PD-1 Inhibitor Dostarlimab Earns Accelerated Approval in Mismatch Repair Deficient Endometrial Cancer

Based on results from the phase 2 GARNET trial, dostarlimab may be used to treat recurrent or advanced endometrial cancer progressing on or after treatment with a platinum-containing chemotherapy that is mismatch repair deficient.

Dostarlimab (Jemperli) was granted accelerated approval for the treatment of patients with recurrent or advanced deficient mismatch repair (dMMR) endometrial cancer that has progressed on or following prior treatment with platinum-containing chemotherapy, as determined by an FDA-approved test.1

The data supporting the decision for the PD-1 inhibitor come from a single-arm, multi-cohort GARNET trial (NCT02715284).

“Today’s approval of Jemperli is evidence of the FDA’s progress in applying precision medicine to expand treatment options for patients with cancer,” Richard Pazdur, MD, director of the FDA's Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research, said in a press release. “This immunotherapy was specifically studied to target dMMR endometrial cancer and leverages scientific knowledge surrounding the mechanism of immunotherapy response in this unmet medical need population.”

A group of 71 patients in the dMMR population of the study support the approval, with 42.3% having an objective response to therapy. In 93% of responders, responses lasted for 6 months or more. Previously reported results for this group show that the disease control rate was 58% (95% CI, 45%-69%), with 13% of patients having a complete response (CR) and 30% having a partial response (PR).2

Patients treated on the trial received 500 mg of dostarlimab once every 3 weeks for 4 doses, followed by 1000 mg once every 6 weeks until disease progression.

The safety population included all patients with dMMR disease who had received dostarlimab (n = 104). Only 2% of patients discontinued the drug because of treatment-related adverse events (TRAEs), which is consistent with the safety profiles of other approved PD-1 inhibitors. The most common TRAEs were asthenia (15%), diarrhea (15%), fatigue (14%), and nausea (13%). There were no grade 5 events reported.

Updated results for the trial were presented at the European Society for Medical Oncology 2020 Congress and showed that in 103 patients with dMMR tumors, the objective response rate was 44.7%, made up of 11 CRs and 35 PRs. With 13 patients achieving stable disease, the DCR was 57.3% (95% CI, 47.2%-67.0%).3 Responses at lower rates were also noted in a separate cohort of patients with mismatch repair proficient (MMRp) tumors.

“Dostarlimab demonstrated durable antitumor activity in both dMMR and MMRp advanced and recurrent endometrial cancer,” Ana Oaknin, MD, PhD, lead study author and head of the Gynecologic Cancer Program at Vall d’Hebron Institute of Oncology, in Barcelona, Spain, said in a presentation during the Congress. “The dMMR status determined by immunohistochemistry was associated with a higher response rate.”

The FDA also approved the VENTANA MMR RxDx Panel, an immunohistochemistry companion diagnostic for dostarlimab.4

Prior to the approval, dostarlimab was granted both Breakthrough Therapy Designation and Priority Review for this indication. Full approval for the agent is contingent upon further clinical trials to verify and describe its clinical benefit in this setting.

References

1. FDA Approves Immunotherapy for Endometrial Cancer with Specific Biomarker. News release. FDA. April 21, 2021. Accessed April 22, 2021.

2. GSK presents new data from the GARNET study demonstrating potential of dostarlimab to treat a subset of women with recurrent or advanced endometrial cancer. News release. GlaxoSmithKline plc. April 24, 2020. Accessed April 22, 2021. https://bit.ly/3cR8fsd.

3. Oaknin A, Gilbert L, Tinker AV, et al. Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient (dMMR) or proficient (MMRp) endometrial cancer: results from GARNET. Ann Oncol. 2020;31(suppl 4):LBA36. doi:10.1016/annonc/annonc325

4. Roche receives FDA approval for first companion diagnostic to identify endometrial cancer patients eligible for immunotherapy. News release. Roche. April 23, 2021. Accessed April 23, 2021. https://bit.ly/3veRWyk