FDA Approves Dostarlimab-gxly for Recurrent, Advanced Mismatch Repair-Deficient Endometrial Cancer

The FDA has approved dostarlimab-gxly (Jemperli; GSK) for the treatment of adults with mismatch repair-deficient (dMMR) recurrent or advanced endometrial cancer that has progressed on or following a prior platinum-containing regimen in any setting and are not candidates for curative surgery or radiation.¹

Dostarlimab-gxly is a programmed death receptor-1 (PD-1)-blocking antibody that binds to the PD-1 receptor and blocks its interaction with the PD-1 ligands PD-L1 and PD-L2. It has potential both alone and in combination with standard of care and future novel cancer therapies, particularly in patients with currently limited treatment options.¹

In April 2021, dostarlimab-gxly received accelerated approval for the treatment of this patient population. The approval is based on additional data from the A1 expansion cohort of the ongoing GARNET trial, a phase 1, multicenter, open-label, single-arm study of dostarlimab-gxly monotherapy in patients with advanced or recurrent solid tumors.¹

Cohort A1 evaluated the efficacy of dostarlimab-gxly in 141 patients with dMMR advanced or recurrent endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen. Participants received 500 mg of dostarlimab-gxly as an intravenous infusion every 3 weeks for 4 doses, followed by 1000 mg once every 6 weeks until disease progression, discontinuation, or withdrawal. The major efficacy outcome measures were overall response rate (ORR) and duration of response (DOR).¹

According to the trial results, the confirmed ORR was 45.4%, with a 15.6% complete response rate and a 29.8% partial response rate. Median DOR was not reached, measured from the time of first response, with 85.9% of patients having a duration of 12 months or longer and 54.7% of patients having a duration of 24 months or longer. Median follow-up for DOR was 27.9 months.¹

“This US regulatory action confirms our confidence in Jemperli as an important treatment option for patients with dMMR recurrent or advanced endometrial cancer,” said Hesham Abdullah, senior vice president and global head of oncology development at GSK, in a press release. “We continue to unlock the potential of Jemperli as the backbone for our immune-oncology development programs to address the unmet needs of patients, including earlier lines of endometrial cancer and other solid tumors.”¹

Treatment-related adverse events (AEs) were consistent with previous analyses for cohort A1. The most common AEs were fatigue or asthenia, anemia, rash, nausea, diarrhea, constipation, and vomiting. The most common grade 3 or 4 AEs were anemia, increased transaminases, urinary tract infection, fatigue or asthenia, and diarrhea.¹

Earlier this week, the FDA Oncologic Drugs Advisory Committee (ODAC) also voted 8 to 5 in support of whether data from 2 proposed single-arm trials will be “sufficient to characterize the benefits and risks” or dostarlimab-gxly in the curative-intent setting for patients with dMMR or microsatellite instability-high (MSI-H) locally advanced rectal cancer. This patient population has significant unmet medical needs, according to a press release.²

“The Committee’s positive vote in favor of our proposed clinical trial program for dostarlimab reinforces our plans to generate data in support of a future US regulatory submission for the potential treatment of patients with dMMR/MSI-H locally advanced rectal cancer, a patient population with significant unmet medical needs and a standard of care that results in serious quality of life concerns,” Abdullah said in a press release. “We thank the committee for the constructive dialogue, and we look forward to continued interactions with FDA as we progress our development program.”²

Dostarlimab-gxly was granted Fast Track designation by the FDA in January 2023 for this indication in rectal cancer. The current standard of care for patients with dMMR-MSI-H locally advanced rectal cancer is neoadjuvant chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy.

Neoadjuvant CRT provides local tumor control in most patients, but nearly one-third ultimately die from distant metastasis. This standard of care is also associated with long-term AEs such as bowel, urinary, and sexual dysfunction, secondary malignancy, and infertility.²

As part of its proposed clinical trial program, GSK is initiating a global, open-label, phase 2 clinical trial to investigate the safety and efficacy of dostarlimab-gxly as monotherapy for treatment-naïve patients with dMMR/MSI-H locally advanced rectal cancer. The primary endpoint of the proposed trial is clinical complete response for 12 months and key secondary endpoints will include clinical complete response for 36 months and event-free survival for 3 years.²

The trial also aims to confirm results generated in a separate, ongoing investigator-initiated trial by researchers at Memorial Sloan Kettering Cancer Center, which were shared in a late-breaking presentation at the 2022 American Society of Clinical Oncology Annual Meeting. GSK intends to use these data plus data from the proposed trial to support a supplemental Biologics License Application for accelerated regulatory approval in this indication.²

REFERENCES

1. US FDA grants regular approval for Jemperli for the treatment of patients with recurrent or advanced mismatch repair-deficient endometrial cancer. News release. GSK; February 10, 2023. Accessed February 10, 2023. https://www.gsk.com/en-gb/media/press-releases/us-fda-grants-regular-approval-for-jemperli-for-the-treatment-of-patients-with-recurrent-or-advanced-mismatch-repair-deficient-endometrial-cancer/
2. US FDA Advisory Committee votes in support of trials designed to evaluate Jemperli (dostarlimab-gxly) as a potential treatment for mismatch repair-deficient/microsatellite instability-high locally advanced rectal cancer. News release. GSK; February 9, 2023. Accessed February 10, 2023. https://www.gsk.com/en-gb/media/press-releases/us-fda-advisory-committee-votes-in-support-of-trials-designed-to-evaluate-jemperli-dostarlimab-gxly-as-a-potential-treatment-for-dmmrmsi-h-locally-advanced-rectal-cancer/