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Pembrolizumab

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Pembrolizumab
FromPDB entry5dk3
Monoclonal antibody
TypeWhole antibody
SourceHumanized (frommouse)
TargetPD-1
Names
Trade namesKeytruda
Other namesMK-3475, lambrolizumab
Clinical data
Drug classAntineoplastic agents
Main usesCancer[1]
Side effectsTiredness, musculoskeletal pain, decreased appetite, itchy skin, diarrhea, nausea, rash, fever, cough, difficulty breathing, constipation, abdominal pain[1]
Pregnancy
category
Routes of
use		IV
External links
AHFS/Drugs.comMonograph
MedlinePlusa614048
Legal
License data
Legal status
Chemical and physical data
FormulaC6534H10004N1716O2036S46
Molar mass146648.64 g·mol−1

Pembrolizumab (formerlylambrolizumab, brand nameKeytruda) is a medication used incancer immunotherapy.[1] This includes to treatmelanoma,lung cancer,head and neck cancer,Hodgkin lymphoma,cervical cancer, andstomach cancer.[1] It is given byslow injection into a vein.[1]

Common side effects include tiredness, musculoskeletal pain, decreased appetite, itchy skin, diarrhea, nausea, rash, fever, cough, difficulty breathing, constipation, and abdominal pain.[1] Other side effects include liver problems and kidney problems.[1] Use during pregnancy or breastfeeding is not recommended.[4] It is an IgG4 isotypehumanized antibody that blocks a protective mechanism of cancer cells and thereby, allows theimmune system to destroy them.[1] It targets theprogrammed cell death protein 1 (PD-1) receptor of lymphocytes.[1]

Pembrolizumab was approved for medical use in the United States in 2014.[1] In 2017, it was approved for any non removable or metastatic solid tumor with certain genetic anomalies (mismatch repair deficiency ormicrosatellite instability).[5] It is on theWorld Health Organization's List of Essential Medicines as an alternative fornivolumab.[6] In the United Kingdom the typical dose costs 5,260 pounds every three weeks as of 2020.[7] In the United States this amount costs 8,760 USD.[8]

Contents

Medical uses

Micrograph showing a PD-L1 positive non-small cell lung carcinoma. PD-L1immunostain

Pembrolizumab is used via intravenous infusion to treat inoperable or metastaticmelanoma, metastaticnon-small cell lung cancer (NSCLC) in certain situations, as a first-line treatment for metastatic bladder cancer in people who can't receive cisplatin-based chemotherapy and have high levels of PD-L1, as a second-line treatment forhead and neck squamous cell carcinoma (HNSCC), afterplatinum-based chemotherapy, for the treatment of adult and children with refractory classicHodgkin's lymphoma (cHL), and recurrent locally advanced or metastaticesophageal squamous cell carcinoma.[9][10][11][12][13][14][15][16]

For NSCLC, pembrolizumab is a first-line treatment if the cancer overexpressesPD-L1, a PD-1 receptor ligand, and the cancer has no mutations inEGFR or inALK; if chemotherapy has already been administered, then pembrolizumab can be used as a second-line treatment, but if the cancer has EGFR or ALK mutations, agents targeting those mutations should be used first.[9][17] Assessment ofPD-L1 expression must be conducted with a validated and approvedcompanion diagnostic.[9][14]

In 2017, the U.S.Food and Drug Administration (FDA) approved pembrolizumab for any unresectable or metastatic solid tumor with certain genetic anomalies (mismatch repair deficiency ormicrosatellite instability).[5][18] This was the first time the FDA approved a cancer drug based on tumor genetics rather than tissue type or tumor site;[medical citation needed] therefore, pembrolizumab is a so-calledtissue-agnostic drug.[medical citation needed]

In the European Union, pembrolizumab is indicated for:

