Researchers observed a statistically significant and clinically meaningful improvement in progression-free survival among patients with primary advanced or recurrent endometrial cancer who were treated with dostarlimab plus carboplatin/paclitaxel compared with those who underwent chemotherapy alone.
This late-breaking abstract, "Dostarlimab in combination with chemotherapy for the treatment of primary advanced or recurrent endometrial cancer: A placebo-controlled randomized Phase III trial (ENGOT-EN6-NSGO/GOG-3031/RUBY)," was presented during the 2023 Society of Gynecologic Oncology 54th Annual Meeting on Women's Cancer. These findings were simultaneously published in the New England Journal of Medicine (2023; doi: 10.1056/NEJMoa2216334).
"Carboplatin/paclitaxel is standard of care for first-line treatment of primary advanced or recurrent endometrial cancer. However, long-term outcomes remain poor, with a median overall survival of less than 3 years," according to Mansoor R. Mirza, MD, principal investigator of the RUBY study and Chief Oncologist at Copenhagen University Hospital in Denmark, who emphasized the need for advances in first-line systemic treatments.
As a PD-1-blocking antibody, dostarlimab as monotherapy is approved for patients with recurrent or advanced mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.
"Our study hypothesis was that dostarlimab plus carboplatin/paclitaxel will improve outcomes in the dMMR/MSI-H and overall primary advanced or recurrent endometrial cancer patient populations versus carboplatin/paclitaxel alone," Mirza noted.
Research Methods
RUBY, a Phase III, global, randomized, double-blind, multicenter, placebo-controlled study, investigated the efficacy and safety of dostarlimab in combination with carboplatin/paclitaxel versus chemotherapy alone among primary advanced or recurrent endometrial cancer patients. Patients with first recurrent or primary advanced Stage III or IV endometrial cancer were eligible for this study. Participants were stratified by the following factors: MMR/microsatellite stability status, prior external pelvic radiotherapy, and disease status.
Mirza and colleagues randomized patients 1:1 to receive dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per mL per minute) and paclitaxel (175 mg per square meter of body surface area), every 3 weeks for 6 cycles. This was then followed by dostarlimab (1,000 mg) or placebo every 6 weeks for up to 3 years. The primary endpoints of this study were progression-free survival by investigator assessment per RECIST version 1.1 and overall survival. Researchers also assessed safety.
Study Results
In this study, 494 patients were randomized-245 to the dostarlimab plus carboplatin/paclitaxel arm and 249 to placebo plus carboplatin/paclitaxel. The study authors reported that 118, or 23.9 percent, had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. Additionally, 47.8 percent had recurrent disease, and 18.6 percent and 33.6 percent had primary Stage III and IV disease, respectively.
Mirza and colleagues observed that progression-free survival was significantly longer among patients in the dostarlimab plus carboplatin/paclitaxel arm versus the chemotherapy alone group in the mismatch repair-deficient/microsatellite instability-high population. Estimated progression-free survival at 24 months was 61.4 percent in patients who received dostarlimab and 15.7 percent in those who did not.
In the overall population, progression-free survival at 24 months was 36.1 percent in the dostarlimab group and 18.1 percent in the chemotherapy alone cohort, according to Mirza. At the first interim analysis, investigators observed a clinically meaningful overall survival trend among patients undergoing dostarlimab plus chemotherapy followed by dostarlimab. This analysis was conducted at 33 percent maturity and statistical significance was not yet reached; however, overall survival follow-up is ongoing and further analysis is planned.
Study authors reported that the most common adverse events that occurred or worsened during treatment included nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequently observed in patients who received dostarlimab compared with those who did not, according to the investigators. Discontinuation of treatment due to a TEAE in the dostarlimab plus carboplatin/paclitaxel and chemotherapy alone groups occurred in 17.4 percent and 9.3 percent of patients, respectively.
Overall, Mirza and colleagues noted that the safety profile of the combination treatment was consistent with the safety profiles of the individual agents. Dostarlimab plus carboplatin/paclitaxel demonstrated statistically significant and clinically meaningful progression-free survival benefit with an early overall survival trend in the overall population, according to Mirza.
While summarizing the study findings, he also noted a substantial, unprecedented benefit in mismatch repair-deficient/microsatellite instability-high patients, as well as clinically meaningful long-term benefit observed in these particular patients. "Dostarlimab plus carboplatin/paclitaxel represents a new standard of care for patients with primary advanced or recurrent endometrial cancer," Mirza concluded during his presentation.
Catlin Nalley is a contributing writer.