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Dostarlimab-gxly Plus Chemotherapy Approved for dMMR or MSI-H Endometrial Cancer

Uterine endometrial carcinoma.

The FDA has approved dostarlimab-gxly (Jemperli®, GlaxoSmithKline) with carboplatin and paclitaxel, followed by single-agent dostarlimab, for patients with mismatch repair–deficient (dMMR) or microsatellite instability­–high (MSI-H) endometrial cancer, as determined by an FDA-approved test.

Background: "Dostarlimab is an immune checkpoint inhibitor that targets the programmed cell death 1 (PD-1) receptor," wrote Mansoor R. Mirza, MD, Chief Oncologist at Copenhagen University Hospital in Denmark, and colleagues, in their published results of the RUBY trial (NCT03981796), on which approval was based."The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer."

What they studied: The efficacy of dostarlimab was investigated in a phase 3, multicenter, double-blind, placebo-controlled trial, which assessed a prespecified subgroup of 122 patients with dMMR or MSI-H primary advanced or recurrent endometrial cancer. Patients' MMR and MSI tumor status was determined by local testing assays using immunohistochemistry, polymerase chain reaction (PCR), or next-generation sequencing (NGS), or by central testing using the Ventana MMR RxDx Panel when local results were not available.

Patients were randomized 1:1 to receive dostarlimab 500 mg or placebo, both in combination with carboplatin area under the concentration–time curve 5 mg/mL/min or paclitaxel 175 mg/m2 every three weeks for six cycles, followed by dostarlimab 1,000 mg or placebo every six weeks for up to three years.The study's primary end points were progression-free survival, as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, and overall survival, with safety as a secondary end point.

What they found: Dostarlimab produced a statistically significant improvement in progression-free survival compared with placebo (30.3 vs 7.7 months), with a hazard ratio of 0.29.

Safety: Immune-mediated adverse events occurring with dostarlimab included pneumonitis, colitis, hepatitis, adverse skin reactions, and endocrinopathies, including hypothyroidism and nephritis with renal dysfunction. The most common adverse events associated with dostarlimab plus carboplatin/paclitaxel, occurring in ≥20% of patients, included rash, diarrhea, hypothyroidism, and hypertension.

What to know: The prescribing information for dostarlimab plus carboplatin/paclitaxel includes warnings and precautions for immune-mediated adverse reactions, and embryo-fetal toxicity. Serious or fatal complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation after treatment with a programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1)–blocking antibody such as dostarlimab.

Patients receiving dostarlimab should be monitored for signs and symptoms of immune-mediated adverse reactions; clinical chemistries such as liver enzymes, creatinine, and thyroid function should be evaluated at baseline and periodically during treatment. Based on the severity of immune-related adverse event experienced, dostarlimab should be withheld or permanently discontinued. For patients experiencing infusion-related reactions, clinicians should interrupt, slow the rate of infusion, or permanently discontinue dostarlimab.

Conclusion: "Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR–MSI-H population," concluded Dr. Mirza and colleagues.

Instructions: The recommended dose of dostarlimab is 500 mg every three weeks with six doses in combination with carboplatin and paclitaxel, followed by 1,000 mg of dostarlimab monotherapy every six weeks, for up to three years or until disease progression or unacceptable toxicity. When administered on the same day as chemotherapy, dostarlimab should be given prior to chemotherapy. Dostarlimab should be administered as an intravenous infusion over 30 minutes.

For More Information

Mirza MR, Chase DM, Slomovitz, et al (2023). Dostarlimab for primary advanced or recurrent endometrial cancer. N Engl J Med, 388(23):2145-2158. DOI:10.1056/NEJMoa2216334

Clinicaltrials.gov (2022). A study to evaluate dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel in participants with recurrent or primary advanced endometrial cancer (RUBY). NLM identifier: NCT03981796.

Jemperli® (dostarlimab-gxly) prescribing information (2023). GlaxoSmithKline. Available at: accessdata.fda.gov/drugsatfda_docs/label/2023/761174s006lbl.pdf

US Food & Drug Administration (2023). FDA approves dostarlimab-gxly with chemotherapy for endometrial cancer. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-dostarlimab-gxly-chemotherapy-endometrial-cancer 

Image credit: Sameem Arif. Licensed under CC BY-SA 4.0


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