  • the treatment of advanced (unresectable or metastatic) melanoma in adults as monotherapy.[19]
  • the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection as monotherapy.[19]
  • the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations as monotherapy.[19]
  • the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations in combination with pemetrexed and platinum chemotherapy.[19]
  • the first-line treatment of metastatic squamous NSCLC in adults in combination with carboplatin and either paclitaxel or nab-paclitaxel.[19]
  • the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥ 1% TPS and who have received at least one prior chemotherapy regimen. People with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving Keytruda as monotherapy.[19]
  • the treatment of adults with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV as monotherapy.[19]
  • the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy as monotherapy.[19]
  • the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD L1 with a combined positive score (CPS) ≥ 10 as monotherapy.[19]
  • the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1 as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy.[19]
  • the treatment of recurrent or metastatic HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy as monotherapy.[19]
  • the first-line treatment of advanced renal cell carcinoma (RCC) in adults in combination with axitinib.[19]

In 2020, the FDA approved pembrolizumab as the first-line treatment for people with unresectable or metastatic microsatellite instability-high (MSI‑H) or mismatch repair deficient (dMMR) colorectal cancer.[20] The approval marks the first immunotherapy approved in the US as a first-line treatment and which is administered to people without also giving chemotherapy.[20]

Dosage

In adults it is often given at a dose of 200 mg every three weeks.[1]

Contraindications

If a person is taking corticosteroids or immunosuppressants, those drugs should be stopped before starting pembrolizumab because they may interfere with pembrolizumab; they may be used after pembrolizumab is started to deal with immune-related adverse effects.[10]

Women of child-bearing age should use contraception when taking pembrolizumab; it should not be administered to pregnant women because animal studies have shown that it can reducetolerance to the fetus, increasing the risk of miscarriage. It is not known whether pembrolizumab is present in breast milk.[10]

As of 2017[update], the drug had not been tested in people with active infections (including any HIV, hepatitis B or hepatitis C infection), kidney or liver disease, activeCNS metastases, active systemic autoimmune disease, interstitial lung disease, prior pneumonia, and people with a history of severe reaction to another monoclonal antibody.[10][needs update]

Side effects

People have had severe infusion-related reactions to pembrolizumab. There have also been severe immune-related adverse effects including lung inflammation (including fatal cases) and inflammation of endocrine organs that causedinflammation of the pituitary gland, of thethyroid (causing bothhypothyroidism andhyperthyroidism in different people), and pancreatitis that causedType 1 diabetes anddiabetic ketoacidosis; some people have had to go on lifelong hormone therapy as a result (e.g. insulin therapy or thyroid hormones). People have also hadcolon inflammation,liver inflammation,kidney inflammation due to the drug.[10][21]

The common adverse reactions have been fatigue (24%), rash (19%), itchiness (pruritus) (17%), diarrhea (12%), nausea (11%) and joint pain (arthralgia) (10%).[10]

Other adverse effects occurring in between 1% and 10% of people taking pembrolizumab have included anemia, decreased appetite, headache, dizziness, distortion of the sense of taste, dry eye, high blood pressure, abdominal pain, constipation, dry mouth, severe skin reactions, vitiligo, various kinds of acne, dry skin, eczema, muscle pain, pain in a limb, arthritis, weakness, edema, fever, chills, myasthenia gravis, and flu-like symptoms.[10]

  • Dermatitis induced by pembrolizumab

    Dermatitis induced by pembrolizumab

  • Bullous pemphigoid induced by pembrolizumab

    Bullous pemphigoid induced by pembrolizumab

  • Bullous pemphigoid induced by pembrolizumab

    Bullous pemphigoid induced by pembrolizumab

  • Bullous pemphigoid induced by pembrolizumab

    Bullous pemphigoid induced by pembrolizumab

Mechanism of action

Pembrolizumab mode of action[22]

Pembrolizumab is atherapeutic antibody that binds to and blocks PD-1 located on lymphocytes. This receptor is generally responsible for preventing the immune system from attacking the body's own tissues; it is a so-calledimmune checkpoint.[23][24] Many cancers make proteins that bind to PD-1, thus shutting down the ability of the body to kill the cancer on its own.[14][23] Inhibiting PD-1 on the lymphocytes prevents this, allowing the immune system to target and destroy cancer cells;[25] this same mechanism also allows the immune system to attack the body itself, andcheckpoint inhibitors like pembrolizumab have immune-dysfunction side effects as a result.[24]

