Background
Phase III, double-blind, placebo-controlled RCT. 816 patients with measurable stage III/IVA, stage IVB, or recurrent endometrial cancer randomized 1:1. Patients stratified by mismatch repair status into two pre-specified cohorts: dMMR (~30%) and pMMR (~70%). Prior adjuvant chemotherapy allowed if treatment-free interval ≥12 months. MMR/MSI testing required at enrollment. NCI-sponsored cooperative group trial.
Interventions and follow up
Arm A: Pembrolizumab 200 mg IV q3w + paclitaxel 175 mg/m² + carboplatin AUC 5 q3w × 6 cycles, then pembrolizumab 400 mg IV q6w maintenance × up to 14 cycles
Arm B: Placebo + paclitaxel 175 mg/m² + carboplatin AUC 5 q3w × 6 cycles, then placebo maintenance × up to 14 cycles
Primary endpoint: PFS in dMMR cohort and pMMR cohort (hierarchical testing: dMMR first, then pMMR)
mFollow up: 12-month interim analysis
Arm B: Placebo + paclitaxel 175 mg/m² + carboplatin AUC 5 q3w × 6 cycles, then placebo maintenance × up to 14 cycles
Primary endpoint: PFS in dMMR cohort and pMMR cohort (hierarchical testing: dMMR first, then pMMR)
mFollow up: 12-month interim analysis
Results
PFS (dMMR cohort): 12-mo KM estimate 74% vs 38%, HR 0.30, 95%CI 0.19-0.48, P<.001
PFS (pMMR cohort): 13.1 vs 8.7 months, HR 0.54, 95%CI 0.41-0.71, P<.001
OS: Not mature at time of primary analysis
PFS (pMMR cohort): 13.1 vs 8.7 months, HR 0.54, 95%CI 0.41-0.71, P<.001
OS: Not mature at time of primary analysis
Adverse events
Overall (Arm A vs Arm B): grade ≥3 AEs ~76% vs ~75%; treatment discontinuation due to AEs higher in the pembrolizumab arm
Immune-mediated (Arm A vs Arm B): any-grade immune AEs ~41% vs ~10%; most common hypothyroidism, adrenal insufficiency, and pneumonitis
Immune-mediated (Arm A vs Arm B): any-grade immune AEs ~41% vs ~10%; most common hypothyroidism, adrenal insufficiency, and pneumonitis
Conclusions
Adding pembrolizumab to standard carboplatin/paclitaxel chemotherapy significantly improved PFS in both dMMR and pMMR advanced/recurrent endometrial cancer. The dMMR benefit was striking (HR 0.30), while pMMR showed meaningful but more modest improvement (HR 0.54), supporting pembrolizumab + chemotherapy as a new first-line standard across MMR status.
Key Limitations
OS data not mature at primary analysis, so the PFS benefit does not guarantee an OS gain, particularly in pMMR disease. The 12-month follow-up is short; durability of benefit, especially in pMMR, remains uncertain. No direct comparison to dostarlimab + chemotherapy (RUBY) or lenvatinib + pembrolizumab as a sequencing strategy. POLE status was not incorporated into stratification, and benefit in previously treated (recurrent) vs primary advanced disease was not separately reported at interim.
Clinical Context
NRG-GY018 and the contemporaneous KEYNOTE-868 trial together led to FDA approval of pembrolizumab + carbo/paclitaxel for advanced/recurrent endometrial cancer in 2023, regardless of MMR status. The dMMR subgroup benefit (HR 0.30) is among the strongest IO signals in solid tumors. Dostarlimab + chemotherapy (RUBY) showed similar dMMR benefit and is an alternative regimen. ESMO-MCBS: 4 (dMMR), 3 (pMMR).