 652 個 DFS 事件 (以較晚發生者為準) 時，將對研究者評定的 DFS 主要終點進行最終分析。The final analysis of the primary endpoint of investigator-assessed DFS will be performed when approximately 322 DFS events in PHAS and 652 DFS events in FAS (whichever occurs later) have been observed.

證明 PHAS 中關於 DFS 的療效所需的估計事件數量係基於以下假設： •   隨機分組比例為 1:1。 •   雙側 α 為 0.038。 •   DFS 曲線遵循指數分佈。 •   安慰劑加阿替利珠單抗臂的中值 DFS 為 65 個月。 •   以 85% 效力檢測之檢測 DFS HR 為 0.70。 •   當 PHAS 中發生約 249 個 DFS 事件時，將進行一項期中分析。停止邊界係使用廣義 Haybitttle-Peto 邊界計算的 (Haybittle,Brit J Radiology,44: 793-797, 1971)，期中及最終 DFS 分析的 p 值不相等，分別為 0.0260 及 0.0252。 •   入組期為約 64 個月。 •   每年脫落率為 5%。The estimated number of events needed to demonstrate efficacy with respect to DFS in PHAS was based on the following assumptions: • The randomization ratio was 1:1. • The two-sided alpha was 0.038. • The DFS curve followed an exponential distribution. • The median DFS in the placebo plus atezolizumab arm was 65 months. • The HR for detecting DFS with 85% power was 0.70. • An interim analysis will be performed when approximately 249 DFS events have occurred in PHAS. The stopping margin was calculated using the generalized Haybitttle-Peto margin (Haybittle,Brit J Radiology, 44: 793-797, 1971), and the p-values for the interim and final DFS analyses were unequal, 0.0260 and 0.0252, respectively. • The enrollment period is approximately 64 months. • The annual shedding rate is 5%.

證明 FAS 中關於 DFS 的療效所需的估計事件數量係基於以下假設： •   隨機分組比例為 1:1。 •   雙側 α 為 0.012。 •   D 曲線遵循指數分佈。 •   安慰劑加阿替利珠單抗臂的中值 DFS 為 51 個月。 •   以 74% 效力檢測之檢測 DFS HR 為 0.78。 •   當 FAS 中發生約 539 個 DFS 事件時，將進行一項期中分析。停止邊界係使用廣義 Haybitttle-Peto 邊界計算的 (Haybittle,Brit J Radiology,44: 793-797, 1971)，p 值不相等，分別為 0.0090 及 0.0071 (期中 DFS 分析及最終 DFS 分析。 •   入組期為約 64 個月。 •   每年脫落率為 5%。The estimated number of events needed to demonstrate efficacy with respect to DFS in FAS is based on the following assumptions: • The randomization ratio is 1:1. • The two-sided alpha is 0.012. • The D curve follows an exponential distribution. • The median DFS in the placebo plus atezolizumab arm is 51 months. • The HR for detecting DFS is 0.78 with 74% power. • An interim analysis will be performed when approximately 539 DFS events have occurred in FAS. The stopping margin was calculated using the generalized Haybitttle-Peto margin (Haybittle,Brit J Radiology, 44: 793-797, 1971), with unequal p-values of 0.0090 and 0.0071 (interim and final DFS analyses, respectively. • The enrollment period was approximately 64 months. • The annual dropout rate was 5%.

根據這些假設，最終 DFS 分析將在第一個參與者被隨機分組後約 120 個月進行。最終分析時 DFS HR 的最小可檢測差異大約為針對 PHAS 的 0.78 及針對 FAS 的 0.81。B.分析集Based on these assumptions, the final DFS analysis will be conducted approximately 120 months after the first participant is randomized. The minimally detectable difference in DFS HR at the final analysis is approximately 0.78 forPHAS and 0.81 for FAS.B.Analysis Set

用於分析目的的參與者分析集定義於表 9 中。表9.參與者分析集參與者分析集描述FAS所有隨機分組參與者；根據分配給參與者的治療將他們納入分析。PHAS所有隨機分組參與者的 PD-L1 50% TC，藉由研究性 VENTANA PD-L1 (SP263) CDx 測定法確定；根據分配給參與者的治療將他們納入分析。SAS全部參與者皆曝露於研究治療；根據參與者實際接受的治療對他們進行分析。阿替利珠單抗 PK 分析集所有參與者皆接受任一劑量的阿替利珠單抗且至少進行 1 次基線後阿替利珠單抗 PK 評定。替瑞利尤單抗 PK 分析集所有參與者皆接受任一劑量的替瑞利尤單抗且至少進行 1 次基線後替瑞利尤單抗 PK 評定。阿替利珠單抗 ADA 分析集所有參與者皆接受至少一劑的阿替利珠單抗治療並具有來自至少一份樣品的 ADA 測定結果。替瑞利尤單抗 ADA 分析集所有參與者皆接受至少一劑的替瑞利尤單抗治療並具有來自至少一份樣品的 ADA 測定結果。ADA = 抗藥物抗體；FAS = 全分析集；PHAS = PD-L1 高分析集；SAS = 安全性分析集；PKAS = 藥物動力學分析集。C.統計分析The analysis set of participants used for analysis purposes is defined in Table 9.Table9.Analysis set of participants Participant Analysis Set describe FAS All randomized participants; participants were included in the analysis according to the treatment to which they were assigned. PHAS PD-L1 in all randomized participants 50% TC, as determined by the investigational VENTANA PD-L1 (SP263) CDx assay; participants were included in the analysis based on their assigned treatment. SAS All participants were exposed to study treatment; participants were analyzed according to the treatment they actually received. Atezolizumab PK Analysis Set All participants received any dose of atezolizumab and underwent at least 1 post-baseline atezolizumab PK assessment. Tirelizumab PK Analysis Set All participants received any dose of tisleliumab and underwent at least 1 post-baseline tisleliumab PK assessment. Atezolizumab ADA Analysis Set All participants received at least one dose of atezolizumab and had an ADA assay result from at least one sample. Tirelizumab ADA Analysis Set All participants received at least one dose of tisleliumab and had an ADA assay result from at least one sample. ADA = anti-drug antibodies; FAS = full analysis set; PHAS = PD-L1 high analysis set; SAS = safety analysis set; PKAS = pharmacokinetic analysis set.C.Statistical analysis

除非另做指定，否則全部療效分析皆針對 PHAS 及 FAS 進行。除非另做指定，否則所有安全性分析皆針對 SAS 進行。主要被估量的估計方法Unless otherwise specified, all efficacy analyses were performed on PHAS and FAS. Unless otherwise specified, all safety analyses were performed on SAS.Estimation Methods for Principal Estimators

研究的主要目的係評估與安慰劑加阿替利珠單抗相比的替瑞利尤單抗加阿替利珠單抗在切除 IIB 期、IIIA 期或選定的 IIIB 期 (僅 T3N2) (AJCC 第 8 版) PD-L1 ≥ 50% TC 且 PD-L1 ≥ 1% TC NSCLC 的已接受輔助鉑類化學療法的參與者中的療效。主要終點係 PHAS 及 FAS 中研究者評定的 DFS。The primary objective of the study was to evaluate the efficacy of tisleliumab plus atezolizumab compared with placebo plus atezolizumab in participants with resected stage IIB, IIIA, or selected stage IIIB (T3N2 only) (AJCC 8th edition) PD-L1 ≥ 50% TC and PD-L1 ≥ 1% TC NSCLC who had received adjuvant platinum-based chemotherapy. The primary endpoint was investigator-assessed DFS in PHAS and FAS.

研究者評定的 DFS 定義為由研究者判定的從隨機分組到發生 NSCLC 局部/區域或遠端復發、新的原發性 NSCLC 或任何原因導致的死亡 (以先發生者為準) 的時間。尚未經歷 NSCLC 局部/區域或遠端復發、新的原發性 NSCLC 或死亡的參與者的資料在上一個腫瘤評定日期進行審查。如果沒有可用的基線後資料，則 DFS 在隨機分組日期進行審查。Investigator-assessed DFS was defined as the time from randomization to the occurrence of local/regional or distant recurrence of NSCLC, new primary NSCLC, or death from any cause, as assessed by the investigator (whichever occurred first). Data for participants who had not experienced local/regional or distant recurrence of NSCLC, new primary NSCLC, or death were reviewed at the date of the last tumor assessment. If no post-baseline data were available, DFS was reviewed at the randomization date.

分層對數秩檢驗用於在兩個治療臂之間對 DFS 進行比較。DFS 的 HR 係使用分層 Cox 迴歸模型以及 95% CI 來估計的。FAS 中分析的分層因素包括組織學 (非鱗狀與鱗狀)、疾病分期 (IIB 期與 IIIA 期 + 選定的 IIIB 期 (T3N2)) 及 PD-L1 狀態 (≥1% 且 ＜50% TC 與 ≥50% TC)。PHAS 中分析的分層因素包括組織學及疾病分期。亦提供未經分層的分析結果。利用 Kaplan-Meier 方法估計各治療臂的中值 DFS，並繪製 Kaplan-Meier 曲線以直觀地描述臂之間的差異。利用 Brookmeyer-Crowley 方法構建各治療臂的中值 DFS 的雙側 95% CI。次要被估量的估計方法總存活The stratified log-rank test was used to compare DFS between the two treatment arms. The HR for DFS was estimated using a stratified Cox regression model with 95% CI. The stratification factors analyzed in FAS included histology (non-squamous vs. squamous), disease stage (stage IIB vs. stage IIIA + selected stage IIIB (T3N2)), and PD-L1 status (≥1% and <50% TC vs. ≥50% TC). The stratification factors analyzed in PHAS included histology and disease stage. Unstratified analysis results are also provided. The median DFS for each treatment arm was estimated using the Kaplan-Meier method, and Kaplan-Meier curves were plotted to visually describe the differences between the arms. The Brookmeyer-Crowley method was used to construct two-sided 95% CIs formedian DFS in each treatment arm.

隨機分組後之總存活 (OS) 定義為從隨機分組到任何原因導致的死亡的時間。在分析日期未報告死亡的參與者的資料將在其最後一次知曉存活的日期被審查。如果沒有可用的基線後資料，則 OS 在隨機分組日期進行審查。Overall survival (OS) after randomization was defined as the time from randomization to death from any cause. Data for participants whose deaths were not reported on the analysis date were censored at the date they were last known to be alive. If no post-baseline data were available, OS was censored at the randomization date.

比較 PHAS 與 FAS 中治療臂之間 OS 的方法與用於研究者評定的 DFS 的主要終點的治療比較的方法相同。在 DFS 分析時分析總存活。研究者評定的3年DFS率、5年DFS率及7年DFS率The method for comparing OS between treatment arms in PHAS and FAS was the same as the treatment comparison used for the primary endpoint of investigator-assessed DFS. Overall survival was analyzed at the time of the DFS analysis.Investigator-assessed3-yearDFSrate,5-yearDFSrate, and7-yearDFSrate

按治療臂分析研究者評定的 3 年 DFS 率、5 年 DFS 率及 7 年 DFS 率。各治療臂的 DFS 率藉由 Kaplan-Meier 方法估計，其中雙側 95% CI 使用 Greenwood 公式計算。臨床結果評定分析The 3-year, 5-year, and 7-year DFS rates assessed by the investigator were analyzed by treatment arm. The DFS rates of each treatment arm were estimated by the Kaplan-Meier method, with the two-sided 95% CIcalculated using the Greenwood formula.

