Phase 3 data show pembrolizumab beats chemotherapy, offering durable first-line control with fewer severe toxicities and chemo-free potential.
Pharmacists have spent the past few years operationalizing chemoimmunotherapy as the frontline standard in advanced endometrial cancer. However, new phase 3 data raise the question of whether chemotherapy is still needed for patients whose tumors are mismatch repair–deficient (dMMR).
In the KEYNOTE-C93/GOG-3064/ENGOT-en15 trial (NCT05173987), first-line pembrolizumab (Keytruda; Merck) monotherapy significantly improved progression-free survival (PFS) compared with carboplatin plus paclitaxel in patients with dMMR advanced or recurrent endometrial cancer.
Brian M. Slomovitz, MD, of the GOG Foundation and Mount Sinai Medical Center in Miami Beach, Florida, presented the prespecified interim analysis at the European Society for Medical Oncology (ESMO) Congress 2026 in Madrid, Spain. The results were published simultaneously in The Lancet.1
The open-label trial randomly assigned 299 patients at 122 sites in 24 countries 1:1 to pembrolizumab 400 mg intravenously (IV) every 6 weeks for up to 18 cycles or carboplatin (AUC 5 or 6) plus paclitaxel 175 mg/m² IV every 3 weeks for 6 cycles.2
Eligible patients had centrally confirmed dMMR status, no prior systemic therapy for advanced disease, and an ECOG performance status of 0 or 1. Patients in the chemotherapy arm whose disease progressed by blinded independent central review (BICR) could cross over to pembrolizumab. The dual primary end points were PFS by BICR and overall survival (OS).2
At a median follow-up of 36.7 months, median PFS was 38.2 months with pembrolizumab versus 8.4 months with chemotherapy (HR, 0.57; 95% CI, 0.42 to 0.79; P = .0002). At 36 months, 52.8% of patients in the pembrolizumab arm were progression-free versus 30.0% in the chemotherapy arm.2
The Kaplan-Meier curves crossed at approximately 6 months—reflecting faster early disease control with chemotherapy and more durable control with pembrolizumab. Objective response rates were nearly identical (64.1% vs 62.1%), but complete responses were more frequent with pembrolizumab (33.8% vs 26.2%), and the median duration of response was not reached vs 10.2 months with chemotherapy.2
In an exploratory subgroup analysis, the PFS benefit was most pronounced in patients with recurrent disease (HR, 0.45; 95% CI, 0.29 to 0.70) and less certain in those with newly diagnosed advanced disease (HR, 0.77; 95% CI, 0.49 to 1.21).2
OS numerically favored pembrolizumab but did not reach statistical significance at the interim analysis (HR, 0.77; 95% CI, 0.52 to 1.15; P = .1000). Crossover likely complicated the comparison: 67% of patients in the chemotherapy arm with BICR-confirmed progression received on-study pembrolizumab, and 58% of the chemotherapy arm overall received subsequent immunotherapy. PFS2 favored pembrolizumab (HR, 0.63; 95% CI, 0.43 to 0.91).2
Treatment-related adverse events (AEs) occurred in 71.1% of patients receiving pembrolizumab vs 97.9% of those receiving chemotherapy, with grade 3 or higher events in 18.1% vs 50.7%. Immune-mediated AEs and infusion reactions occurred in 41.6% versus 17.4%, driven largely by hypothyroidism, which affected about a quarter of patients in the pembrolizumab arm.2
Two treatment-related deaths occurred with pembrolizumab (hepatic failure and bacterial meningitis) and 1 with chemotherapy (pulmonary embolism). The investigators cautioned that the much longer treatment duration with pembrolizumab—median 23.4 vs 3.5 months—should be considered when comparing AE rates.2
Patient-reported outcomes favored pembrolizumab at week 12, with improvement in global health status/quality of life compared with a decline in the chemotherapy arm. Patients receiving chemotherapy reported substantial worsening in tingling/numbness, hair loss, and taste change.2
The current standard is chemotherapy plus immunotherapy, which produced PFS HRs of roughly 0.3 to 0.4 in dMMR populations in earlier phase 3 trials. KEYNOTE-C93 does not show that pembrolizumab alone matches that combination—only that it outperforms chemotherapy alone.2
Still, for patients in whom chemotherapy carries particular risk—preexisting neuropathy, frailty, or a strong preference to avoid alopecia—the data support a chemotherapy-free option. The early crossing of the PFS curves, however, suggests caution in patients with a high symptom burden who may need a rapid response.2
Practically, the regimen shifts pharmacist attention from managing myelosuppression, neuropathy, and premedications toward long-term immune-related AE surveillance, particularly thyroid function monitoring across nearly 2 years of therapy. Every-6-week dosing also reduces chair time. And because the option hinges entirely on dMMR status, the data reinforce the importance of universal mismatch repair testing at diagnosis.
