On July 31, 2023, the FDA approved a new indication for dostarlimab-gxly (Jemperli; GlaxoSmithKline), a PD-1 inhibitor, in combination with carboplatin and paclitaxel, followed by single-agent dostarlimab, for primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR), as determined by an FDA-approved test, or microsatellite instability-high (MSI-H). The FDA granted dostarlimab priority review and breakthrough therapy designations for this indication.
Dostarlimab is the newest front-line option approved in decades for dMMR or MSI-H primary advanced or recurrent endometrial cancer and is the only immuno-oncology therapy approved in the front-line setting in combination with chemotherapy for these patients.
Dostarlimab was previously approved as monotherapy for certain adults with dMMR recurrent or advanced endometrial cancer that progressed during or after treatment with a platinum-containing regimen, as well as monotherapy for certain adults with dMMR recurrent or advanced solid tumors that progressed during or after treatment.
This new approval was based on the results of the phase 3 RUBY clinical trial (NCT03981796), a randomized, multicenter, double-blind, placebo-controlled study. The trial assessed efficacy in a prespecified subgroup of 122 patients with dMMR or MSI-H primary advanced or recurrent endometrial cancer. The study investigators determined the MMR or MSI tumor status via local assays (immunohistochemistry, polymerase chain reaction, or next-generation sequencing), or with central testing (immunohistochemistry) with the Ventana MMR RxDx Panel when local testing results were unavailable.
The patients were randomized in a 1:1 ratio to dostarlimab with carboplatin and paclitaxel, followed by dostarlimab, or to placebo with carboplatin and paclitaxel, followed by placebo. The chemotherapy regimens are described in the full prescribing information. The trial stratified randomization by MMR or MSI status, previous external pelvic radiotherapy, and disease status (recurrent, primary stage III, or primary stage IV).
Investigator-assessed progression-free survival (PFS) was the trial’s primary efficacy measure. The patients with dMMR or MSI-H had a significant improvement in PFS, with a median PFS of 30.3 months for dostarlimab-containing regimens versus 7.7 months for regimens with placebo (hazard ratio, 0.29; 95% confidence interval, 0.17-0.50; P<.0001).
The immune-mediated adverse events that occurred with dostarlimab included pneumonitis; colitis; hepatitis; endocrinopathies, such as hypothyroidism; nephritis with renal dysfunction; and skin-related adverse events. The most common (≥20%) adverse events with dostarlimab plus carboplatin and paclitaxel included rash, diarrhea, hypothyroidism, and hypertension. A complete list of adverse events is included in the prescribing information.
“As a clinician, I celebrate the practice-changing potential of adding Jemperli to chemotherapy for patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer who have had limited treatment options. Based on the results from the RUBY clinical trial, I look forward to the addition of Jemperli to chemotherapy becoming a new standard of care for patients,” said Matthew Powell, MD, Chief, Division of Gynecologic Oncology, Washington University School of Medicine, St Louis, MO, and US principal investigator of the RUBY trial.
This approval “changes the treatment paradigm for a population with long-term unmet needs….As an endometrial cancer survivor, I know how much this approval offers hope for patients with primary advanced or recurrent dMMR/MSI-H endometrial cancer,” said Wenora Johnson, President, Board of Directors, Facing Our Risk of Cancer Empowered (FORCE).
The recommended dose of dostarlimab is 500 mg every 3 weeks for 6 doses with carboplatin and paclitaxel, followed by 1000 mg of monotherapy with dostarlimab every 6 weeks until disease progression or unacceptable adverse events, or for up to 3 years of treatment. When dostarlimab and chemotherapy are administered on the same day, dostarlimab should be administered before chemotherapy.