藉由治療組總結在藉由 EORTC QLQ-C30 測量的患者報告的角色、情緒及身體功能以及 GHS/QoL 方面相對於基線保持或具有有意義的改善的參與者比例。一般來說，Osoba 等人 (J Clin Oncol,16: 139-144, 1998) 確定了 EORTC QLQ-C30 量表上 10 分或更多的變化係臨床上有意義的。這在肺癌患者的研究中得到了很大程度上的證實，並將應用對肺癌中 EORTC QLQ-C30 及 LC13 個體量表的具體估計值 (Coon 等人,Patient, 15: 691-702, 2022；Musoro 等人,Eur J Cancer, 188: 171-182, 2023)。基線保持被定義為這些領域的惡化程度增加或減少小於 10 分。安全性分析The proportion of participants who maintained or had a significant improvement from baseline in patient-reported role, emotional, and physical functioning and GHS/QoL as measured by the EORTC QLQ-C30 was summarized by treatment group. In general, Osoba et al. (J Clin Oncol, 16: 139-144, 1998) determined that a change of 10 points or more on the EORTC QLQ-C30 scale was clinically significant. This has been largely confirmed in studies of lung cancer patients and will apply to specific estimates of the EORTC QLQ-C30 and LC13 individual scales in lung cancer (Coon et al.,Patient , 15: 691-702, 2022; Musoro et al.,Eur J Cancer , 188: 171-182, 2023). Baseline maintenance was defined as an increase or decrease in deterioration of less than 10 points in these domains.Safety Analysis

安全性分析在 SAS 中進行，SAS 定義為接受至少一劑替瑞利尤單抗/安慰劑或阿替利珠單抗的參與者。藉由對研究治療藥物的暴露、不良事件、實驗室檢查結果的變化以及生命徵象及 ECG 的變化來評估安全性。Safety analyses were performed in the SAS, defined as participants who received at least one dose of tisleliumab/placebo or atezolizumab. Safety was assessed by exposure to study treatment, adverse events, changes in laboratory test results, and changes in vital signs and ECGs.

研究性治療暴露 (例如，治療持續時間、已接受的總劑量、週期數及劑量調整) 藉由描述性統計資料進行總結。Study treatment exposure (e.g., duration of treatment, total dose received, number of cycles, and dose adjustments) was summarized using descriptive statistics.

所有逐字記錄不良事件術語皆映射到醫學管理活動 (MedDRA) 詞典術語，且不良事件嚴重程度根據 NCI CTCAE v5.0 分級。細胞介素釋放症候群 (CRS) 根據 ASTCT CRS 共識分級量表進行分級。在第一劑研究治療期間或之後發生或惡化的全部不良事件、嚴重不良事件、導致死亡的不良事件、特別關注的不良事件以及導致研究治療中止的不良事件 (亦即，治療中出現的不良事件) 按映射的術語、適當的同義詞庫級別及嚴重程度等級進行匯總。對於嚴重程度不同的事件，總結中使用最高等級。總結死亡及死亡原因。All verbatim adverse event terms were mapped to Medically Regulatory Activities (MedDRA) dictionary terms, and the severity of adverse events was graded according to NCI CTCAE v5.0. Cytokine release syndrome (CRS) was graded according to the ASTCT CRS consensus grading scale. All adverse events that occurred or worsened during or after the first dose of study treatment, serious adverse events, adverse events leading to death, adverse events of special concern, and adverse events leading to discontinuation of study treatment (i.e., treatment-emergent adverse events) were summarized by mapped term, appropriate thesaurus level, and severity grade. For events of varying severity, the highest grade was used in the summary. Deaths and causes of death were summarized.

按時間顯示相關的實驗室檢查、生命徵象 (脈率、呼吸頻率、血壓、及體溫) 及 ECG 資料，並在適當時識別等級。此外，使用選定實驗室檢查的移位表來總結基線時及基線後的最高嚴重程度等級。總結生命徵象及 ECG 的變化。探索性分析臨床結果評定分析Relevant laboratory tests, vital signs (pulse rate, respiratory rate, blood pressure, and temperature), and ECG data were displayed over time and with grade identification when appropriate. In addition, a shift table of selected laboratory tests was used to summarize the highest severity grade at baseline and after baseline. Changes in vital signs and ECG were summarized.Exploratory AnalysesClinical Outcome Assessment Analysis

EORTC QLQ-C30 及 QLQ-LC13 的分析群體為 FAS。使用 FAS 按治療臂總結 EORTC QLQ-C30、QLQ-LC13 及 EQ-5D-5L 在各時間點的完成率。The analysis population for EORTC QLQ-C30 and QLQ-LC13 was FAS. Completion rates of EORTC QLQ-C30, QLQ-LC13, and EQ-5D-5L at each time point were summarized by treatment arm using FAS.

報告 EORTC QLQ-C30 及 EORTC QLQ-LC13 的所有項目及分量表的總結統計資料 (平均值、標準偏差 (SD)、中值、第 25 個及第 75 個百分位數以及範圍) 以及線性轉換評分相對於基線的平均變化。在每次訪視時按治療臂總結在 EORTC QLQ-C30 及 QLQ-LC13 量表中之每一者上有所改善、惡化或保持穩定的參與者的數量及比例。進行治療組之間的比較。Summary statistics (mean, standard deviation (SD), median, 25th and 75th percentiles, and range) and mean changes from baseline in linearly transformed scores were reported for all items and subscales of the EORTC QLQ-C30 and EORTC QLQ-LC13. The number and proportion of participants who improved, worsened, or remained stable on each of the EORTC QLQ-C30 and QLQ-LC13 scales were summarized by treatment arm at each visit. Comparisons between treatment groups were performed.

PRO-CTCAE 及 EORTC IL46 的分析群體為 SAS。資料隨時間的總結係基於各時間點提供資料的參與者數量。使用 SAS 群體按治療臂總結 PRO-CTCAE 及 EORTC IL46 在各時間點的完成率。The analysis population for PRO-CTCAE and EORTC IL46 was SAS. Data were summarized over time based on the number of participants who provided data at each time point. Completion rates for PRO-CTCAE and EORTC IL46 at each time point were summarized by treatment arm using the SAS population.

對於患者報告的耐受性，PRO-CTCAE 分析主要係描述性的，重點係表徵研究過程中症狀性 AE 發生的模式。PRO-CTCAE 資料根據目前 NCI 資料處理建議以項目水準進行分析 (Basch 等人,J Natl Cancer Inst, 106: 1-11, 2014)。每次就診時按治療臂報告按頻率、嚴重程度及乾擾報告症狀的參與者數量 (百分比)。每次訪視時亦按治療臂總結每種症狀之反應頻率相對於基線的變化。For patient-reported tolerability, PRO-CTCAE analyses were primarily descriptive, with an emphasis on characterizing the pattern of symptomatic AEs that occurred during the study. PRO-CTCAE data were analyzed at the item level according to current NCI data processing recommendations (Basch et al.,J Natl Cancer Inst , 106: 1-11, 2014). The number of participants (percentage) reporting symptoms by frequency, severity, and interference were reported by treatment arm at each visit. The change from baseline in the frequency of each symptom was also summarized by treatment arm at each visit.

在各評定時間點描述性總結藉由 EORTC IL46 項目測量的患者報告的副作用困擾。每次訪視時按治療臂報道報告困擾的參與者數量 (百分比)。每次訪視時亦按治療臂總結反應頻率相對於基線的變化。亞組療效分析Patient-reported side effect bothersomeness as measured by the EORTC IL46 item was summarized descriptively at each assessment time point. The number of participants (percentage) reporting bothersomeness was reported by treatment arm at each visit. The change in frequency of reactions from baseline was also summarized by treatment arm at each visit.Subgroup efficacy analysis

在 PHAS 及 FAS 中檢查人口統計學 (例如，年齡、性別、種族/族裔) 及基線預後特徵 (例如，腫瘤分期、研究性 VENTANA PD-L1 (SP263) CDx 測定法確定的 PD-L1 表現水平、隨機分組前的化學療法方案、組織學、吸菸史及 ECOG 體能狀態) 對研究者評定的 DFS 及 OS 之持續時間的影響。DFS 及 OS 的總結，包括根據 Cox 比例風險模型估計的未分層 HR 及中值存活時間的 Kaplan-Meier 估計值，係針對分類變量的各等級單獨產生的。里程碑時間點的DFS及OS率The effects of demographics (e.g., age, sex, race/ethnicity) and baseline prognostic characteristics (e.g., tumor stage, PD-L1 expression level as determined by the investigational VENTANA PD-L1 (SP263) CDx assay, chemotherapy regimen prior to randomization, histology, smoking history, and ECOG performance status) on the duration of investigator-assessed DFS and OS were examined in PHAS and FAS. Summary summaries of DFS and OS, including unstratified HRs estimated from Cox proportional hazards models and Kaplan-Meier estimates of median survival, were generated separately for each level of the categorical variables.DFSandOSratesat milestone time points

除了作為次要終點的 3 年 DFS 率、5 年 DFS 率及 7 年 DFS 率之外，PHAS 及 FAS 中各種其他時間點的 DFS 及 OS 率 (例如，3 年率、5 年率及 7 年率) 藉由 Kaplan-Meier 方法針對各治療臂進行估計，使用 Greenwood 公式計算雙側 95% CI，以用於探索性目的。生物標記分析In addition to the 3-year DFS rate, 5-year DFS rate, and 7-year DFS rate as secondary endpoints, DFS and OS rates at various other time points in PHAS and FAS (e.g., 3-year rate, 5-year rate, and 7-year rate) were estimated for each treatment arm by the Kaplan-Meier method, with two-sided 95% CIscalculated using the Greenwood formula for exploratory purposes.

研究了探索性生物標記分析，包括但不限於腫瘤及免疫相關基因特徵以及循環腫瘤 DNA 水準及動力學。此外，研究探索了 ctDNA 水準作為疾病復發的早期指標。藥物動力學分析Exploratory biomarker analyses were investigated, including but not limited to tumor and immune-related gene signatures and circulating tumor DNA levels and kinetics. In addition, ctDNA levels were explored as an early marker of disease recurrence.Pharmacokinetic Analysis

阿替利珠單抗的藥物動力學 (PK) 分析群體由所有接受任一劑量的阿替利珠單抗且至少進行 1 次基線後阿替利珠單抗 PK 評定的參與者組成。替瑞利尤單抗的 PK 分析群體由所有接受任一劑量的替瑞利尤單抗且至少進行 1 次基線後替瑞利尤單抗 PK 評定的參與者組成。收集樣品進行 PK 分析，且在適當情況下及資料允許的情況下，按治療臂及週期，將阿替利珠單抗及替瑞利尤單抗的血清濃度報告為單個值並總結 (平均值、標準偏差、變異係數、中值、範圍、幾何平均值及幾何平均值變異係數)。針對可 PK 評估的參與者，按天繪製單個及中值血清阿替利珠單抗及替瑞利尤單抗濃度。免疫原性分析The pharmacokinetic (PK) analysis population for atezolizumab consisted of all participants who received any dose of atezolizumab and had at least 1 post-baseline atezolizumab PK assessment. The PK analysis population for tisleliumab consisted of all participants who received any dose of tisleliumab and had at least 1 post-baseline tisleliumab PK assessment. Samples were collected for PK analysis, and serum concentrations of atezolizumab and tisleliumab were reported as single values and summarized (mean, standard deviation, coefficient of variation, median, range, geometric mean, and coefficient of variation of the geometric mean) by treatment arm and period, when appropriate and as data permitted. Individual and median serum atezolizumab andtisleliumab concentrations are plotted by day for PK-evaluable participants.