Tumors that have mutations that cause impairedDNA mismatch repair, which often results inmicrosatellite instability, tend to generate many mutated proteins that could serve astumor antigens; pembrolizumab appears to facilitate clearance of any such tumor by the immune system, by preventing the self-checkpoint system from blocking the clearance.[14][26]

Pharmacology

Since pembrolizumab is cleared from the circulation through non-specificcatabolism, no metabolicdrug interactions are expected and no studies were done on routes of elimination.[10]

The systemic clearance [rate] is about 0.2 L/day and theterminal half-life is about 25 days.[10]

Chemistry and manufacturing

Pembrolizumab is animmunoglobulin G4, with a variable region against the human PD-1 receptor, a humanized mouse monoclonal [228-L-proline(H10-S>P)]γ4 heavy chain (134-218') disulfide and a humanized mouse monoclonal κ light chain dimer (226-226:229-229)-bisdisulfide.[27]

It is recombinantly manufactured inChinese hamster ovary (CHO) cells.[28][19]

History

Pembrolizumab was invented by scientists Gregory Carven, Hans van Eenennaam and John Dulos atOrganon after which they worked withMedical Research Council Technology (which became LifeArc) starting in 2006, to humanize the antibody;Schering-Plough acquired Organon in 2007, andMerck & Co. acquired Schering-Plough two years later.[29] Carven, van Eenennaam and Dulos were recognized as Inventors of the Year by the Intellectual Property Owners Education Foundation in 2016.[30]

The development program for pembrolizumab was seen as high priority at Organon, but low at Schering and later Merck. In early 2010, Merck terminated development and began preparing to out-license it.[31] Later, in 2010, scientists fromBristol Myers Squibb published a paper inThe New England Journal of Medicine showing that their checkpoint inhibitor,ipilimumab (Yervoy) had shown strong promise in treating metastatic melanoma[32] and that a second Bristol-Myers Squibb checkpoint inhibitor,nivolumab, (Opdivo) was also promising.[31] Merck at that time had little commitment or expertise in either oncology or immunotherapy, but understood the opportunity and reacted strongly, reactivating the program and filing itsIND by the end of 2010.[31] As one example, Martin Huber was one of the few senior people at Merck with strong experience in lung cancer drug development, but had been promoted to senior management and was no longer involved in product development. He stepped down from his role to lead clinical development of pembrolizumab for lung cancer.[31]

Scientists at the company argued for developing acompanion diagnostic and limiting testing of the drug only to patients withbiomarkers showing they were likely to respond, and received agreement from management. Some people, including shareholders and analysts, criticized this decision as it limited the potential market size for the drug, while others argued it increased the chances of proving the drug would work and would make clinical trials faster. (The trials would need fewer patients because of the likelihood of greater effect size.) Moving quickly and reducing the risk of failure was essential for catching up with Bristol-Myers Squibb, which had an approximate five year lead over Merck.[31] The phase I study started in early 2011, and Eric Rubin, who was running the melanoma trial, argued for and was able to win expansion of the trial until it reached around 1300 people. This was the largest Phase I study ever run in oncology, with the patients roughly divided between melanoma and lung cancer.[31]

In 2013, Merck quietly applied for and won abreakthrough therapy designation for the drug. This regulatory pathway was new at the time and not well understood. One of its advantages is that the US FDA holds more frequent meetings with drug developers, reducing the risk of developers making mistakes or misunderstandings arising between regulators' expectations and what the developers want to do. This was Merck's first use of the designation and the reduction in regulatory risk was one of the reasons management was willing to put company resources into development.[31]

In 2013, theUnited States Adopted Name (USAN) name was changed from lambrolizumab to pembrolizumab.[27] In that year clinical trial results in advanced melanoma were published inThe New England Journal of Medicine.[33] This was part of the large Phase I NCT01295827 trial.[34]

