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Dostarlimab subject to accelerated FDA approval for the treatment of advanced dMMR endometrial cancer

The Food and Drug Administration (FDA) granted accelerated approval to dostarlimab on April 2021 for patients with recurrent or advanced deficient mismatch repair (dMMR) endometrial cancer that have progressed on or after platinum-based chemotherapy1. Endometrial cancer is the fifth most common cancer-related death in the United States, with 13-30% of endometrial cancers being dMMR endometrial cancer2,3; patients who have progressed following first-line therapy represent an unmet medical need.

Dostarlimab is a humanized anti-programmed death (PD)-1 monoclonal antibody that inhibits PD-1 receptor interaction with its ligands PD-L1 and PD-L2. The multicenter, open-label, single-arm Phase I GARNET study (NCT02715284) investigated the clinical activity and safety of dostarlimab in adult patients (n = 71) with dMMR recurrent or advanced endometrial cancer. Additional cohorts included patients with non-small cell lung cancer and ovarian cancer, but approval of dostarlimab was solely based on the endometrial cancer cohort. Patients were intravenously given 500 mg dostarlimab once every three weeks for four doses, followed by 1,000 mg once every six weeks4.

The primary endpoints were duration of response (DOR) and objective response rate (ORR). Median DOR was not reached and there was an ORR of 42% (95% CI: 0.31, 0.55), with 13% of patients demonstrating a complete response and 30% of patients obtaining a partial response. No deaths were reported and only 2% of patients discontinued treatment as a result of treatment-related adverse events (TRAEs), demonstrating the tolerability of dostarlimab. The most common grade 3/4 TRAEs were anemia (12%), abdominal pain (5%), and dyspnea (4%)5.

The preliminary results of the GARNET trial are promising, potentially fulfilling an unmet need for treating advanced or recurrent dMMR endometrial cancer. This is especially true for patients whose cancer recurs on or after platinum-based chemotherapy, as there is generally no accepted standard of care6.

Dr. Ana Oaknin, the primary investigator for the GARNET trial, and the Head of the Gynecologic Cancer Program at Vall d’Hebron Institute of Oncology, Barcelona, Spain commented that7:

“There are limited treatment options for women with advanced or recurrent endometrial cancer, and prognosis of these patients is poor. The results observed in the GARNET trial indicate the potential of dostarlimab to offer a new treatment option for women with this challenging disease”

Dr. Thierry André, Professor of Medical Oncology, Sorbonne University and Saint-Antoine Hospital in Paris, France, also comments that:

“It’s clear that [dostarlimab] is a good one, it works well with a response rate in this population and with a good tolerability profile.”

References

  1. Center for Drug Evaluation and Research. FDA grants accelerated approval to dostarlimab-gxly for dMMR endometrial cancer [Internet]. U.S. Food and Drug Administration. FDA; 2021 [Last accessed 26/04/2021]. Available from: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-dostarlimab-gxly-dmmr-endometrial-cancer
  2. Green AK, Feinberg J, Makker V. A Review of Immune Checkpoint Blockade Therapy in Endometrial Cancer. Am Soc Clin Oncol Educ Book. 2020;(40):238–44.
  3. Brooks RA, Fleming GF, Lastra RR, et al. Current recommendations and recent progress in endometrial cancer. CA: Cancer J Clin. 2019;69(4):258–79. 
  4. Oaknin A, Gilbert L, Tinker AV, et al. LBA36 Safety and antitumor activity of dostarlimab in patients (pts) with advanced or recurrent DNA mismatch repair deficient (dMMR) or proficient (MMRp) endometrial cancer (EC): Results from GARNET. Ann Oncol. 2020;31:S1166. 
  5. Burke WM, Orr J, Leitao M, et al. Endometrial Cancer: a review and current management strategies: part II. Gynecol Oncol. 2014;134(2):393-402.
  6. GSK presents new data from the GARNET study demonstrating potential of dostarlimab to treat a subset of women with recurrent or advanced endometrial cancer. GSK; 2020 [Last accessed 26/042021]. Available from: https://www.gsk.com/en-gb/media/press-releases/gsk-presents-new-data-from-the-garnet-study-demonstrating-potential-of-dostarlimab-to-treat-a-subset-of-women-with-recurrent-or-advanced-endometrial-cancer/

Written by Simon Ng