免疫原性分析包括接受任何 ADA 評定的參與者，並根據接受的治療對參與者進行分組。總結替瑞利尤單抗及阿替利珠單抗兩者的治療中出現的 ADA 陽性參與者及 ADA 陰性參與者的數量及比例。ADA 狀態與安全性、療效及 PK 終點之間的關係可以藉由描述性統計進行分析及報告。D.期中分析Immunogenicity analyses included participants who received any ADA assessment and were divided into groups according to the treatment received. The number and proportion of ADA-positive and ADA-negative participants who developed in both tisleliumab and atezolizumab treatments were summarized. The relationship between ADA status and safety, efficacy, and PK endpoints was analyzed and reported using descriptive statistics.D.Interim Analysis

計劃對 PHAS 及 FAS 中研究者評定的 DFS 進行一項期中分析。當 PHAS 中發生約 249 個 DFS 事件 (佔計劃 DFS 事件總數的 77%) 並且 FAS 中發生約 539 個 DFS 事件 (佔計劃 DFS 事件總數的 83%) (以較晚發生者為準) 時，進行計劃的 DFS 期中分析。此期中分析估計在第一位參與者入組研究後約 90 個月發生。An interim analysis of investigator-assessed DFS in PHAS and FAS is planned. The planned DFS interim analysis will be conducted when approximately 249 DFS events have occurred in PHAS (77% of the total planned DFS events) and approximately 539 DFS events have occurred in FAS (83% of the total planned DFS events), whichever occurs later. This interim analysis is estimated to occur approximately 90 months after the first participant is enrolled in the study.

當 PHAS 中發生大約 322 個 DFS 事件並且在 FAS 中發生大約 652 個 DFS 事件 (以較晚發生者為準) 時，進行最終的 DFS 分析。這估計在第一位參與者入組研究後約 120 個月進行。The final DFS analysis will be conducted when approximately 322 DFS events have occurred in PHAS and approximately 652 DFS events have occurred in FAS, whichever occurs later. This is estimated to be approximately 120 months after the first participant is enrolled in the study.

DFS 的期中及最終分析的停止邊界係使用廣義 Haybitttle-Peto 邊界計算的 (Haybittle,Brit J Radiology,44: 793-797, 1971)，依分析順序，PHAS 的雙側 p 值不相等，為 0.0260 及 0.0252，且 FAS 的雙側 p 值不相等，為 0.0090 及 0.0071。如果 PHAS 達到統計顯著性，則 α 將回收到FAS，且 FAS 的雙側 p 值為 0.0250 及 0.0436。如果 FAS 達到統計顯著性，則 α 將回收到PHAS，且 PHAS 的雙側 p 值為 0.0350 及 0.0331。The stopping boundaries for the interim and final analyses of DFS were calculated using the generalized Haybitttle-Peto boundary (Haybittle,Brit J Radiology, 44: 793-797, 1971), with unequal two-sided p-values of 0.0260 and 0.0252 for PHAS and unequal two-sided p-values of 0.0090 and 0.0071 for FAS, depending on the analysis order. If PHAS reached statistical significance, α would revert to FAS, with two-sided p-values of 0.0250 and 0.0436 for FAS. If FAS reached statistical significance, α would revert to PHAS, with two-sided p-values of 0.0350 and 0.0331 for PHAS.

儘管為了清楚理解起見，藉由圖示及實例的方式對上述發明進行了詳細描述，但是此等描述及實例不應被解釋是限製本發明之範圍。本文引用的所有專利及科學文獻的揭露內容皆以引用的方式明確納入其所有內容。Although the above invention is described in detail by way of illustrations and examples for the sake of clear understanding, such descriptions and examples should not be interpreted as limiting the scope of the invention. The disclosures of all patents and scientific documents cited herein are expressly incorporated by reference in their entirety.

圖1係顯示 GO45006 研究總體設計的示意圖。NSCLC = 非小細胞肺癌。Q4W = 每四週。「1% 至 49%」的 PD-L1 狀態係指高於背景的 PD-L1 膜染色 (TC) 等於或大於 1% 且小於 50%。序列表Figure1 is a schematic diagram showing the overall design of the GO45006 study. NSCLC = non-small cell lung cancer. Q4W = every four weeks. PD-L1 status of "1% to 49%" means PD-L1 membrane staining (TC) above background is equal to or greater than 1% and less than 50%.SEQUENCE LISTING

本申請包含序列表，該序列表已經以 XML 格式以電子方式提交，並以全文引用的方式併入本文中。該 XML 複本創建於 2024 年 8 月 20 日，命名為 50474-337TW2_Sequence_Listing_8_20_24，且大小為 33,043 位元組。This application contains a sequence listing that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on August 20, 2024, is named 50474-337TW2_Sequence_Listing_8_20_24, and is 33,043 bytes in size.

TW202515614A_113131711_SEQL.xmlTW202515614A_113131711_SEQL.xml

Claims (168)

