| Monoclonal antibody | |
|---|---|
| Type | Whole antibody |
| Source | Humanized |
| Target | PDCD1 |
| Clinical data | |
| Trade names | Jemperli |
| Other names | TSR-042, WBP-285, dostarlimab-gxly |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a621030 |
| License data | |
| Pregnancy category | |
| Routes of administration | Intravenous |
| Drug class | Antineoplastic |
| ATC code | |
| Legal status | |
| Legal status | |
| Identifiers | |
| CAS Number | |
| PubChem SID | |
| DrugBank | |
| UNII | |
| KEGG | |
| Chemical and physical data | |
| Formula | C6420H9832N1690O2014S44 |
| Molar mass | 144325.73 g·mol−1 |
Dostarlimab, sold under the brand nameJemperli, is amonoclonal antibody used as ananti-cancer medication for the treatment ofendometrial cancer.[5][6][10] Dostarlimab is aprogrammed death receptor-1 (PD-1)–blocking monoclonal antibody.[5][6][8]
The most common side effects reported in the US includefatigue/asthenia, nausea, diarrhea,anemia, and constipation.[5][6] Additional side effects reported in the European Union include vomiting, joint pain, itching, rash, fever, andhypothyroidism (low levels of thyroid hormones).[8]
Dostarlimab was approved for the treatment of endometrial cancer in both the United States and the European Union in April 2021.[5][6][11][8][12]
Based on the Garnet trial, dostarlimab gained accelerated approval from the USFood and Drug Administration (FDA) in April 2021,[6] and full approval in February 2023.[7]
Dostarlimab has been approved to treat specific cancers in various jurisdictions.
In endometrial cancer cancerous cells reside in the lining of theuterus (endometrium).[13] The four stages in endometrial cancer range from settling in the endometrium to metastasizing to other organs.[13] This disease can be treated if discovered early enough.[14] Studies report that chemoresistant MSI-high tumors can be treated with dostarlimab andpembrolizumab.[14]
In the European Union, dostarlimab is indicated asmonotherapy for the treatment of adults withmismatch repair deficient (dMMR)/microsatellite instability-high (MSI H) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with aplatinum-based regimen such ascisplatin,carboplatin oroxaliplatin.[15]
Dostarlimab is approved in the US for adults with dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment and who lack satisfactory alternative treatment options.[16][17] Dostarlimab, in combination withcarboplatin andpaclitaxel, followed by single-agent dostarlimab, is approved for primary advanced or recurrent dMMR endometrial cancer.[18][19] Efficacy was evaluated in RUBY (NCT03981796), a randomized, multicenter, double-blind,placebo-controlled trial. Efficacy was assessed in a pre-specified subgroup of 122 participants with dMMR/MSI-H primary advanced or recurrent endometrial cancer. MMR/MSI tumor status was assessed by local testing assays (IHC, PCR, or NGS), or central testing (IHC), using the Ventana MMR RxDx Panel, when local results were unavailable.[19] In August 2024, theFood and Drug Administration approved dostarlimab with carboplatin and paclitaxel, followed by single-agent dostarlimab, for adults with primary advanced or recurrent endometrial cancer.[20] Dostarlimab previously was approved with carboplatin and paclitaxel, followed by single-agent dostarlimab, for primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H).[20]
Solid tumors are tumors that do not contain any liquid orcysts, which can occur in many places including bones, muscles and organs. The most common types of solid tumors aresarcomas andcarcinomas.[22] Dostarlimab can be used to treat recurrent or advanced tumors for patients who have tried alternative treatment options.[23]
In a Phase II clinical trial, dostarlimab-gxly completely eradicated tumors in all 42 patients. dMMR cancers comprise 5-10% of colorectal cancers. Traditional surgery patients often experience life-long impacts, such as bowel, urinary and sexual dysfunction, as well as secondary cancers and infertility.[24][25]
Serious adverse reactions in >2% of patients includedsepsis,acute kidney injury,urinary tract infection,abdominal pain, andfever (pyrexia).[5][6]
Immune-mediated adverse reactions can occur includingpneumonitis,colitis,hepatitis,endocrine disease (endocrinopathies), andnephritis.[5][6]
The most common side effects reported while taking this medication during a trial weredyspnea,asthenia, fatigue, and nausea.[26]
Symptoms of overdose are similar to the side effect profile of the medication, so it could involve significantimmune-mediated reactions.[27]
Dostarlimab is a monoclonal antibody that binds to PD-1 to block it from binding PD-1 ligands to remove inhibition of immune response.[5] With this, it causes risk for immune-mediatedadverse reactions.[5] These reactions can be severe or fatal and occur in any part of the body: organs or tissues.[5]
Examples of immune-mediated adverse reactions include immune-mediatedpneumonitis,colitis,hepatitis,adrenal insufficiency,hypophysitis,thyroid disorders,nephritis with renal dysfunction, anddermatologic reactions.[5]
Dostarlimab can cause harm to a fetus.[5] The death of the fetus can occur from the immune system's reaction to the fetus through the examination of its mechanism in animal studies.[5] Dostarlimab is a humanimmunoglobulin G (IgG4), which could permeate through the placental barrier.[5] This may risk harm to the developing fetus as the drug may be passed on from the mother.[5]