On 4 September 2014, the USFood and Drug Administration (FDA) approved pembrolizumab under theFast Track Development Program.[35] It is approved for use following treatment withipilimumab, or after treatment with ipilimumab and aBRAF inhibitor in advancedmelanoma patients who carry aBRAF mutation.[36]

As of 2015[update], the only PD-1/PD-L1 targeting drugs on the market were pembrolizumab and nivolumab, with clinical developments in the class of drugs receiving coverage inThe New York Times.[37]

By April 2016, Merck applied for approval to market the drug in Japan and signed an agreement withTaiho Pharmaceutical to co-promote it there.[38]

In July 2015, pembrolizumab received marketing approval in Europe.[10][39][19]

On 2 October 2015, the US FDA approved pembrolizumab for the treatment ofmetastaticnon-small cell lung cancer (NSCLC) in patients whose tumors expressPD-L1 and who have failed treatment with otherchemotherapeutic agents.[40]

In July 2016, the US FDA accepted for priority review an application for recurrent or metastatichead and neck squamous cell carcinoma (HNSCC) after a platinum-based chemotherapy.[41] They grantedaccelerated approval to pembrolizumab as a treatment for patients with recurrent or metastatic (HNSCC) ("regardless of PD-L1 staining") following progression on a platinum-based chemotherapy, based onobjective response rates (ORR) in the Phase Ib KEYNOTE-012 study in August of the same year.[42][43] Full approval depended on the results of the Phase III KEYNOTE-040 study (NCT02252042), which ran until Jan 2017.[43]

In May 2017, pembrolizumab received an accelerated approval from the US FDA for use in any unresectable or metastatic solid tumor withDNA mismatch repair deficiencies or amicrosatellite instability-high state (or, in the case of colon cancer, tumors that have progressed following chemotherapy).[44] This approval marked the first instance in which the FDA approved marketing of a drug based only on the presence of a genetic mutation, with no limitation on the site of the cancer or the kind of tissue in which it originated.[44][18][26][45] The approval was based on a clinical trial of 149 patients with microsatellite instability-high or mismatch repair deficient cancers who enrolled on one of five single-arm trials. Ninety patients had colorectal cancer, and 59 patients had one of 14 other cancer types. The objective response rate for all patients was 39.6%. Response rates were similar across all cancer types, including 36% in colorectal cancer and 46% across the other tumor types. Notably, there were 11 complete responses, with the remainder partial responses. Responses lasted for at least six months in 78% of responders.[26] Because the clinical trial was fairly small, Merck is obligated to conduct further post-marketing studies to ensure that the results are valid.[46] Pembrolizumab was granted orphan drug designation for SCLC in October 2017.[47]

In June 2018, the US FDA approved pembrolizumab for use in both advancedcervical cancer for PD-L1 positive patients[48] and for the treatment of adult and pediatric patients with refractoryprimary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after two or more prior lines of therapy.[49]

In August 2018, the US FDA updated the prescribing information for pembrolizumabatezolizumab to require the use of an FDA-approved companion diagnostic test to determine PD-L1 levels in tumor tissue from patients with locally advanced or metastatic urothelial cancer who are cisplatin-ineligible.[50] On 16 August 2018, the FDA approved the Dako PD-L1 IHC 22C3 PharmDx Assay (Dako North America, Inc.) as a companion diagnostic to select patients with locally advanced or metastatic urothelial carcinoma who are cisplatin-ineligible for treatment with pembrolizumab.[50] The 22C3 assay determines PD-L1 expression by using a combined positive score (CPS) assessing PD-L1 staining in tumor and immune cells.[50] As of August 2018[update], pembrolizumab is indicated for the treatment of those with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 [Combined Positive Score (CPS) ≥ 10] as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.[50]

In November 2018, the US FDA granted accelerated approval to pembrolizumab for those with hepatocellular carcinoma (HCC) who have been previously treated withsorafenib.[51]

In February 2019, the US FDA approved pembrolizumab for the adjuvant treatment of people with melanoma with involvement of lymph node(s) following complete resection.[52] The FDA granted the applicationorphan drug designation.[52]