Translated fromChinese

一種治療患有非小細胞肺癌 (NSCLC) 之個體之方法，該方法包含向該個體投予一個或多個給藥週期之替瑞利尤單抗 (tiragolumab) 及阿替利珠單抗 (atezolizumab)，其中該 NSCLC 已完全切除且該個體已接受輔助化學療法。A method of treating an individual having non-small cell lung cancer (NSCLC), the method comprising administering to the individual one or more dosing cycles of tiragolumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received adjuvant chemotherapy.一種治療患有非小細胞肺癌 (NSCLC) 之個體之方法，該方法包含向該個體投予輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除。A method of treating an individual having non-small cell lung cancer (NSCLC), the method comprising administering to the individual adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected.如請求項 1 或 2 之方法，其中該完全切除係肺葉切除術 (lobectomy)、袖式肺葉切除術 (sleeve lobectomy)、雙肺葉切除術 (bilobectomy) 或肺切除術 (pneumonectomy)。The method of claim 1 or 2, wherein the complete resection is a lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.如請求項 1 至 3 中任一項之方法，其中該完全切除係產生 (i) 無殘留腫瘤及 (ii) 所有手術切緣均呈侵襲性癌 (invasive carcinoma) 陰性之切除。The method of any of claims 1 to 3, wherein the complete resection is a resection resulting in (i) no residual tumor and (ii) all surgical margins being negative for invasive carcinoma.如請求項 1、3 及 4 中任一項之方法，其中該個體已接受介於一個給藥週期與四個給藥週期之間之該輔助化學療法。The method of any of claims 1, 3, and 4, wherein the subject has received between one dosing cycle and four dosing cycles of the adjuvant chemotherapy.如請求項 5 之方法，其中該個體已接受四個給藥週期之該輔助化學療法。The method of claim 5, wherein the subject has received four dosing cycles of the adjuvant chemotherapy.如請求項 2 至 4 中任一項之方法，其中該方法包含向該個體投予介於一個給藥週期與四個給藥週期之間之該輔助化學療法。The method of any one of claims 2 to 4, wherein the method comprises administering to the subject between one dosing cycle and four dosing cycles of the adjuvant chemotherapy.如請求項 7 之方法，其中該方法包含向該個體投予四個給藥週期之該輔助化學療法。The method of claim 7, wherein the method comprises administering four dosing cycles of the adjuvant chemotherapy to the individual.如請求項 1 至 8 中任一項之方法，其中該輔助化學療法為鉑類輔助化學療法。The method of any one of claims 1 to 8, wherein the adjuvant chemotherapy is platinum-adjuvant chemotherapy.如請求項 9 之方法，其中該鉑類輔助化學療法包含順鉑。The method of claim 9, wherein the platinum-assisted chemotherapy comprises cis-platinum.如請求項 9 之方法，其中該鉑類輔助化學療法包含卡鉑。The method of claim 9, wherein the platinum-assisted chemotherapy comprises carboplatin.如請求項 9 至 11 中任一項之方法，其中該鉑類輔助化學療法進一步包含一種或多種另外的化學治療劑。The method of any one of claims 9 to 11, wherein the platinum-assisted chemotherapy further comprises one or more additional chemotherapeutic agents.如請求項 12 之方法，其中該一種或多種另外的化學治療劑包含長春花屬生物鹼 (vinca alkaloid)、紫杉烷 (taxane)、抗代謝物、拓樸異構酶 II 抑制劑或其組合。The method of claim 12, wherein the one or more additional chemotherapeutic agents comprises a vinca alkaloid, a taxane, an anti-metabolite, a topoisomerase II inhibitor, or a combination thereof.如請求項 13 之方法，其中該長春花屬生物鹼為長春瑞濱 (vinorelbine)；該紫杉烷為多西紫杉醇 (docetaxel) 或紫杉醇 (paclitaxel)；該抗代謝物為吉西他濱 (gemcitabine) 或培美曲塞 (pemetrexed)；或者該拓樸異構酶 II 抑制劑為依托泊苷 (etoposide)。The method of claim 13, wherein the vinca alkaloid is vinorelbine; the taxane is docetaxel or paclitaxel; the anti-metabolite is gemcitabine or pemetrexed; or the topoisomerase II inhibitor is etoposide.如請求項 9 之方法，其中該鉑類輔助化學療法為鉑類輔助雙效化學療法 (platinum-based adjuvant doublet chemotherapy)。The method of claim 9, wherein the platinum-based adjuvant chemotherapy is platinum-based adjuvant doublet chemotherapy.如請求項 15 之方法，其中該鉑類輔助雙效化學療法包含： (i) 以一個或多個 21 天給藥週期投予之順鉑及培美曲塞，其中在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞； (ii) 以一個或多個 21 天給藥週期投予之順鉑及吉西他濱，其中在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且在各 21 天給藥週期之第 1 天及第 8 天以約 1250 mg/m²的劑量投予吉西他濱； (iii) 以一個或多個 21 天給藥週期投予之順鉑及多西紫杉醇，其中在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量投予多西紫杉醇； (iv) 以一個或多個 28 天給藥週期投予之順鉑及長春瑞濱，其中在各 28 天給藥週期之第 1 天及第 8 天以約 50 mg/m²的劑量靜脈內投予順鉑，且在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 25 mg/m²的劑量投予長春瑞濱； (v) 以一個或多個 28 天給藥週期投予之順鉑及長春瑞濱，其中在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，且在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 30 mg/m²的劑量投予長春瑞濱； (vi) 以一個或多個 21 天給藥週期投予之順鉑及長春瑞濱，其中在各 21 天給藥週期之第 1 天及第 8 天以約 75 至 80 mg/m²的劑量靜脈內投予順鉑，且在各 21 天給藥週期之第 1 天及第 8 天以約 25 至 30 mg/m²的劑量投予長春瑞濱； (vii) 以一個或多個 28 天給藥週期投予之順鉑及依托泊苷，其中在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，且在各 28 天給藥週期之第 1 天至第 3 天以約 100 mg/m²的劑量投予依托泊苷； (viii) 以一個或多個 21 天給藥週期投予之卡鉑及紫杉醇，其中在各 21 天給藥週期之第 1 天以 AUC 6 靜脈內投予卡鉑，且在各 21 天給藥週期之第 1 天以約 200 mg/m²的劑量投予紫杉醇； (ix) 以一個或多個 21 天給藥週期投予之卡鉑及吉西他濱，其中在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，且在各 21 天給藥週期之第 1 天及第 8 天以約 1000 mg/m²的劑量投予吉西他濱；或者 (x) 以一個或多個 21 天給藥週期投予之卡鉑及吉西他濱，其中在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，且在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞。The method of claim 15, wherein the platinum-based adjuvant dual-acting chemotherapy comprises: (i) cis-platinum and pemetrexed administered in one or more 21-day dosing cycles, wherein cis-platinum is administered intravenously at a dose of about 75 mg/^m2 on day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/^m2 on day 1 of each 21-day dosing cycle; (ii) cis-platinum and gemcitabine administered in one or more 21-day dosing cycles, wherein cis-platinum is administered intravenously at a dose of about 75 mg/m2 on day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/^m2 on day 1 of each 21-day dosing cycle (iii) cisplatin and docetaxel administered in one or more 21-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 75 mg/^m2 on Day 1 of each 21-day dosing cycle and docetaxel is administered at a dose of about 75 mg/^m2 on Day 1 of each 21-day dosing cycle; (iv) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein vinorelbine is administered intravenously at a dose of about 50 mg/^m2 on Day 1 and Day 8 of each 28-day dosing cycle. (v) cisplatin and vinorelbine administered in one or more^28- day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 30 mg/^m2 on day 1, day 8, day 15, and day 22 of each 28-day dosing cycle; (vi) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 100 mg/^{m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 30 mg/m2} on day 1, day 8, day 15, and day 22 of each 28-day dosing cycle; (vii) cisplatin and etoposide administered in one or more 28-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered intravenously at a dose of about 25 to 30 mg/^m2 on day 1 and day 8 of each 21-day dosing cycle; (viii) carboplatin and paclitaxel administered in one or more²¹ -day cycles, wherein carboplatin is administered intravenously at AUC 6 on Day 1 of each 21-day cycle and paclitaxel is administered at a dose of about 200 mg/^m2 on Day 1 of each 21-day cycle; (ix) carboplatin and gemcitabine administered in one or more 21-day cycles, wherein carboplatin is administered intravenously at AUC 5 on Day 1 of each 21-day cycle and gemcitabine is administered at a dose of about 1000 mg/^m2 on Days 1 and 8 of each 21-day cycle; or (x) Carboplatin and gemcitabine were administered in 21-day dosing cycles, with carboplatin administered intravenously at AUC 5 on Day 1 of each 21-day dosing cycle and pemetrexed administered at a dose of approximately 500 mg/m² on Day 1 of each 21-day dosing cycle.如請求項 1 至 16 中任一項之方法，其中在最後投予的一劑該輔助化學療法之後十週內開始該一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗之投予。The method of any of claims 1 to 16, wherein the one or more dosing cycles of tisleliumab and atezolizumab are initiated within ten weeks after the last dose of the adjuvant chemotherapy.如請求項 1 至 17 中任一項之方法，其中該個體在該完全切除後尚未經歷該 NSCLC 之復發。The method of any one of claims 1 to 17, wherein the individual has not experienced recurrence of the NSCLC following the complete resection.如請求項 1 至 18 中任一項之方法，其中該個體在該輔助化學療法後尚未經歷該 NSCLC 之復發。The method of any one of claims 1 to 18, wherein the individual has not experienced recurrence of the NSCLC following the adjuvant chemotherapy.如請求項 1 至 19 中任一項之方法，其中該方法包含每四週以約 1680 mg 之固定劑量向該個體投予阿替利珠單抗。The method of any one of claims 1 to 19, wherein the method comprises administering to the subject atezolizumab at a fixed dose of about 1680 mg every four weeks.如請求項 1 至 20 中任一項之方法，其中該方法包含每四週以約 840 mg 之固定劑量向該個體投予替瑞利尤單抗。The method of any one of claims 1 to 20, wherein the method comprises administering to the subject tisleliumab at a fixed dose of about 840 mg every four weeks.如請求項 1 至 21 中任一項之方法，其中替瑞利尤單抗及阿替利珠單抗之該一個或多個給藥週期中之各者的長度為 28 天。The method of any of claims 1 to 21, wherein the length of each of the one or more dosing cycles of tisleliumab and atezolizumab is 28 days.如請求項 22 之方法，其中該方法包含在各 28 天給藥週期之約第 1 天向該個體投予阿替利珠單抗。The method of claim 22, wherein the method comprises administering atezolizumab to the individual on about day 1 of each 28-day dosing cycle.如請求項 22 或 23 之方法，其中該方法包含在各 28 天給藥週期之約第 1 天向該個體投予替瑞利尤單抗。The method of claim 22 or 23, wherein the method comprises administering tisleliumab to the individual on about day 1 of each 28-day dosing cycle.如請求項 1 至 24 中任一項之方法，其中該方法包含向該個體共同投予阿替利珠單抗及替瑞利尤單抗。The method of any one of claims 1 to 24, wherein the method comprises co-administering atezolizumab and tisleliumab to the individual.如請求項 25 之方法，其中該方法包含藉由靜脈內共同輸注向該個體共同投予阿替利珠單抗及替瑞利尤單抗。The method of claim 25, wherein the method comprises co-administering atezolizumab and tisleliumab to the individual by intravenous co-infusion.如請求項 26 之方法，其中將阿替利珠單抗及替瑞利尤單抗調配在一起並作為固定劑量組合 (FDC) 靜脈內投予。The method of claim 26, wherein atezolizumab and tisleliumab are formulated together and administered intravenously as a fixed-dose combination (FDC).如請求項 1 至 24 中任一項之方法，其中該方法包含在替瑞利尤單抗之前向該個體投予阿替利珠單抗。The method of any one of claims 1 to 24, wherein the method comprises administering atezolizumab to the individual prior to tislelizumab.如請求項 1 至 24 中任一項之方法，其中該方法包含在阿替利珠單抗之前向該個體投予替瑞利尤單抗。The method of any one of claims 1 to 24, wherein the method comprises administering tisleliumab to the individual prior to atezolizumab.如請求項 28 或 29 之方法，其中該方法包含向該個體靜脈內投予替瑞利尤單抗及阿替利珠單抗。The method of claim 28 or 29, wherein the method comprises administering tisleliumab and atezolizumab intravenously to the individual.如請求項 1 至 30 中任一項之方法，其中該 NSCLC 為： (a) IIB 期 NSCLC； (b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。The method of any of claim 1 to 30, wherein the NSCLC is:(a) stage IIB NSCLC;(b) stage IIIA NSCLC; or(c) T3N2 stage IIIB NSCLC.如請求項 31 之方法，其中 NSCLC 分期係依照聯合國際癌症中心 (Union Internationale Contre Ie Cancer)/美國癌症聯合委員會 (American Joint Committee on Cancer) (UICC/AJCC) 分期系統，第 8 版。