Background
Phase III, double-blind, placebo-controlled RCT. 816 patients with newly diagnosed stage III/IV or first-recurrence endometrial cancer eligible for systemic therapy. Enrolled regardless of MMR/MSI status; ~33% had dMMR/MSI-H tumors. Randomized 1:1.
Interventions and follow up
Arm A: Pembrolizumab 200 mg q3wk + carboplatin AUC 5 + paclitaxel 175 mg/m² q3wk × 6 cycles, then pembrolizumab 400 mg q6wk maintenance × up to 14 cycles
Arm B: Placebo + carboplatin + paclitaxel × 6 cycles, then placebo × up to 14 cycles
Primary endpoint: PFS in dMMR/MSI-H population and overall population
mFollow up: 12 months
Arm B: Placebo + carboplatin + paclitaxel × 6 cycles, then placebo × up to 14 cycles
Primary endpoint: PFS in dMMR/MSI-H population and overall population
mFollow up: 12 months
Results
mPFS (dMMR/MSI-H): 13.1 vs 8.7 months (Arm A vs Arm B), HR 0.54, P<.001
mPFS (overall): 13.1 vs 8.9 months, HR 0.72, P<.001
OS (dMMR, preliminary): HR 0.30 - striking but immature
OS (overall, preliminary): HR 0.65 - immature
mPFS (overall): 13.1 vs 8.9 months, HR 0.72, P<.001
OS (dMMR, preliminary): HR 0.30 - striking but immature
OS (overall, preliminary): HR 0.65 - immature
Adverse events
Overall (Arm A vs Arm B): grade ≥3 AEs 67.0% vs 59.7%; treatment-related discontinuation 14.4% vs 8.9%
Immune-mediated (Arm A vs Arm B): any-grade immune AEs 38.5% vs 18.5%; hypothyroidism 26.5% vs 9.0%
Immune-mediated (Arm A vs Arm B): any-grade immune AEs 38.5% vs 18.5%; hypothyroidism 26.5% vs 9.0%
Conclusions
Adding pembrolizumab to carboplatin-paclitaxel significantly improved PFS in advanced/recurrent endometrial cancer in both dMMR and all-comer populations, with a particularly striking preliminary OS signal in the dMMR/MSI-H subgroup.
Key Limitations
OS data immature at time of primary analysis; durability of benefit in pMMR/MSS tumors (the majority) remains uncertain. Benefit in pMMR tumors is modest (HR 0.74 for PFS), and whether this translates to OS benefit is unclear. Concurrent RUBY trial (dostarlimab) published the same week - both positive, creating two competing IO + chemo standards without head-to-head data.
Clinical Context
FDA approved pembrolizumab + carboplatin-paclitaxel for primary advanced or recurrent endometrial cancer in 2023. Now standard of care regardless of MMR status, though benefit is greatest in dMMR/MSI-H. ESMO-MCBS score: A (dMMR). Alongside RUBY (dostarlimab), immunotherapy + chemotherapy has replaced chemotherapy alone as the first-line standard in this disease.
References