Background
Phase III, double-blind, placebo-controlled RCT. 494 patients with newly diagnosed stage III/IV or first-recurrent endometrial carcinoma. ~30% had dMMR/MSI-H tumors. Published simultaneously with KEYNOTE-868, transforming the standard of care in a single week. Randomized 1:1.
Interventions and follow up
Arm A: Dostarlimab 500 mg q3wk + carboplatin AUC 5 + paclitaxel 175 mg/m² q3wk × 6 cycles, then dostarlimab 1000 mg q6wk maintenance up to 3 years
Arm B: Placebo + carboplatin + paclitaxel × 6 cycles, then placebo maintenance
Primary endpoint: PFS in dMMR/MSI-H population and overall population
mFollow up: 24.8 months (updated analysis)
Arm B: Placebo + carboplatin + paclitaxel × 6 cycles, then placebo maintenance
Primary endpoint: PFS in dMMR/MSI-H population and overall population
mFollow up: 24.8 months (updated analysis)
Results
mPFS (dMMR/MSI-H, ~30%): not reached vs 7.7 months (Arm A vs Arm B), HR 0.28, P<.001
mPFS (all): 11.8 vs 7.9 months, HR 0.64, P<.001
mOS (dMMR, 24-mo update): not reached vs 15.7 months, HR 0.32
mOS (all, 24-mo update): not reached vs 27.0 months, HR 0.69
mPFS (all): 11.8 vs 7.9 months, HR 0.64, P<.001
mOS (dMMR, 24-mo update): not reached vs 15.7 months, HR 0.32
mOS (all, 24-mo update): not reached vs 27.0 months, HR 0.69
Adverse events
Overall (Arm A vs Arm B): grade ≥3 AEs 41.8% vs 38.7%; treatment discontinuation due to AEs 6.3% vs 2.0%
Immune-related (Arm A vs Arm B): any-grade immune AEs 45.5% vs 21.4%; hypothyroidism 29.0% vs 10.5%; grade ≥3 hepatitis 1.9% vs 0%
Immune-related (Arm A vs Arm B): any-grade immune AEs 45.5% vs 21.4%; hypothyroidism 29.0% vs 10.5%; grade ≥3 hepatitis 1.9% vs 0%
Conclusions
Dostarlimab + carboplatin-paclitaxel followed by dostarlimab maintenance significantly improved PFS in advanced/recurrent endometrial cancer, with a particularly striking and durable benefit in dMMR/MSI-H patients including an early OS signal.
Key Limitations
OS data not yet mature in the overall population at primary analysis. Benefit in pMMR/MSS patients (the majority) is present but modest (HR 0.76 for PFS), and long-term OS benefit in this subgroup remains uncertain. No head-to-head comparison with KEYNOTE-868 (pembrolizumab): both trials are positive, both approved, and the choice between agents is currently based on institutional preference and access rather than efficacy data.
Clinical Context
FDA approved dostarlimab + carboplatin-paclitaxel for primary advanced or recurrent endometrial cancer in 2023. Along with KEYNOTE-868 (pembrolizumab), IO + chemotherapy is now the standard first-line approach. The dMMR/MSI-H subgroup has one of the most striking IO benefits seen in any solid tumor (OS HR 0.32). ESMO-MCBS score: A (dMMR).
References