The method of claim 31, wherein the NSCLC staging is based on the United Nations Internationale Contre Ie Cancer/American Joint Committee on Cancer (UICC/AJCC) staging system, 8th edition.如請求項 1 至 32 中任一項之方法，其中該 NSCLC 為鱗狀 NSCLC。The method of any one of claims 1 to 32, wherein the NSCLC is squamous NSCLC.如請求項 1 至 32 中任一項之方法，其中該 NSCLC 為非鱗狀 NSCLC。The method of any one of claims 1 to 32, wherein the NSCLC is non-squamous NSCLC.如請求項 1 至 34 中任一項之方法，其中從該個體獲得的腫瘤樣品的 PD-L1 陽性腫瘤細胞分數已藉由免疫組織化學 (IHC) 測定來判定。The method of any one of claims 1 to 34, wherein the PD-L1 positive tumor cell fraction of the tumor sample obtained from the individual has been determined by immunohistochemistry (IHC) assay.如請求項 35 之方法，其中該 PD-L1 陽性腫瘤細胞分數係藉由用抗 PD-L1 抗體進行陽性染色來判定，其中該抗 PD-L1 抗體為 SP263、22C3、SP142 或 28-8。The method of claim 35, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142 or 28-8.如請求項 36 之方法，其中該 PD-L1 陽性腫瘤細胞分數係使用 Ventana SP263 IHC 測定、pharmDx 22C3 IHC 測定、Ventana SP142 IHC 測定或 pharmDx 28-8 IHC 測定來判定。The method of claim 36, wherein the PD-L1 positive tumor cell fraction is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay.如請求項 35 至 37 中任一項之方法，其中該 PD-L1 陽性腫瘤細胞分數已使用 Ventana SP263 IHC 測定來判定。The method of any of claims 35 to 37, wherein the PD-L1 positive tumor cell fraction is determined using a Ventana SP263 IHC assay.如請求項 38 之方法，其中從該個體獲得的該腫瘤樣品已被判定具有等於或大於 1% 的任何膜染色高於背景的腫瘤細胞百分比 (TC)。The method of claim 38, wherein the tumor sample obtained from the individual has been determined to have a tumor cell percentage (TC) equal to or greater than 1% with any membrane staining above background.如請求項 39 之方法，其中從該個體獲得的該腫瘤樣品已被判定具有等於或大於 50% 的 TC。The method of claim 39, wherein the tumor sample obtained from the individual has been determined to have a TC equal to or greater than 50%.如請求項 1 至 40 中任一項之方法，其中該個體不具有上皮生長因子受體 (epidermal growth factor receptor，EGFR) 或退行性淋巴瘤激酶 (anaplastic lymphoma kinase，ALK) 基因體腫瘤畸變。The method of any one of claims 1 to 40, wherein the individual does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration.如請求項 1 至 33 及 35 至 40 中任一項之方法，其中該個體患有鱗狀 NSCLC 並且尚未針對 EGFR 或 ALK 基因體腫瘤畸變進行評定。The method of any one of claims 1 to 33 and 35 to 40, wherein the individual has squamous NSCLC and has not been assessed for EGFR or ALK genomic tumor aberrations.如請求項 1 至 42 中任一項之方法，其中該個體未接受過使用 CD137 促效劑或免疫查核點阻斷療法之先前治療。The method of any one of claims 1 to 42, wherein the individual has not received prior treatment with a CD137 agonist or immune checkpoint blockade therapy.如請求項 1 至 43 中任一項之方法，其中向該個體投予至多 13 個給藥週期之替瑞利尤單抗及阿替利珠單抗。The method of any one of claims 1 to 43, wherein the subject is administered up to 13 dosing cycles of tisleliumab and atezolizumab.如請求項 1 至 44 中任一項之方法，其中向該個體投予若干給藥週期之替瑞利尤單抗及阿替利珠單抗，持續至多一年。The method of any of claims 1 to 44, wherein the individual is administered dosing cycles of tisleliumab and atezolizumab for up to one year.如請求項 1 至 45 中任一項之方法，其中與參考無疾病存活 (DFS) 持續時間相比，該治療引起 DFS 持續時間增加。The method of any of claims 1 to 45, wherein the treatment results in an increase in disease-free survival (DFS) duration compared to a reference DFS duration.如請求項 46 之方法，其中該參考 DFS 持續時間係已接受對照治療之個體群體的平均或中值 DFS 持續時間。The method of claim 46, wherein the reference DFS duration is the mean or median DFS duration of a population of individuals who have received a control treatment.如請求項 1 至 47 中任一項之方法，其中與參考總存活 (OS) 持續時間相比，該治療引起 OS 持續時間增加。The method of any one of claims 1 to 47, wherein the treatment results in an increase in overall survival (OS) duration compared to a reference OS duration.如請求項 48 之方法，其中該參考 OS 持續時間係已接受對照治療之個體群體的平均或中值 OS 持續時間。The method of claim 48, wherein the reference OS duration is the mean or median OS duration of a population of individuals who have received a control treatment.如請求項 1 至 49 中任一項之方法，其中與參考 DFS 率相比，該治療引起 DFS 率增加。The method of any of claims 1 to 49, wherein the treatment results in an increase in DFS rate compared to a reference DFS rate.如請求項 50 之方法，其中該 DFS 率為 3 年 DFS 率、5 年 DFS 率或 7 年 DFS 率。The method of claim 50, wherein the DFS rate is a 3-year DFS rate, a 5-year DFS rate, or a 7-year DFS rate.如請求項 50 或 51 之方法，其中該參考 DFS 率係已接受對照治療之個體群體的 DFS 率。The method of claim 50 or 51, wherein the reference DFS rate is the DFS rate for a population of individuals who have received a control treatment.如請求項 47、49 及 52 中任一項之方法，其中該對照治療為阿替利珠單抗單一療法。The method of any of claims 47, 49, and 52, wherein the control treatment is atezolizumab monotherapy.一種治療患有 NSCLC 之個體之方法，該方法包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且該個體已接受介於一個週期與四個週期之間之鉑類輔助化學療法，其中該 NSCLC 為： (a) IIB 期 NSCLC； (b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。A method of treating an individual with NSCLC, the method comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received between one and four cycles of adjuvant platinum-based chemotherapy, wherein the NSCLC is:(a) Stage IIB NSCLC;(b) Stage IIIA NSCLC; or(c) T3N2 Stage IIIB NSCLC.一種治療患有 NSCLC 之個體之方法，該方法包含向該個體投予介於一個週期與四個週期之間之鉑類輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除，其中該 NSCLC 為： (a) IIB 期 NSCLC； (b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。A method of treating an individual with NSCLC, the method comprising administering to the individual between one and four cycles of platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is:(a) Stage IIB NSCLC;(b) Stage IIIA NSCLC; or(c) T3N2 Stage IIIB NSCLC.如請求項 1 至 55 中任一項之方法，其中該個體為人。A method as claimed in any one of claims 1 to 55, wherein the individual is a human.一種替瑞利尤單抗及/或阿替利珠單抗在藥物的製造中之用途，該藥物用於治療患有 NSCLC 之個體，該治療包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且該個體已接受輔助化學療法。A use of tisleliumab and/or atezolizumab in the manufacture of a medicament for treating an individual with NSCLC, the treatment comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received adjuvant chemotherapy.一種替瑞利尤單抗及/或阿替利珠單抗在藥物的製造中之用途，該藥物用於治療患有 NSCLC 之個體，該治療包含向該個體投予輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除。A use of tisleliumab and/or atezolizumab in the manufacture of a medicament for treating an individual with NSCLC, the treatment comprising administering to the individual adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected.如請求項 57 或 58 之用途，其中該完全切除係肺葉切除術、袖式肺葉切除術、雙肺葉切除術或肺切除術。The use of claim 57 or 58, wherein the complete resection is a lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.如請求項 57 至 59 中任一項之用途，其中該完全切除係產生 (i) 無殘留腫瘤及 (ii) 所有手術切緣均呈侵襲性癌陰性之切除。The use of any of claims 57 to 59, wherein the complete resection is a resection resulting in (i) no residual tumor and (ii) all surgical margins being negative for invasive cancer.如請求項 57、59 及 60 中任一項之用途，其中該個體已接受介於一個給藥週期與四個給藥週期之間之該輔助化學療法。The use of any of claims 57, 59 and 60, wherein the subject has received between one dosing cycle and four dosing cycles of the adjuvant chemotherapy.如請求項 61 之用途，其中該個體已接受四個給藥週期之該輔助化學療法。The use of claim 61, wherein the individual has received four administration cycles of the adjuvant chemotherapy.如請求項 57 至 60 中任一項之用途，其中待向該個體投予介於一個給藥週期與四個給藥週期之間之該輔助化學療法。The use of any one of claims 57 to 60, wherein the adjuvant chemotherapy is to be administered to the subject for between one dosing cycle and four dosing cycles.如請求項 63 之用途，其中待向該個體投予四個給藥週期之該輔助化學療法。The use of claim 63, wherein the adjuvant chemotherapy is administered to the individual for four dosing cycles.如請求項 57 至 64 中任一項之用途，其中該輔助化學療法為鉑類輔助化學療法。The use of any one of claims 57 to 64, wherein the adjuvant chemotherapy is platinum-adjuvant chemotherapy.如請求項 65 之用途，其中該鉑類輔助化學療法包含順鉑。The use of claim 65, wherein the platinum-assisted chemotherapy comprises cis-platinum.如請求項 65 之用途，其中該鉑類輔助化學療法包含卡鉑。The use of claim 65, wherein the platinum-assisted chemotherapy comprises carboplatin.如請求項 65 至 67 中任一項之用途，其中該鉑類輔助化學療法進一步包含一種或多種另外的化學治療劑。The use of any one of claims 65 to 67, wherein the platinum-assisted chemotherapy further comprises one or more additional chemotherapeutic agents.如請求項 68 之用途，其中該一種或多種另外的化學治療劑包含長春花屬生物鹼、紫杉烷、抗代謝物、拓樸異構酶 II 抑制劑或其組合。The use of claim 68, wherein the one or more additional chemotherapeutic agents comprises a vinca alkaloid, a taxane, an anti-metabolite, a topoisomerase II inhibitor, or a combination thereof.如請求項 69 之用途，其中該長春花屬生物鹼為長春瑞濱；該紫杉烷為多西紫杉醇或紫杉醇；該抗代謝物為吉西他濱或培美曲塞；或者該拓樸異構酶 II 抑制劑為依托泊苷。The use of claim 69, wherein the vinca alkaloid is vinorelbine; the taxane is docetaxel or paclitaxel; the anti-metabolite is gemcitabine or pemetrexed; or the topoisomerase II inhibitor is etoposide.如請求項 65 之用途，其中該鉑類輔助化學療法為鉑類輔助雙效化學療法。The use as in claim 65, wherein the platinum-assisted chemotherapy is platinum-assisted double-effect chemotherapy.如請求項 71 之用途，其中該鉑類輔助雙效化學療法包含： (i) 以一個或多個 21 天給藥週期投予之順鉑及培美曲塞，其中待在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且待在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞； (ii) 以一個或多個 21 天給藥週期投予之順鉑及吉西他濱，其中待在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且待在各 21 天給藥週期之第 1 天及第 8 天以約 1250 mg/m²的劑量投予吉西他濱； (iii) 以一個或多個 21 天給藥週期投予之順鉑及多西紫杉醇，其中待在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且待在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量投予多西紫杉醇； (iv) 以一個或多個 28 天給藥週期投予之順鉑及長春瑞濱，其中待在各 28 天給藥週期之第 1 天及第 8 天以約 50 mg/m²的劑量靜脈內投予順鉑，且待在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 25 mg/m²的劑量投予長春瑞濱； (v) 以一個或多個 28 天給藥週期投予之順鉑及長春瑞濱，其中待在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，且待在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 30 mg/m²的劑量投予長春瑞濱； (vi) 以一個或多個 21 天給藥週期投予之順鉑及長春瑞濱，其中待在各 21 天給藥週期之第 1 天及第 8 天以約 75 至 80 mg/m²的劑量靜脈內投予順鉑，且待在各 21 天給藥週期之第 1 天及第 8 天以約 25 至 30 mg/m²的劑量投予長春瑞濱； (vii) 以一個或多個 28 天給藥週期投予之順鉑及依托泊苷，其中待在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，且待在各 28 天給藥週期之第 1 天至第 3 天以約 100 mg/m²的劑量投予依托泊苷； (viii) 以一個或多個 21 天給藥週期投予之卡鉑及紫杉醇，其中待在各 21 天給藥週期之第 1 天以 AUC 6 靜脈內投予卡鉑，且待在各 21 天給藥週期之第 1 天以約 200 mg/m²的劑量投予紫杉醇； (ix) 以一個或多個 21 天給藥週期投予之卡鉑及吉西他濱，其中待在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，且待在各 21 天給藥週期之第 1 天及第 8 天以約 1000 mg/m²的劑量投予吉西他濱；或者 (x) 以一個或多個 21 天給藥週期投予之卡鉑及吉西他濱，其中待在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，且待在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞。