The treatment of high-risk endometrial cancer is rapidly changing, largely due to our understanding of molecular subtypes and the use of immunotherapy. While mismatch repair deficiency (dMMR) has been established as a key biomarker for a positive response to checkpoint inhibitors, the role of these drugs in the more common mismatch repair proficient (pMMR) population has been unclear. The ENGOT-en11/GOG-3053/KEYNOTE-B21 trial, a global Phase III study, aimed to clarify this by evaluating the addition of pembrolizumab to standard chemotherapy, with or without radiotherapy (RT), in this high-risk group.
The study randomized patients with high-risk endometrial cancer to receive either pembrolizumab or placebo along with standard carboplatin-paclitaxel chemotherapy. RT, including external beam (EBRT), brachytherapy (BT), or both, was administered at the discretion of the treating physician. The trial was stratified to ensure a balanced comparison within the pMMR subgroup by RT usage.
The primary results confirmed a significant benefit from pembrolizumab in the dMMR subgroup, showing a striking improvement in disease-free survival (DFS) (HR 0.31). However, in the overall study population, there was no benefit (HR 1.02).
Approximately 56% of patients received EBRT, often combined with BT. At ASTRO 2025, Jyoti S. Mayadev, MD, FASTRO, presented an exploratory analysis focused on disease-specific–free survival (DSFS) in the pMMR cohort. The data showed that adding pembrolizumab did not improve DSFS, regardless of whether patients received RT. This was consistent across all subgroups, including those who received EBRT, BT, or a combination. The safety analysis was also reassuring; adverse events were manageable, with no new safety signals or long-term toxicities identified from combining pembrolizumab with RT.
These findings provide several important lessons. First, they reinforce that pembrolizumab's effectiveness in endometrial cancer is primarily limited to dMMR tumors. For patients with pMMR disease, adding pembrolizumab to chemotherapy or RT does not appear to provide extra benefit. Second, the study offers crucial insights into the safety of combining immunotherapy with pelvic radiation. The lack of increased toxicity is reassuring for ongoing and future trials that may explore these combinations.
Finally, the data underscore the continued importance of RT in managing high-risk endometrial cancer, particularly in pMMR patients. Best summarized in Dr. Mayadev’s own words, “These findings highlight the continued role of radiation therapy in high-risk endometrial cancer, particularly for patients with pMMR disease. Radiation remains important for achieving local control, and the study suggests that pembrolizumab does not replace its established benefits in pMMR disease.”
Abstract 343 - Phase 3 Study of Pembrolizumab (Pembro) + Adjuvant Chemotherapy (CT) ± Radiotherapy (RT) for Newly Diagnosed, High-Risk Endometrial Cancer (EC): Exploratory Analysis of Disease-Specific–Free Survival (DSFS) and Safety by Radiation Usage was presented at SS 24 - GYN 4: GYN Clinical Trials - Challenging the Paradigm in Gynecologic Cancers during ASTRO’s 67th Annual Meeting.
