The following is a summary of “ENGOT-en11/GOG-3053/KEYNOTE-B21: A Randomised, Double-Blind, Phase 3 Study of Pembrolizumab or Placebo Plus Adjuvant Chemotherapy With or Without Radiotherapy in Patients With Newly Diagnosed, High-Risk Endometrial Cancer,” published in the September 2024 issue of Oncology by Gorp et al.

The addition of pembrolizumab to adjuvant chemotherapy provides a promising therapeutic option, especially for patients with mismatch repair-deficient dMMR endometrial cancer (EC). Still, its overall efficacy in high-risk cases remains a subject of investigation. This study evaluates the combination of pembrolizumab with chemotherapy, with or without radiation, in newly diagnosed high-risk patients with EC who had no residual macroscopic disease following surgery with curative intent. Patients at high risk are included in stage I/II non-endometrioid histology, endometrioid histology with p53/TP53 abnormalities, or stage III/IVA of any histology. The trial randomly assigned 1,095 patients to receive either pembrolizumab (200 mg Q3W for 6 cycles) or placebo alongside carboplatin-paclitaxel, followed by maintenance pembrolizumab (400 mg Q6W for 6 cycles) or placebo. 

Radiotherapy was administered at the investigator’s discretion. The primary endpoints were disease-free survival (DFS) and overall survival, assessed in an intention-to-treat population.

At the interim analysis (data cutoff March 4, 2024), no significant difference in DFS was observed between the pembrolizumab and placebo groups, with 119 DFS events (22%) in the pembrolizumab arm and 121 events (22%) in the placebo arm (HR 1.02, 95% CI, 0.79–1.32; P=0.570). The 2-year DFS rates were nearly identical, at 75% for pembrolizumab and 76% for placebo. However, subgroup analysis revealed a striking benefit in the dMMR population, where pembrolizumab substantially improved DFS (HR 0.31, 95% CI, 0.14–0.69), while no benefit was observed in the pMMR population (HR 1.20, 95% CI, 0.91–1.57). In terms of safety, grade ≥3 adverse events (AEs) were more frequent in the pembrolizumab group (71%) compared to placebo (63%), though no treatment-related grade 5 AEs occurred.

In conclusion, adjuvant pembrolizumab plus chemotherapy did not demonstrate an overall improvement in DFS for the broad population of newly diagnosed, high-risk patients with EC. However, the treatment showed a marked benefit in patients with dMMR tumors, indicating the importance of stratifying patients by tumor biology. The safety profile of pembrolizumab remained manageable, making it a viable option in the dMMR subset of high-risk EC.

Source: sciencedirect.com/science/article/pii/S0923753424038225