The use of claim 71, wherein the platinum-based adjuvant dual-acting chemotherapy comprises: (i) c-platinum and pemetrexed administered in one or more 21-day dosing cycles, wherein c-platinum is administered intravenously at a dose of about 75 mg/^m2 on day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/^m2 on day 1 of each 21-day dosing cycle; (ii) c-platinum and gemcitabine administered in one or more 21-day dosing cycles, wherein c-platinum is administered intravenously at a dose of about 75 mg/m2 on day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/^m2 on day 1 of each 21-day dosing cycle (iii) cisplatin and docetaxel administered in one or more 21-day cycles, wherein cisplatin is administered intravenously at a dose of about 75 mg/^m2 on Day 1 of each 21-day cycle, and docetaxel is administered at a dose of about 75 mg/^m2 on Day 1 of each 21-day cycle; (iv) cisplatin and vinorelbine administered in one or more 28-day cycles, wherein vinorelbine is administered intravenously at a dose of about 50 mg/^m2 on Day 1 and Day 8 of each 28-day cycle. (v) cisplatin and vinorelbine administered in one or more^28- day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 30 mg/m2 on day 1, day 8, day 15, and day 22 of each 28-day dosing cycle; (vi) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 30 mg/^m2 on day 1, day 8, day 15, and day 22 of each 28-day dosing cycle; (vii) cisplatin and etoposide administered in one or more 28-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered intravenously at a dose of about 25 to 30 mg/^m2 on day 1 and day 8 of each 21-day dosing cycle; (viii) carboplatin and paclitaxel administered in one or more 21-day dosing cycles, wherein carboplatin is administered intravenously at AUC 6 on Day 1 of each 21-day dosing cycle, and paclitaxel is administered at a dose of about 200 mg/m² on Day 1 of each 21-day dosing cycle; (ix) carboplatin and gemcitabine administered in one or more 21-day dosing cycles, wherein carboplatin is administered intravenously at AUC 5 on Day 1 of^each 21-day dosing cycle, and gemcitabine is administered at a dose of about 1000 mg/m² on Days 1 and 8 of each 21-day dosing cycle; or (x) Carboplatin and gemcitabine are administered in one or more 21-day dosing cycles, wherein carboplatin is administered intravenously at AUC 5 on Day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/m² on Day 1 of each 21-day dosing cycle.如請求項 57 至 72 中任一項之用途，其中待在最後投予的一劑該輔助化學療法之後十週內開始該一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗之投予。The use of any of claims 57 to 72, wherein the administration of the one or more dosing cycles of tisleliumab and atezolizumab is initiated within ten weeks after the last dose of the adjuvant chemotherapy.如請求項 57 至 73 中任一項之用途，其中該個體在該完全切除後尚未經歷該 NSCLC 之復發。The use of any of claims 57 to 73, wherein the individual has not experienced recurrence of the NSCLC following the complete resection.如請求項 57 至 74 中任一項之用途，其中該個體在該輔助化學療法後尚未經歷該 NSCLC 之復發。The use of any of claims 57 to 74, wherein the individual has not experienced recurrence of the NSCLC after the adjuvant chemotherapy.如請求項 57 至 75 中任一項之用途，其中待每四週以約 1680 mg 之固定劑量投予阿替利珠單抗。The use of any one of claims 57 to 75, wherein atezolizumab is administered at a fixed dose of about 1680 mg every four weeks.如請求項 57 至 76 中任一項之用途，其中待每四週以約 840 mg 之固定劑量投予替瑞利尤單抗。The use of any one of claims 57 to 76, wherein tisleliumab is administered at a fixed dose of about 840 mg every four weeks.如請求項 57 至 77 中任一項之用途，其中替瑞利尤單抗及阿替利珠單抗之該一個或多個給藥週期中之各者的長度為 28 天。The use of any of claims 57 to 77, wherein the length of each of the one or more dosing cycles of tisleliumab and atezolizumab is 28 days.如請求項 78 之用途，其中待在各 28 天給藥週期之約第 1 天向該個體投予阿替利珠單抗。The use of claim 78, wherein atezolizumab is administered to the individual on approximately day 1 of each 28-day dosing cycle.如請求項 78 或 79 之用途，其中待在各 28 天給藥週期之約第 1 天向該個體投予替瑞利尤單抗。The use of claim 78 or 79, wherein tirelimumab is administered to the individual on about day 1 of each 28-day dosing cycle.如請求項 57 至 80 中任一項之用途，其中待向該個體共同投予阿替利珠單抗及替瑞利尤單抗。The use of any one of claims 57 to 80, wherein atezolizumab and tisleliumab are to be co-administered to the individual.如請求項 81 之用途，其中待藉由靜脈內共同輸注向該個體共同投予阿替利珠單抗及替瑞利尤單抗。The use of claim 81, wherein atezolizumab and tisleliumab are to be co-administered to the individual by intravenous co-infusion.如請求項 82 之用途，其中待將阿替利珠單抗及替瑞利尤單抗調配在一起並作為固定劑量組合 (FDC) 靜脈內投予。The use of claim 82, wherein atezolizumab and tisleliumab are to be formulated together and administered intravenously as a fixed-dose combination (FDC).如請求項 57 至 80 中任一項之用途，其中待在替瑞利尤單抗之前向該個體投予阿替利珠單抗。The use of any one of claims 57 to 80, wherein atezolizumab is administered to the individual prior to tislelizumab.如請求項 57 至 80 中任一項之用途，其中待在阿替利珠單抗之前向該個體投予替瑞利尤單抗。The use of any one of claims 57 to 80, wherein tirelimumab is administered to the individual prior to atezolizumab.如請求項 84 或 85 之用途，其中待向該個體靜脈內投予替瑞利尤單抗及阿替利珠單抗。The use of claim 84 or 85, wherein tislelizumab and atezolizumab are to be administered intravenously to the individual.如請求項 57 至 86 中任一項之用途，其中該 NSCLC 為： (a) IIB 期 NSCLC； (b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。For the use of any of claim items 57 to 86, wherein the NSCLC is:(a) Stage IIB NSCLC;(b) Stage IIIA NSCLC; or(c) T3N2 Stage IIIB NSCLC.如請求項 87 之用途，其中 NSCLC 分期係依照聯合國際癌症中心/美國癌症聯合委員會 (UICC/AJCC) 分期系統，第 8 版。For purposes of claim 87, NSCLC staging is based on the United International Cancer Center/American Joint Committee on Cancer (UICC/AJCC) staging system, 8th edition.如請求項 1 至 88 中任一項之用途，其中該 NSCLC 為鱗狀 NSCLC。The use of any one of claim 1 to 88, wherein the NSCLC is squamous NSCLC.如請求項 1 至 88 中任一項之用途，其中該 NSCLC 為非鱗狀 NSCLC。The use of any of claim 1 to 88, wherein the NSCLC is non-squamous NSCLC.如請求項 1 至 90 中任一項之用途，其中從該個體獲得的腫瘤樣品的 PD-L1 陽性腫瘤細胞分數已藉由免疫組織化學 (IHC) 測定來判定。The use of any one of claims 1 to 90, wherein the PD-L1 positive tumor cell fraction of the tumor sample obtained from the individual has been determined by immunohistochemistry (IHC) assay.如請求項 91 之用途，其中該 PD-L1 陽性腫瘤細胞分數係藉由用抗 PD-L1 抗體進行陽性染色來判定，其中該抗 PD-L1 抗體為 SP263、22C3、SP142 或 28-8。The use of claim 91, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142 or 28-8.如請求項 92 之用途，其中該 PD-L1 陽性腫瘤細胞分數係使用 Ventana SP263 IHC 測定、pharmDx 22C3 IHC 測定、Ventana SP142 IHC 測定或 pharmDx 28-8 IHC 測定來判定。The use of claim 92, wherein the PD-L1 positive tumor cell fraction is determined using a Ventana SP263 IHC assay, a pharmDx 22C3 IHC assay, a Ventana SP142 IHC assay, or a pharmDx 28-8 IHC assay.如請求項 91 至 93 中任一項之用途，其中該 PD-L1 陽性腫瘤細胞分數已使用 Ventana SP263 IHC 測定來判定。The use of any of claims 91 to 93, wherein the PD-L1 positive tumor cell fraction is determined using a Ventana SP263 IHC assay.如請求項 94 之用途，其中從該個體獲得的該腫瘤樣品已被判定具有等於或大於 1% 的任何膜染色高於背景的腫瘤細胞百分比 (TC)。The use of claim 94, wherein the tumor sample obtained from the individual has been determined to have a tumor cell percentage (TC) equal to or greater than 1% with any membrane staining above background.如請求項 95 之用途，其中從該個體獲得的該腫瘤樣品已被判定具有等於或大於 50% 的 TC。The use of claim 95, wherein the tumor sample obtained from the individual has been determined to have a TC equal to or greater than 50%.如請求項 57 至 96 中任一項之用途，其中該個體不具有上皮生長因子受體 (EGFR) 或退行性淋巴瘤激酶 (ALK) 基因體腫瘤畸變。The use of any one of claims 57 to 96, wherein the individual does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration.如請求項 57 至 89 及 91 至 97 中任一項之用途，其中該個體患有鱗狀 NSCLC 並且尚未針對 EGFR 或 ALK 基因體腫瘤畸變進行評定。The use of any of claims 57 to 89 and 91 to 97, wherein the individual has squamous NSCLC and has not been assessed for EGFR or ALK genomic tumor aberrations.如請求項 57 至 98 中任一項之用途，其中該個體未接受過使用 CD137 促效劑或免疫查核點阻斷療法之先前治療。The use of any of claims 57 to 98, wherein the individual has not received prior treatment with a CD137 agonist or immune checkpoint blockade therapy.如請求項 57 至 99 中任一項之用途，其中待向該個體投予至多 13 個給藥週期之替瑞利尤單抗及阿替利珠單抗。The use of any one of claims 57 to 99, wherein up to 13 dosing cycles of tisleliumab and atezolizumab are administered to the individual.如請求項 57 至 100 中任一項之用途，其中待向該個體投予若干給藥週期之替瑞利尤單抗及阿替利珠單抗，持續至多一年。The use of any of claims 57 to 100, wherein a number of dosing cycles of tislelizumab and atezolizumab are administered to the individual for up to one year.如請求項 57 至 101 中任一項之用途，其中與參考無疾病存活 (DFS) 持續時間相比，該治療引起 DFS 持續時間增加。The use of any of claims 57 to 101, wherein the treatment results in an increase in the duration of disease-free survival (DFS) compared to a reference DFS duration.如請求項 102 之用途，其中該參考 DFS 持續時間係已接受對照治療之個體群體的平均或中值 DFS 持續時間。For use as in claim 102, wherein the reference DFS duration is the mean or median DFS duration for a population of individuals who have received a control treatment.如請求項 57 至 103 中任一項之用途，其中與參考總存活 (OS) 持續時間相比，該治療引起 OS 持續時間增加。The use of any of claims 57 to 103, wherein the treatment results in an increase in overall survival (OS) duration compared to a reference OS duration.如請求項 104 之用途，其中該參考 OS 持續時間係已接受對照治療之個體群體的平均或中值 OS 持續時間。The use of claim 104, wherein the reference OS duration is the mean or median OS duration for a population of individuals who have received a control treatment.如請求項 57 至 105 中任一項之用途，其中與參考 DFS 率相比，該治療引起 DFS 率增加。The use of any of claims 57 to 105, wherein the treatment results in an increase in DFS rate compared to a reference DFS rate.如請求項 106 之用途，其中該 DFS 率為 3 年 DFS 率、5 年 DFS 率或 7 年 DFS 率。For purposes of claim 106, wherein the DFS rate is a 3-year DFS rate, a 5-year DFS rate, or a 7-year DFS rate.如請求項 106 或 107 之用途，其中該參考 DFS 率係已接受對照治療之個體群體的 DFS 率。The use of claim 106 or 107, wherein the reference DFS rate is the DFS rate for a population of individuals who have received a control treatment.如請求項 103、105 及 108 中任一項之用途，其中該對照治療為阿替利珠單抗單一療法。The use of any of claims 103, 105, and 108, wherein the control treatment is atezolizumab monotherapy.一種替瑞利尤單抗及/或阿替利珠單抗在藥物的製造中之用途，該藥物用於治療患有 NSCLC 之個體，該治療包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且該個體已接受介於一個週期與四個週期之間之鉑類輔助化學療法，其中該 NSCLC 為： (a) IIB 期 NSCLC； (b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。A use of tisleliumab and/or atezolizumab in the manufacture of a medicament for treating an individual with NSCLC, the treatment comprising administering to the individual one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected and the individual has received between one and four cycles of platinum-based adjuvant chemotherapy, wherein the NSCLC is:(a) stage IIB NSCLC;(b) stage IIIA NSCLC; or(c) T3N2 stage IIIB NSCLC.一種替瑞利尤單抗及/或阿替利珠單抗在藥物的製造中之用途，該藥物用於治療患有 NSCLC 之個體，該治療包含向該個體投予介於一個週期與四個週期之間之鉑類輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除，其中該 NSCLC 為： (a) IIB 期 NSCLC； (b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。A use of tisleliumab and/or atezolizumab in the manufacture of a medicament for treating an individual with NSCLC, the treatment comprising administering to the individual between one cycle and four cycles of platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is:(a) Stage IIB NSCLC;(b) Stage IIIA NSCLC; or(c) T3N2 Stage IIIB NSCLC.如請求項 57 至 111 中任一項之用途，其中該個體為人。