FDA Approves Dostarlimab for Recurrent or Advanced dMMR Endometrial Cancer

The FDA has granted accelerated approval to dostarlimab-gxly (Jemperli) for the treatment of adult patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with platinum-containing chemotherapy and whose cancers have a specific genetic feature known as mismatch repair deficiency (dMMR), as determined by an FDA approved test.^1,2

“The approval of dostarlimab has the potential to change the way we’ve been treating dMMR advanced or recurrent endometrial cancer after standard platinum-based chemotherapy, especially given the overall response rate and durability of response that we saw in the GARNET trial,” said investigator Jubilee Brown, MD, professor and director of the Division of Gynecologic Oncology at Levine Cancer Institute, Atrium Health, in a statement.

Dostarlimab, when made available to clinicians, will address the issue of having limited frontline therapeutic options for a population that represents approximately 25% to 30% of patients with advanced endometrial cancer.

"Today's approval of Jemperli is evidence of the FDA's progress in applying precision medicine to expand treatment options for patients with cancer," said 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. "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."

Approval of dostarlimab for this indication was granted based on results from a single-arm, multi-cohort clinical trial of 71 patients with dMMR recurrent or advanced endometrial cancer. In the study, treatment with dostarlimab achieved complete responses (CRs) or partial responses (PRs) in 42.3% of patients. Notably, 93% of the responders had responses lasting at least 6 months.1,3

The common toxicities observed with dostarlimab include fatigue, nausea, diarrhea, anemia, and constipation. Immune-mediated adverse events associated with the agent include pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.

Dostarlimab targets and blocks PD-1/PD-L1 pathway and aids the body's immune system in its fight against cancer cells. The agent's ability to activate responses in patients with dMMR disease was also demonstrated in an endometrial cancer cohort of phase 1 GARNET study (NCT02715284), which included 126 patients with dMMR endometrial cancer.^3,4

In a subgroup analysis of patients with dMMR endometrial cancer, the objective response rate observed was 44.7%, which included CRs in 11 patients, PRs in 35 patients, and stable disease in 39 patients. The median duration of response (DOR) was not reached in the cohort (range, 2.63-28.09+).

The safety of the agent was demonstrated in the primary analysis of the GARNET study. Any-grade treatment-emergent adverse effects (TEAEs) occurred in 95.2% of patients in the dMMR cohort. Grade 3 or higher TEAEs were seen in 48.4% of the patients with dMMR endometrial cancer. More than 63% of the toxicities observed in the cohort were considered related to the study drug, and there were serious toxicities reported in 9.5%.

Immune-related TRAEs of any grade were also reported in the study, with the most common being hypothyroidism in 5.6%, diarrhea in 4.8%, and increased aspartate aminotransferase in 1.6%. Grade 3 or higher immune-related TRAEs of increased ALT occurred in 1.6% of patients as did diarrhea. Grade 3 or higher increased amylase was observed in 0.8 of the cohort.

GARNET is ongoing and evaluating the use of dostarlimab in patients with advanced solid tumors. The total study population is 740 patients. In the dMMR endometrial cancer cohort, patients received dostarlimab 160 mg, 20 mg/mL, 500 mg, or 50 mg/mL. The primary end points of the study include ORR and DOR. The study is also exploring multiple safety end points.

_Reference:

_{1. FDA approves immunotherapy for endometrial cancer with specific biomarker. FDA. April 22, 2021. Accessed April 22, 2021. https://bit.ly/3dIIIod}

_{2. FDA grants accelerated approval for GSK’s JEMPERLI (dostarlimab-gxly) for women with recurrent or advanced dMMR endometrial cancer. News release. GlaxoSmithKline plc. April 22, 2021. Accessed April 22, 2021. https://bit.ly/3esABv0}

_{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. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA36.}

_{4. 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 23, 2020. Accessed April 22, 2021. https://bit.ly/3tLDsWp}