On April 22, 2021, the PD-1 inhibitor dostarlimab-gxly was granted accelerated approval for treatment of adults with mismatch repair–deficient recurrent or advanced endometrial cancer, as determined by a U.S. Food and Drug Administration (FDA)-approved test, that has progressed on or following a prior platinum-containing regimen.^1,2

The FDA concurrently approved the Ventana MMR RxDx Panel as a companion diagnostic device for selecting patients with endometrial cancer for treatment with dostarlimab.

Supporting Efficacy Data

Approval was based on findings in a cohort (A1) of the multicohort, multicenter, phase I GARNET trial (ClinicalTrials.gov identifier NCT02715284).^2,3 The efficacy population consisted of 71 patients with mismatch repair–deficient recurrent or advanced endometrial cancer who experienced disease progression on or after a platinum-containing regimen. Patients received dostarlimab-gxly at 500 mg intravenously (IV) every 3 weeks for four doses followed by 1,000 mg IV every 6 weeks. Patients who received prior treatment with PD-1–/PD-L1–blocking antibodies or other immune checkpoint inhibitor therapy and patients with autoimmune disease who required systemic therapy with immunosuppressant agents within 2 years were excluded from the study.

The main efficacy endpoints were overall response rate and duration of response on blinded independent central review according to Response Evaluation Criteria in Solid Tumors, version 1.1. The confirmed objective response rate was 42.3% (95% confidence interval = 30.6%–54.6%), with a complete response in 12.7% of patients. At median follow-up for duration of response of 14.1 months, median response duration was not reached (range = 2.6–22.4+ months), with 93.3% of responses maintained for at least 6 months.

How It Works

Binding of the PD-1 ligands PD-L1 and PD-L2 to the PD-1 receptor found on T cells inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors, and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. 

Dostarlimab is a humanized monoclonal antibody of the IgG4 isotype that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway–mediated inhibition of the immune response, including the antitumor immune response. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth.

How It Is Used

Patients with recurrent or advanced endometrial cancer that progressed on or following prior treatment with a platinum-containing regimen must be selected for treatment with dostarlimab based on the presence of mismatch repair–deficient endometrial cancer in tumor specimens as detected by an FDA-approved test.

The recommended dostarlimab dose/schedule is 500 mg via 30-minute IV infusion every 3 weeks for doses one to four, with subsequent dosing beginning 3 weeks after dose four at 1,000 mg via 30-minute IV infusion every 6 weeks. Treatment should be continued until disease progression or unacceptable toxicity.

Infusion should be interrupted or slowed for grade 1 or 2 infusion-related reactions, and treatment should be permanently discontinued for grade 3 or 4 reactions.

No dose reductions for dostarlimab are recommended. In general, dostarlimab should be withheld for grade 3 immune-mediated adverse reactions and permanently discontinued for grade 4 immune-mediated adverse reactions, recurrent grade 3 immune-mediated reactions that require systemic immunosuppressive treatment, or an inability to reduce the corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating steroids.

Specific instructions are provided in the product labeling for dose modification, including withholding or discontinuing treatment, for adverse reactions including the following immune-mediated adverse reactions: pneumonitis, colitis, hepatitis with and without tumor involvement of the liver, endocrinopathies, nephritis with renal dysfunction, exfoliative dermatologic conditions (including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug rash with eosinophilia and systemic symptoms), myocarditis, neurologic toxicity, and infusion-related reactions.

Safety Profile

Safety data are from 104 patients in the GARNET study, who received at least one dose of dostarlimab. In the trial, 47% of patients were exposed to treatment for at least 6 months and 20% for at least 1 year.

The most common adverse events of any grade (≥ 20%) were fatigue/asthenia (48%), nausea (30%), diarrhea (26%), anemia (24%), and constipation (20%). The most common grade 3 or 4 adverse event (≥ 2%) was anemia (13%). The most common grade 3 or 4 laboratory abnormalities were lymphopenia (9%) and hyponatremia (4.8%).

Serious adverse events occurred in 34% of patients, the most common being sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia (2.9% each). Adverse events led to dose interruptions in 23% of patients, the most common causes (≥ 1% of patients) being anemia, diarrhea, increased lipase, and pyrexia. Treatment was permanently discontinued due to adverse events in five patients (4.8%), with causes including increased transaminases, sepsis, bronchitis, and pneumonitis.

Dostarlimab has warnings/precautions for immune-mediated adverse reactions, which can occur in any organ system or tissue, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and dermatologic adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity. Patients should be monitored for signs and symptoms of immune-mediated adverse reactions. Clinical chemistries, including liver and thyroid function, should be evaluated at baseline and periodically during treatment. Patients should be advised not to breastfeed while receiving dostarlimab. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-endometrial-cancer. Accessed May 7, 2021.

2. Jemperli (dostarlimab-gxly) injection, for intravenous use, prescribing information, GlaxoSmithKline LLC, April 2021. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761174s000lbl.pdf. Accessed May 7, 2021.

3. Oaknin A, Tinker AV, Gilbert L, et al: Clinical activity and safety of the anti–programmed death 1 monoclonal antibody dostarlimab for patients with recurrent or advanced mismatch repair–deficient endometrial cancer: A nonrandomized phase 1 clinical trial. JAMA Oncol 6:1766-1772, 2020.