The use as claimed in any one of claims 57 to 111, wherein the individual is a human.一種替瑞利尤單抗及/或阿替利珠單抗，其使用於治療患有 NSCLC 之個體，該治療包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且該個體已接受輔助化學療法。A method of treating an individual with NSCLC using tisleliumab and/or atezolizumab, the treatment comprising administering one or more dosing cycles of tisleliumab and atezolizumab to the individual, wherein the NSCLC has been completely resected and the individual has received adjuvant chemotherapy.一種替瑞利尤單抗及/或阿替利珠單抗，其使用於治療患有 NSCLC 之個體，該治療包含向該個體投予輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除。A method of treating an individual with NSCLC comprising administering adjuvant chemotherapy to the individual followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected.如請求項 113 或 114 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該完全切除係肺葉切除術、袖式肺葉切除術、雙肺葉切除術或肺切除術。The use of tislelizumab and/or atezolizumab as described in claim 113 or 114, wherein the complete resection is a lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy.如請求項 113 至 115 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該完全切除係產生 (i) 無殘留腫瘤及 (ii) 所有手術切緣均呈侵襲性癌陰性之切除。The use of tislelizumab and/or atezolizumab as claimed in any of claims 113 to 115, wherein the complete resection is a resection resulting in (i) no residual tumor and (ii) all surgical margins being negative for invasive cancer.如請求項 113、114 及 116 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該個體已接受介於一個給藥週期與四個給藥週期之間之該輔助化學療法。Tisrelizumab and/or atezolizumab for use as claimed in any of claims 113, 114 and 116, wherein the individual has received between one dosing cycle and four dosing cycles of the adjuvant chemotherapy.如請求項 117 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該個體已接受四個給藥週期之該輔助化學療法。The use of tisleliumab and/or atezolizumab as described in claim 117, wherein the individual has received four cycles of such adjuvant chemotherapy.如請求項 113 至 116 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待向該個體投予介於一個給藥週期與四個給藥週期之間之該輔助化學療法。For use of tisleliumab and/or atezolizumab as claimed in any of claims 113 to 116, wherein the adjuvant chemotherapy is to be administered to the individual for between one dosing cycle and four dosing cycles.如請求項 119 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待向該個體投予四個給藥週期之該輔助化學療法。The use of tisleliumab and/or atezolizumab as claimed in claim 119, wherein the adjuvant chemotherapy is administered to the individual for four dosing cycles.如請求項 113 至 120 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該輔助化學療法為鉑類輔助化學療法。The use of tislelizumab and/or atezolizumab as claimed in any one of claims 113 to 120, wherein the adjuvant chemotherapy is platinum-based adjuvant chemotherapy.如請求項 121 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該鉑類輔助化學療法包含順鉑。For use of tislelizumab and/or atezolizumab as claimed in claim 121, wherein the platinum-based adjuvant chemotherapy comprises cis-platinum.如請求項 121 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該鉑類輔助化學療法包含卡鉑。For use of tisleliumab and/or atezolizumab as claimed in claim 121, wherein the platinum-based adjuvant chemotherapy comprises carboplatin.如請求項 120 至 123 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該鉑類輔助化學療法進一步包含一種或多種另外的化學治療劑。Tisrelizumab and/or atezolizumab for use as claimed in any one of claims 120 to 123, wherein the platinum-based adjuvant chemotherapy further comprises one or more additional chemotherapeutic agents.如請求項 124 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該一種或多種另外的化學治療劑包含長春花屬生物鹼、紫杉烷、抗代謝物、拓樸異構酶 II 抑制劑或其組合。The use of tislelizumab and/or atezolizumab as claimed in claim 124, wherein the one or more additional chemotherapeutic agents comprises a vinca alkaloid, a taxane, an anti-metabolite, a topoisomerase II inhibitor, or a combination thereof.如請求項 125 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該長春花屬生物鹼為長春瑞濱；該紫杉烷為多西紫杉醇或紫杉醇；該抗代謝物為吉西他濱或培美曲塞；或者該拓樸異構酶 II 抑制劑為依托泊苷。For use of tislelizumab and/or atezolizumab as claimed in claim 125, wherein the vinca alkaloid is vinorelbine; the taxane is docetaxel or paclitaxel; the anti-metabolite is gemcitabine or pemetrexed; or the topoisomerase II inhibitor is etoposide.如請求項 121 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該鉑類輔助化學療法為鉑類輔助雙效化學療法。For example, the use of tislelizumab and/or atezolizumab as described in claim 121, wherein the platinum-adjuvant chemotherapy is platinum-adjuvant double-acting chemotherapy.如請求項 127 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該鉑類輔助雙效化學療法包含： (i) 以一個或多個 21 天給藥週期投予之順鉑及培美曲塞，其中待在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且待在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞； (ii) 以一個或多個 21 天給藥週期投予之順鉑及吉西他濱，其中待在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且待在各 21 天給藥週期之第 1 天及第 8 天以約 1250 mg/m²的劑量投予吉西他濱； (iii) 以一個或多個 21 天給藥週期投予之順鉑及多西紫杉醇，其中待在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量靜脈內投予順鉑，且待在各 21 天給藥週期之第 1 天以約 75 mg/m²的劑量投予多西紫杉醇； (iv) 以一個或多個 28 天給藥週期投予之順鉑及長春瑞濱，其中待在各 28 天給藥週期之第 1 天及第 8 天以約 50 mg/m²的劑量靜脈內投予順鉑，且待在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 25 mg/m²的劑量投予長春瑞濱； (v) 以一個或多個 28 天給藥週期投予之順鉑及長春瑞濱，其中待在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，且待在各 28 天給藥週期之第 1 天、第 8 天、第 15 天及第 22 天以約 30 mg/m²的劑量投予長春瑞濱； (vi) 以一個或多個 21 天給藥週期投予之順鉑及長春瑞濱，其中待在各 21 天給藥週期之第 1 天及第 8 天以約 75 至 80 mg/m²的劑量靜脈內投予順鉑，且待在各 21 天給藥週期之第 1 天及第 8 天以約 25 至 30 mg/m²的劑量投予長春瑞濱； (vii) 以一個或多個 28 天給藥週期投予之順鉑及依托泊苷，其中待在各 28 天給藥週期之第 1 天以約 100 mg/m²的劑量靜脈內投予順鉑，且待在各 28 天給藥週期之第 1 天至第 3 天以約 100 mg/m²的劑量投予依托泊苷； (viii) 以一個或多個 21 天給藥週期投予之卡鉑及紫杉醇，其中待在各 21 天給藥週期之第 1 天以 AUC 6 靜脈內投予卡鉑，且待在各 21 天給藥週期之第 1 天以約 200 mg/m²的劑量投予紫杉醇； (ix) 以一個或多個 21 天給藥週期投予之卡鉑及吉西他濱，其中待在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，且待在各 21 天給藥週期之第 1 天及第 8 天以約 1000 mg/m²的劑量投予吉西他濱；或者 (x) 以一個或多個 21 天給藥週期投予之卡鉑及吉西他濱，其中待在各 21 天給藥週期之第 1 天以 AUC 5 靜脈內投予卡鉑，且待在各 21 天給藥週期之第 1 天以約 500 mg/m²的劑量投予培美曲塞。As used in claim 127, tisleliumab and/or atezolizumab, wherein the platinum-based adjuvant double-acting chemotherapy comprises: (i) cis-platinum and pemetrexed administered in one or more 21-day dosing cycles, wherein cis-platinum is administered intravenously at a dose of about 75 mg/^m2 on day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/^m2 on day 1 of each 21-day dosing cycle; (ii) cis-platinum and gemcitabine administered in one or more 21-day dosing cycles, wherein cis-platinum is administered intravenously at a dose of about 75 mg/m2 on day 1 of each 21-day dosing cycle, and pemetrexed is administered intravenously at a dose of about 500 mg/m2 on day 1 of each 21-day dosing cycle. (iii)^cisplatin and docetaxel administered in one or more 21-day cycles, wherein cisplatin is administered intravenously at a dose of about 75 mg/^m2 on Day 1 of each 21-day cycle, and gemcitabine is administered at a dose of about 1250 mg/^m2 on Day 1 and Day 8 of each 21-day cycle; (iv) cisplatin and vinorelbine administered in one or more 28-day cycles, wherein docetaxel is administered intravenously at a dose of about 75 mg/^m2 on Day 1 of each 21-day cycle, and gemcitabine is administered at a dose of about 1250 mg/m2 on Day 1 and Day 8 of each 28-day cycle; (v) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 30 mg/^m2 on days 1, 8, 15, and 22 of each 28-day dosing cycle; (vi) cisplatin and vinorelbine administered in one or more 28-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 50 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered at a dose of about 25 mg/^m2 on days 1, 8, 15, and 22 of each 28-day dosing cycle; (vii) cisplatin and etoposide administered in one or more 28-day dosing cycles, wherein cisplatin is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered intravenously at a dose of about 100 mg/^m2 on day 1 of each 28-day dosing cycle, and vinorelbine is administered intravenously at a dose of about 25 to 30 mg/^m2 on day 1 and day 8 of each 21-day dosing cycle; (viii) carboplatin and paclitaxel administered in one or more 21-day dosing cycles, wherein carboplatin is administered intravenously at AUC 6 on Day 1 of each 21-day dosing cycle, and paclitaxel is administered at a dose of about 200 mg/m² on Day 1 of each 21-day dosing cycle; (ix) carboplatin and gemcitabine administered in one or more 21-day dosing cycles, wherein carboplatin is administered intravenously at AUC 5 on Day 1 of^each 21-day dosing cycle, and gemcitabine is administered at a dose of about 1000 mg/m² on Days 1 and 8 of each 21-day dosing cycle; or (x) Carboplatin and gemcitabine are administered in one or more 21-day dosing cycles, wherein carboplatin is administered intravenously at AUC 5 on Day 1 of each 21-day dosing cycle, and pemetrexed is administered at a dose of about 500 mg/m² on Day 1 of each 21-day dosing cycle.如請求項 113 至 128 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待在最後投予的一劑該輔助化學療法之後十週內開始該一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗之投予。The use of tisleliumab and/or atezolizumab as claimed in any of claims 113 to 128, wherein the administration of the one or more dosing cycles of tisleliumab and atezolizumab is initiated within ten weeks after the last dose of the adjuvant chemotherapy.如請求項 113 至 129 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該個體在該完全切除後尚未經歷該 NSCLC 之復發。The use of tisleliumab and/or atezolizumab as claimed in any of claims 113 to 129, wherein the individual has not experienced recurrence of the NSCLC after the complete resection.如請求項 113 至 130 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該個體在該輔助化學療法後尚未經歷該 NSCLC 之復發。The use of tisleliumab and/or atezolizumab as claimed in any of claims 113 to 130, wherein the individual has not experienced recurrence of the NSCLC after the adjuvant chemotherapy.如請求項 113 至 131 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待每四週以約 1680 mg 之固定劑量投予阿替利珠單抗。Tisrelizumab and/or atezolizumab for use as claimed in any of claims 113 to 131, wherein atezolizumab is administered at a fixed dose of about 1680 mg every four weeks.如請求項 113 至 132 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待每四週以約 840 mg 之固定劑量投予替瑞利尤單抗。Tisrelizumab and/or atezolizumab for use as claimed in any of claims 113 to 132, wherein tisrelizumab is administered at a fixed dose of about 840 mg every four weeks.如請求項 113 至 133 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中替瑞利尤單抗及阿替利珠單抗之該一個或多個給藥週期中之各者的長度為 28 天。For use of tisleliumab and/or atezolizumab as claimed in any of claims 113 to 133, wherein the length of each of the one or more dosing cycles of tisleliumab and atezolizumab is 28 days.