In June 2019, the US FDA granted accelerated approval to pembrolizumab for those withmetastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy,[47] and the FDA approved pembrolizumab for the first-line treatment of people with metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC).[53] Pembrolizumab was approved for use in combination with platinum and fluorouracil (FU) for all patients and as a single agent for patients whose tumors express PD‑L1 (Combined Positive Score [CPS] ≥1) as determined by an FDA‑approved test.[53] The FDA also expanded the intended use for the PD-L1 IHC 22C3 pharmDx kit to include use as a companion diagnostic device for selecting patients with HNSCC for treatment with pembrolizumab as a single agent.[53]

In July 2019, the FDA approved pembrolizumab for people with recurrent, locally advanced or metastatic, squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (Combined Positive Score [CPS] ≥10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.[15] The FDA also approved a new use for the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting people for the above indication.[15]

In June 2020, theUS FDA approved pembrolizumab as monotherapy for the treatment of adult and children with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.[54]

Society and culture

Pembrolizumab was priced at $150,000 per year when it launched (late 2014).[55]

Research

In 2015, Merck reported results in 13 cancer types; much attention was given to early results inhead and neck cancer.[14][56][57]

As of May 2016[update], pembrolizumab was in Phase IB clinical trials fortriple-negative breast cancer (TNBC),gastric cancer,urothelial cancer, andhead and neck cancer (all under the "Keynote-012" trial) and in Phase II trial for TNBC (the "Keynote-086" trial).[58] At ASCO, in June 2016, Merck reported that the clinical development program was directed to around 30 cancers and that it was running over 270 clinical trials (around 100 in combination with other treatments) and had four registration-enabling studies in process.[59]

Results of a Phase III clinical trial intriple-negative breast cancer were reported in Annals of Oncology in October 2019.[60]

Results of a Phase II clinical trial inMerkel-cell carcinoma were reported inThe New England Journal of Medicine in June 2016.[61]

Results of a clinical trial in people with untreatable metastases arising from various solid tumors were published inScience in 2017.[62]

A clinical Phase III trial in combination withepacadostat, anIndoleamine 2,3-dioxygenase(IDO1) inhibitor to treat melanoma was completed in 2019.[14][63]

