On July 31, the U.S. Food and Drug Administration (FDA) approved dostarlimab-gxly (Jemperli) with carboplatin and paclitaxel followed by single-agent dostarlimab for patients with 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).
RUBY Trial
Efficacy was evaluated in RUBY (ClinicalTrials.gov identifier NCT03981796), a randomized, multicenter, double-blind, placebo-controlled trial. Efficacy was assessed in a prespecified subgroup of 122 patients with dMMR/MSI-H primary advanced or recurrent endometrial cancer. MMR/MSI tumor status was determined by local testing assays (immunohistochemistry [IHC], polymerase chain reaction, or next-generation sequencing), or central testing (IHC) using the Ventana MMR RxDx Panel when local results were unavailable.
Patients were randomly assigned 1:1 to receive either dostarlimab with carboplatin and paclitaxel followed by dostarlimab or placebo with carboplatin and paclitaxel followed by placebo. Chemotherapy regimens are described in detail in the prescribing information for dostarlimab. Random assignment was stratified by MMR/MSI status, prior external pelvic radiotherapy, and disease status (recurrent, primary stage III, or primary stage IV).
The primary efficacy outcome measure was investigator-assessed progression-free survival using Response Evaluation Criteria in Solid Tumors version 1.1.
Progression-Free Survival
A statistically significant progression-free survival improvement was observed in the dMMR/MSI-H population, with a median progression-free survival of 30.3 vs 7.7 months (hazard ratio = 0.29, 95% confidence interval = 0.17–0.50, P < .0001) for the dostarlimab and placebo-containing regimens, respectively.
Immune-mediated adverse reactions occurred in patients receiving dostarlimab, including pneumonitis, colitis, hepatitis, endocrinopathies (such as hypothyroidism), nephritis with renal dysfunction, and dermatologic adverse reactions. The most common adverse reactions (≥ 20%) with dostarlimab in combination with carboplatin and paclitaxel were rash, diarrhea, hypothyroidism, and hypertension.
The recommended dostarlimab dose is 500 mg every 3 weeks for six doses with carboplatin and paclitaxel, followed by 1,000 mg as monotherapy every 6 weeks until disease progression or unacceptable toxicity or for up to 3 years. Dostarlimab should be administered before chemotherapy when administered on the same day.
This review was conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence. Project Orbis provides a framework for the concurrent submission and review of oncology drugs among international partners. For this review, the FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, Switzerland’s Swissmedic, and the United Kingdom’s Medicines and Healthcare Products Regulatory Agency. The application reviews are ongoing at the other regulatory agencies.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s review. The FDA approved this application 2 months prior to its goal date.
This application was granted Priority Review and Breakthrough designation.