如請求項 134 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待在各 28 天給藥週期之約第 1 天向該個體投予阿替利珠單抗。The use of tisleliumab and/or atezolizumab as claimed in claim 134, wherein atezolizumab is administered to the individual on about day 1 of each 28-day dosing cycle.如請求項 134 或 135 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待在各 28 天給藥週期之約第 1 天向該個體投予替瑞利尤單抗。The use of tisleliumab and/or atezolizumab as claimed in claim 134 or 135, wherein tisleliumab is administered to the individual on about day 1 of each 28-day dosing cycle.如請求項 113 至 136 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待向該個體共同投予阿替利珠單抗及替瑞利尤單抗。The use of tislelizumab and/or atezolizumab as claimed in any one of claims 113 to 136, wherein atezolizumab and tislelizumab are to be co-administered to the individual.如請求項 137 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待藉由靜脈內共同輸注向該個體共同投予阿替利珠單抗及替瑞利尤單抗。Tisrelizumab and/or atezolizumab for use as claimed in claim 137, wherein atezolizumab and tisrelizumab are to be co-administered to the individual by intravenous co-infusion.如請求項 138 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待將阿替利珠單抗及替瑞利尤單抗調配在一起並作為固定劑量組合 (FDC) 靜脈內投予。Tisrelizumab and/or atezolizumab for use as claimed in claim 138, wherein atezolizumab and tisrelizumab are to be formulated together and administered intravenously as a fixed-dose combination (FDC).如請求項 113 至 136 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待在替瑞利尤單抗之前向該個體投予阿替利珠單抗。The use of tisleliumab and/or atezolizumab as claimed in any of claims 113 to 136, wherein atezolizumab is administered to the individual prior to tisleliumab.如請求項 113 至 136 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待在阿替利珠單抗之前向該個體投予替瑞利尤單抗。The use of tisleliumab and/or atezolizumab as claimed in any of claims 113 to 136, wherein tisleliumab is administered to the individual prior to atezolizumab.如請求項 140 或 141 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待向該個體靜脈內投予替瑞利尤單抗及阿替利珠單抗。For use of tisleliumab and/or atezolizumab as claimed in claim 140 or 141, wherein tisleliumab and atezolizumab are to be administered intravenously to the individual.如請求項 113 至 142 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該 NSCLC 為： (a) IIB 期 NSCLC； (b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。For use of tislelizumab and/or atezolizumab as described in any of claim items 113 to 142, where the NSCLC is:(a) Stage IIB NSCLC;(b) Stage IIIA NSCLC; or(c) T3N2 Stage IIIB NSCLC.如請求項 143 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中 NSCLC 分期係依照聯合國際癌症中心/美國癌症聯合委員會 (UICC/AJCC) 分期系統，第 8 版。For use of tislelizumab and/or atezolizumab as in claim 143, where the NSCLC stage is based on the United International Cancer Center/American Joint Committee on Cancer (UICC/AJCC) staging system, 8th edition.如請求項 113 至 144 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該 NSCLC 為鱗狀 NSCLC。The use of tislelizumab and/or atezolizumab as claimed in any of claims 113 to 144, wherein the NSCLC is squamous NSCLC.如請求項 113 至 144 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該 NSCLC 為非鱗狀 NSCLC。The use of tislelizumab and/or atezolizumab as claimed in any of claims 113 to 144, wherein the NSCLC is non-squamous NSCLC.如請求項 113 至 146 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中從該個體獲得的腫瘤樣品的 PD-L1 陽性腫瘤細胞分數已藉由免疫組織化學 (IHC) 測定來判定。The use of tisleliumab and/or atezolizumab as claimed in any of claims 113 to 146, wherein the PD-L1 positive tumor cell fraction of a tumor sample obtained from the individual has been determined by immunohistochemistry (IHC).如請求項 147 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該 PD-L1 陽性腫瘤細胞分數係藉由用抗 PD-L1 抗體進行陽性染色來判定，其中該抗 PD-L1 抗體為 SP263、22C3、SP142 或 28-8。The method of claim 147 for use of tislelizumab and/or atezolizumab, wherein the PD-L1 positive tumor cell fraction is determined by positive staining with an anti-PD-L1 antibody, wherein the anti-PD-L1 antibody is SP263, 22C3, SP142 or 28-8.如請求項 148 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該 PD-L1 陽性腫瘤細胞分數係使用 Ventana SP263 IHC 測定、pharmDx 22C3 IHC 測定、Ventana SP142 IHC 測定或 pharmDx 28-8 IHC 測定來判定。As claimed in claim 148, tisleliumab and/or atezolizumab, wherein the PD-L1 positive tumor cell fraction is determined using the Ventana SP263 IHC assay, the pharmDx 22C3 IHC assay, the Ventana SP142 IHC assay, or the pharmDx 28-8 IHC assay.如請求項 147 至 149 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該 PD-L1 陽性腫瘤細胞分數已使用 Ventana SP263 IHC 測定來判定。For use of tisleliumab and/or atezolizumab as claimed in any of claims 147 to 149, wherein the PD-L1 positive tumor cell fraction is determined using the Ventana SP263 IHC assay.如請求項 150 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中從該個體獲得的該腫瘤樣品已被判定具有等於或大於 1% 的任何膜染色高於背景的腫瘤細胞百分比 (TC)。The use of tislelizumab and/or atezolizumab as claimed in claim 150, wherein the tumor sample obtained from the individual has been determined to have a tumor cell percentage (TC) of any membrane staining above background equal to or greater than 1%.如請求項 151 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中從該個體獲得的該腫瘤樣品已被判定具有等於或大於 50% 的 TC。The use of tislelizumab and/or atezolizumab as claimed in claim 151, wherein the tumor sample obtained from the individual has been determined to have a TC equal to or greater than 50%.如請求項 113 至 152 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該個體不具有上皮生長因子受體 (EGFR) 或退行性淋巴瘤激酶 (ALK) 基因體腫瘤畸變。Tisrelizumab and/or atezolizumab for use as claimed in any of claims 113 to 152, wherein the individual does not have an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberration.如請求項 113 至 145 及 147 至 153 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該個體患有鱗狀 NSCLC 並且尚未針對 EGFR 或 ALK 基因體腫瘤畸變進行評定。For use of tislelizumab and/or atezolizumab as described in any of claims 113 to 145 and 147 to 153, wherein the individual has squamous NSCLC and has not been evaluated for EGFR or ALK genomic tumor aberrations.如請求項 113 至 154 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該個體未接受過使用 CD137 促效劑或免疫查核點阻斷療法之先前治療。The use of tislelizumab and/or atezolizumab as claimed in any of claims 113 to 154, wherein the individual has not received prior treatment with a CD137 agonist or immune checkpoint blockade therapy.如請求項 113 至 155 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待向該個體投予至多 13 個給藥週期之替瑞利尤單抗及阿替利珠單抗。Tisrelizumab and/or atezolizumab for use as claimed in any of claims 113 to 155, wherein the individual is administered at most 13 dosing cycles of tisrelizumab and atezolizumab.如請求項 113 至 156 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中待向該個體投予若干給藥週期之替瑞利尤單抗及阿替利珠單抗，持續至多一年。The use of tisleliumab and/or atezolizumab as claimed in any of claims 113 to 156, wherein the individual is administered a number of dosing cycles of tisleliumab and atezolizumab lasting up to one year.如請求項 113 至 157 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中與參考無疾病存活 (DFS) 持續時間相比，該治療引起 DFS 持續時間增加。Tisrelizumab and/or atezolizumab for use as claimed in any of claims 113 to 157, wherein the treatment results in an increase in disease-free survival (DFS) duration compared to a reference DFS duration.如請求項 158 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該參考 DFS 持續時間係已接受對照治療之個體群體的平均或中值 DFS 持續時間。For example, the use of tisleliumab and/or atezolizumab as described in claim 158, wherein the reference DFS duration is the mean or median DFS duration of a population of individuals who have received control treatment.如請求項 113 至 159 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中與參考總存活 (OS) 持續時間相比，該治療引起 OS 持續時間增加。Tisrelizumab and/or atezolizumab for use as claimed in any of claims 113 to 159, wherein the treatment results in an increase in overall survival (OS) duration compared to a reference OS duration.如請求項 160 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該參考 OS 持續時間係已接受對照治療之個體群體的平均或中值 OS 持續時間。For example, the use of tisleliumab and/or atezolizumab as described in claim 160, wherein the reference OS duration is the mean or median OS duration in a population of individuals who have received control treatment.如請求項 113 至 161 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中與參考 DFS 率相比，該治療引起 DFS 率增加。Tisrelizumab and/or atezolizumab for use as claimed in any of claims 113 to 161, wherein the treatment results in an increase in DFS rate compared to a reference DFS rate.如請求項 162 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該 DFS 率為 3 年 DFS 率、5 年 DFS 率或 7 年 DFS 率。For claim 162, the use of tisleliumab and/or atezolizumab, wherein the DFS rate is the 3-year DFS rate, the 5-year DFS rate or the 7-year DFS rate.如請求項 162 或 163 之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該參考 DFS 率係已接受對照治療之個體群體的 DFS 率。For claim 162 or 163, the use of tisleliumab and/or atezolizumab, where the reference DFS rate is the DFS rate for a population of individuals who have received a control treatment.如請求項 159、161 及 164 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該對照治療為阿替利珠單抗單一療法。As claimed in any of claims 159, 161 and 164, tislelizumab and/or atezolizumab, wherein the control treatment is atezolizumab monotherapy.一種替瑞利尤單抗及/或阿替利珠單抗，其使用於治療患有 NSCLC 之個體，該治療包含向該個體投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除且該個體已接受介於一個週期與四個週期之間之鉑類輔助化學療法，其中該 NSCLC 為： (a) IIB 期 NSCLC； (b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。A method of treating an individual with NSCLC comprising administering one or more cycles of tisleliumab and atezolizumab to the individual, wherein the NSCLC has been completely resected and the individual has received between one and four cycles of adjuvant platinum chemotherapy, wherein the NSCLC is:(a) stage IIB NSCLC;(b) stage IIIA NSCLC; or(c) T3N2 stage IIIB NSCLC.一種替瑞利尤單抗及/或阿替利珠單抗，其使用於治療患有 NSCLC 之個體，該治療包含向該個體投予介於一個週期與四個週期之間之鉑類輔助化學療法，接著投予一個或多個給藥週期之替瑞利尤單抗及阿替利珠單抗，其中該 NSCLC 已完全切除，其中該 NSCLC 為： (a) IIB 期 NSCLC； (b) IIIA 期 NSCLC；或者 (c) T3N2 IIIB 期 NSCLC。A composition of tisleliumab and/or atezolizumab for use in treating an individual with NSCLC, the composition comprising administering to the individual between one and four cycles of platinum-based adjuvant chemotherapy followed by one or more dosing cycles of tisleliumab and atezolizumab, wherein the NSCLC has been completely resected, wherein the NSCLC is:(a) Stage IIB NSCLC;(b) Stage IIIA NSCLC; or(c) T3N2 Stage IIIB NSCLC.如請求項 113 至 167 中任一項之使用之替瑞利尤單抗及/或阿替利珠單抗，其中該個體為人。For use of tislelizumab and/or atezolizumab as claimed in any of claims 113 to 167, wherein the individual is a human.