References

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  2. ↑2.02.1"Pembrolizumab (Keytruda) Use During Pregnancy".Drugs.com. 24 September 2019.Archived from the original on 14 June 2020. Retrieved10 January 2020.
  3. ↑"Keytruda 50 mg powder for concentrate for solution for infusion - Summary of Product Characteristics (SmPC)".(emc). 7 April 2020. Archived fromthe original on 13 December 2017. Retrieved30 April 2020.
  4. ↑"Pembrolizumab (Keytruda) Use During Pregnancy".Drugs.com.Archived from the original on 14 June 2020. Retrieved19 October 2020.
  5. ↑5.05.1Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (2017). "De-novo and acquired resistance to immune checkpoint targeting".The Lancet Oncology.18 (12): e731–e741.doi:10.1016/s1470-2045(17)30607-1.PMID 29208439.
  6. ↑World Health Organization (2019).World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization.hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
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  8. ↑Huang, M; Lou, Y; Pellissier, J; Burke, T; Liu, FX; Xu, R; Velcheti, V (August 2017). "Cost Effectiveness of Pembrolizumab vs. Standard-of-Care Chemotherapy as First-Line Treatment for Metastatic NSCLC that Expresses High Levels of PD-L1 in the United States".PharmacoEconomics.35 (8): 831–844.doi:10.1007/s40273-017-0527-z.PMID 28620848.
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  11. ↑Redman, Jason M.; Gibney, Geoffrey T.; Atkins, Michael B. (6 February 2016)."Advances in immunotherapy for melanoma".BMC Medicine.14 (1): 20.doi:10.1186/s12916-016-0571-0.PMC 4744430.PMID 26850630.
  12. ↑Fuereder, Thorsten (20 June 2016)."Immunotherapy for head and neck squamous cell carcinoma".Memo - Magazine of European Medical Oncology.9 (2): 66–69.doi:10.1007/s12254-016-0270-8.PMC 4923082.PMID 27429658.
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  14. ↑14.014.114.214.314.414.5Syn, Nicholas L; Teng, Michele W L; Mok, Tony S K; Soo, Ross A (2017). "De-novo and acquired resistance to immune checkpoint targeting".The Lancet Oncology.18 (12): e731–e741.doi:10.1016/s1470-2045(17)30607-1.PMID 29208439.
  15. ↑15.015.115.2"FDA approves pembrolizumab for advanced esophageal squamous cell cancer".U.S.Food and Drug Administration (FDA) (Press release). 30 July 2019.Archived from the original on 12 January 2020. Retrieved10 January 2020.Public DomainThis article incorporates text from this source, which is in thepublic domain.
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  21. ↑Linardou, Helena; Gogas, Helen (July 2016)."Toxicity management of immunotherapy for patients with metastatic melanoma".Annals of Translational Medicine.4 (14): 272.doi:10.21037/atm.2016.07.10.PMC 4971373.PMID 27563659.
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  32. ↑Hodi FS, O'Day SJ, McDermott DF, et al. (August 2010)."Improved survival with ipilimumab in patients with metastatic melanoma".New England Journal of Medicine.363 (8): 711–723.doi:10.1056/nejmoa1003466.ISSN 0028-4793.PMC 3549297.PMID 20525992.
  33. ↑Hamid O, Robert C, Daud A, et al. (July 2013)."Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma".New England Journal of Medicine.369 (2): 134–44.doi:10.1056/nejmoa1305133.PMC 4126516.PMID 23724846.
  34. ↑Clinical trial numberNCT01295827 for "Study of Pembrolizumab (MK-3475) in Participants With Progressive Locally Advanced or Metastatic Carcinoma, Melanoma, or Non-small Cell Lung Carcinoma (P07990/MK-3475-001/KEYNOTE-001) (KEYNOTE-001)" atClinicalTrials.gov
  35. ↑"FDA approves Keytruda for advanced melanoma" (Press release). U.S.Food and Drug Administration (FDA). 4 September 2014. Archived fromthe original on 27 December 2015. Retrieved24 December 2015.Public DomainThis article incorporates text from this source, which is in thepublic domain.
  36. ↑"FDA Approves Anti-PD-1 Drug for Advanced Melanoma".cancernetwork.com. Archived fromthe original on 10 January 2016. Retrieved7 September 2014.
  37. ↑Pollack, Andrew (29 May 2015)."New Class of Drugs Shows More Promise in Treating Cancer".The New York Times.Archived from the original on 29 May 2015. Retrieved30 May 2015.
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  41. ↑Potential Biomarkers Identified for Pembrolizumab in Head and Neck Cancer. July 2016[permanent dead link]
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  43. ↑43.043.1"FDA Approves Pembrolizumab for Head and Neck Cancer. Aug 2016".Archived from the original on 7 August 2016. Retrieved6 August 2016.
  44. ↑44.044.1"FDA approves first cancer treatment for any solid tumor with a specific genetic feature".U.S.Food and Drug Administration (FDA) (Press release). 23 May 2017.Archived from the original on 12 January 2020. Retrieved10 January 2020.Public DomainThis article incorporates text from this source, which is in thepublic domain.
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  47. ↑47.047.1"FDA approves pembrolizumab for metastatic small cell lung cancer".U.S.Food and Drug Administration (FDA) (Press release). 17 June 2019.Archived from the original on 6 April 2020. Retrieved10 January 2020.Public DomainThis article incorporates text from this source, which is in thepublic domain.
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  52. ↑52.052.1"FDA approves pembrolizumab for adjuvant treatment of melanoma".U.S.Food and Drug Administration (FDA) (Press release). 15 February 2019.Archived from the original on 12 January 2020. Retrieved10 January 2020.Public DomainThis article incorporates text from this source, which is in thepublic domain.
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  63. ↑Clinical trial numberNCT02752074 for "A Phase 3 Study of Pembrolizumab + Epacadostat or Placebo in Subjects With Unresectable or Metastatic Melanoma (Keynote-252 / ECHO-301)" atClinicalTrials.gov

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