Data is not available regarding the presence of dostarlimab in breastmilk.[5]
Dostarlimab causes mild to moderate elevations to serum aminotransferase andalkaline phosphatase in 15-25% of recipients.[27] SerumALT elevation above five times the normal range occurs in 2-3% of recipients.[27] Some people treated with dostarlimab can develop immune related liver injury.[27]
Some symptoms of liver injury or acute liver failure can includejaundice, pain in the upper right abdomen,ascites, nausea/vomiting, and disorientation or confusion.[28]
Dostarlimab is a humanized IgG4 monoclonal antibody that was derived from a mouse antibody which was humanized viaComplementarity Determining Region (CDR) grafting.[29] Its serumhalf-life is 25.4 days.[5]
Other PD-1 antibodies includednivolumab (Opdivo) andpembrolizumab (Keytruda), both of which have uses in many different types of cancers which includeclassical Hodgkin lymphoma,renal cell carcinoma, andbreast cancer.[29] Another PD-1 antibody iscemiplimab (Libtayo) which was approved for treatment ofsquamous cell carcinoma,basal cell carcinoma andnon-small cell lung cancer.[29]
Dostarlimab binds to the PD-1 receptor, with high affinity, to block its activity with PD-1 ligands (PD-L1 and PD-L2).[15][30] PD-1 is a co-inhibitory receptor that is an important checkpoint protein for regulatingT-cell tolerance.[5][29] When PD-1 is constantly stimulated by PD-1 ligands, which are highly expressed in cancer cells, it allows cancer cells to dodge T-cell mediated immune responses.[29] Therefore, blocking the binding of PD-1 to these ligands can allow T-cells to function normally and prevent tumor cells from bypassing immune surveillance.[29] In mouse tumor models, it was shown that inhibiting PD-1 activity decreased tumor growth.[5]
In the Garnet Trial, dostarlimab achieved favorable results in decreasing the size of the tumor in those with endometrial cancer.[31] The study observed people with endometrial cancer from seven different countries and the size of the tumor was reduced in 42% of the population studied.[31]
Dostarlimab exhibits better efficacy than PD-L1 inhibitors, such asavelumab anddurvalumab, in dMMR advanced endometrial cancers.[32] Efficacy of the drug is measured by the response rate, which is 47% for dostarlimab.[32]
In 2020, dostarlimab, a PD-1 inhibitor, was undergoingphase I/II and phase III clinical trials.[31][33][34]
In 2020, the manufacturer,Tesaro, announced preliminary successful results from the phase I/II GARNET study.[31][35]
In 2020, the Garnet study announced that dostarlimab had promising potential to treat a specific subset of individuals with recurrent or advanced endometrial cancer.[31]
In April 2021, dostarlimab was approved for the treatment of recurrent or advanced endometrial cancer with mismatch repair deficient (dMMR), which are genetic abnormalities that disrupt DNA repair, in individuals who had previously been treated with platinum-containing regimens.[36]
In April 2021, the USFood and Drug Administration (FDA) granted accelerated approval to dostarlimab-gxly (Jemperli, GSK).[6] Efficacy was evaluated based on cohort (A1) in Garnet Trial (NCT02715284), a multicenter, multicohort,open-label trial in participants with advanced solid tumors.[6] The FDA approved dostarlimab based on evidence from the GARNET trial (NCT02715284) of 71 participants with advanced or recurrent endometrial cancer that was shown to be mismatch repair deficient (dMMR), and for which certain types of chemotherapy did not work or was no longer working.[37] The cohort used for the approved indication was conducted at 40 sites in 7 countries in North America and Europe.[37]
In 2022, an early clinical study of dostarlimab reported a 100% remission rate in 14 patients withrectal cancer who had mismatch repair deficiency, a type of genetic mutation that only affects 5-10% of cases.[38][39][40]
In February 2023, the FDA approved dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for adults with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and are not candidates for curative surgery or radiation.[7]
Dostarlimab is theinternational nonproprietary name (INN),[41] and theUnited States Adopted Name (USAN).[42]
In February 2021, theCommittee for Medicinal Products for Human Use (CHMP) of theEuropean Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a conditional marketing authorization for the medicinal product Jemperli, intended for the treatment of certain types of recurrent or advanced endometrial cancer.[43] The applicant for this medicinal product is GSK (Ireland) Limited.[43] Dostarlimab was approved for medical use in the European Union in April 2021.[8]
In the United States, dostarlimab costs aroundUS$11,000 per dose.[44]
Among those who are insured, those who haveMedicaid insurance are less likely to receive full care forgynecologic cancer.[45] Those insured through private insurance still experience economical hardships while getting treatment.[45] Uninsured patients do not tend to get screened regularly, which results in late diagnosis of the disease.[45]
This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain. This article incorporates text from this source, which is in thepublic domain.
