B.M. Slomovitz

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. RESULTS: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

At interim analysis (IA) 1 of Part 1 of the RUBY trial (NCT03981796), statistically significant benefit in PFS was observed with dostarlimab+carboplatin-paclitaxel (D+CP) vs placebo (PBO)+CP in the overall and mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) populations of pts with pA/rEC. Here we report OS from IA2. Pts with pA/rEC were randomized 1:1 to D+CP or PBO+CP followed by D or PBO for ≤3 years or until progression. OS was a dual-primary endpoint in the overall population and a prespecified, exploratory analysis in the dMMR/MSI-H and mismatch repair proficient/microsatellite stable (MMRp/MSS) populations. OS by molecular subgroup was a post-hoc analysis. Safety was a secondary endpoint. 494 pts were randomized (245 D+CP; 249 PBO+CP). In the overall population, there was a significant reduction in the risk of death by 31% and clinically meaningful improvement of 16.4 mo in median OS (mOS) for D+CP vs PBO+CP (Table). In the dMMR/MSI-H population, hazard ratio (HR) for OS was 0.32; mOS was not reached for D+CP and was 31.4 mo for PBO+CP. In the MMRp/MSS population, HR for OS was 0.79; mOS was 34.0 mo for D+CP and 27.0 mo for PBO+CP. At IA2, in 400 pts with whole exome sequencing, a trend towards clinical benefit with D+CP was observed in the dMMR/MSI-H, TP53 mutated, and no specific molecular profile subgroups. Table: 37MOSafety at IA2 was similar to IA1Dostarlimab+CPPlacebo+CPOS, HR (95% CI)Overall, N2452490.69 (0.54–0.89)P=0.002OS, median (95% CI), mo44.6 (32.6–NR)28.2 (22.1–35.6)–dMMR/MSI-H, n53650.32 (0.17–0.63)OS, median (95% CI), moNR (NR–NR)31.4 (20.3–NR)–MMRp/MSS, n1921840.79 (0.60–1.04)OS, median (95% CI), mo34.0 (28.6–NR)27.0 (21.5–35.6)–Post hoc exploratory molecular subgroup analysis of OSaPOLEmut, n23No events in either armdMMR/MSI-H, n39520.40 (0.19–0.83)TP53mut, n47410.59 (0.33–1.03)NSMP, n1031130.89 (0.61–1.29)aAnalyses were conducted in 400 patients with whole exome sequencing results. Mut, mutant; NR, not reached; NSMP, no specific molecular profile. Open table in a new tab aAnalyses were conducted in 400 patients with whole exome sequencing results. Mut, mutant; NR, not reached; NSMP, no specific molecular profile. D+CP showed statistically significant and clinically relevant OS benefit in the overall population compared with CP alone. A substantial survival difference was seen in the dMMR/MSI-H population. In the MMRp/MSS population, there was a 7 mo difference in median OS vs CP alone, with a 21% risk reduction for death. OS by molecular subgroup at IA2 was consistent with IA1. RUBY is the only trial to demonstrate a statistically significant OS benefit in pts with pA/rEC and supports the use of dostarlimab+CP as a standard of care in the 1L setting.