The phase 3 RUBY trial has demonstrated that dostarlimab combined with carboplatin and paclitaxel significantly improves clinical outcomes in patients with advanced endometrial carcinoma across multiple molecular subgroups, with particularly striking benefits observed in patients with deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) tumors.
Molecular Subgroup Analysis Reveals Broad Clinical Benefit
According to findings from the randomized, double-blind ENGOT-EN6-NSGO/GOG-3031/RUBY trial presented at the 2023 European Society for Medical Oncology Annual Congress, three of four molecular subgroups consistently demonstrated clinical benefit from dostarlimab treatment. The molecular classification algorithm using whole exome DNA sequencing on 400 of 495 patients identified that 22.75% had dMMR/MSI-H tumors, 22% were TP53 aberrant, 54% were classified as no specific molecular profile (NSMP), and 1.2% had POLε mutations.
"The TP53 mutation group was surprising to me," said lead author Mansoor Raza Mirza, MD, chief oncologist at Rigshospitalet in Copenhagen, Denmark, during the presentation of the data.
Dramatic Survival Benefits in dMMR/MSI-H Population
Patients with dMMR/MSI-H tumors experienced the most substantial clinical benefit from dostarlimab treatment. After a median follow-up of 24.8 months, the dMMR/MSI-H cohort showed significant improvement in progression-free survival, with 61.4% of patients in the dostarlimab arm remaining progression-free compared to 15.7% in the placebo arm (HR, 0.28; 95% CI, 0.162%-0.495%; P < .0001).
The overall survival data were equally compelling for this subgroup, with a probability of survival of 83.3% in the dostarlimab arm versus 58.7% in the placebo arm (HR, 0.30; 95% CI, 0.127%-0.699%). This represents a substantial improvement in outcomes for patients with this molecular subtype.
Unexpected Benefits in TP53 Mutation Subgroup
The TP53 mutation subgroup demonstrated surprising clinical benefit from dostarlimab treatment. Progression-free survival rates reached 32.4% in the dostarlimab arm compared to 17.8% in the placebo arm (HR, 0.55; 95% CI, 0.30%-0.99%). Even more striking were the overall survival results, with 70.8% of patients in the dostarlimab arm surviving versus 33.2% in the placebo arm, achieving the same hazard ratio of 0.40 as observed in the dMMR/MSI-H subgroup.
Overall Population Benefits
In the overall intention-to-treat population, dostarlimab demonstrated significant clinical benefit after a median follow-up of 25.4 months. The probability of progression-free survival doubled from 18.1% to 36.1% (HR, 0.64; 95% CI, 0.507%-0.800%; P < .0001). Overall survival probability increased from 56.0% in the placebo arm to 71.3% in the dostarlimab arm (HR, 0.64; 95% CI, 0.464%-0.870%; P < .0021).
"This finding was important despite the fact that about one-third of the population in the placebo arm received immunotherapy upon progression," Mirza noted.
Trial Design and Patient Population
The RUBY trial enrolled patients with primary advanced or recurrent endometrial cancer who were randomly assigned to receive either dostarlimab at 500 mg, carboplatin at 5 mg/mL, and paclitaxel at 175 mg/m² every 3 weeks for 6 cycles, or placebo with the same chemotherapy regimen. This was followed by dostarlimab at 1000 mg every 6 weeks for up to 3 years, with a similar schedule for placebo.
The trial evaluated patients with locally advanced and recurrent disease who had received adjuvant chemotherapy for early-stage disease and could enter the trial if they had a platinum-free interval of more than 6 months. Baseline characteristics and demographics were equal across the mutational subgroups for age, race, ECOG performance status, and median body mass index.
Implications for Clinical Practice
When progression-free survival was evaluated according to histological subgroups, all treatment arms benefited, including patients with endometrioid carcinoma, carcinosarcoma, serous adenocarcinoma, and other histological types.
"These data are critical to help the scientific community understand endometrial cancer," Mirza said. "These findings further support the use of dostarlimab and carboplatin/paclitaxel as a new standard of care in patients with newly diagnosed primary advanced or recurrent endometrial cancer."
The NSMP subgroup showed a positive trend with a progression-free survival rate of 31.0% versus 20.1% in the placebo arm, though Mirza noted that this subgroup did not have enough events for overall survival analysis and will require more follow-up. The POLε mutation subgroup was the only group that showed no progression in either the treatment or placebo arm.
