Pembrolizumab Plus Adjuvant Chemotherapy for Newly Diagnosed High-Risk dMMR Endometrial Cancer

Mismatch repair-deficient (dMMR) endometrial cancer is characterized by inflammation and poor outcomes, especially in high-risk cases, with limited adjuvant treatment options. A report published in the Journal of Clinical Oncology presents results from the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 study, a prespecified subgroup analysis of newly diagnosed patients with high-risk endometrial cancer who have dMMR tumors following surgery.

The study involved patients randomized to receive either pembrolizumab (200 mg) or a placebo alongside adjuvant carboplatin-paclitaxel for 6 3-week cycles, followed by pembrolizumab (400 mg) or placebo for an additional 6 cycles. Total treatment lasted about 1 year, contingent on recurrence or discontinuation. The researchers determined radiotherapy pre-randomization.

Primary endpoints of the study included disease-free survival (DFS) and overall survival (OS), which were assessed using imaging and histopathological confirmation. To determine statistical analyses, researchers used the Kaplan-Meier method and the Cox proportional hazards model. No formal hypothesis testing was conducted.

The trial included 1095 patients who were randomized from January 2021 to October 2022. Of these, 281 patients had dMMR tumors and were treated with pembrolizumab (n = 141) or a placebo (n = 140). Most participants had stage III disease (74.7%) and a majority were tumor mutational burden (TMB)-high (87.9%) and programmed death ligand 1 (PD-L1)-positive (91.5%).

As of the interim analysis on March 4, 2024, with a median follow-up of 24.6 months, DFS was notably better in the pembrolizumab group, with only 5.7% experiencing DFS events compared to 17.9% in the placebo group. The hazard ratio for DFS was 0.31, indicating a significant reduction in recurrence risk with pembrolizumab. The 2-year DFS rates were 92.4% for pembrolizumab versus 80.2% for placebo. Safety data revealed that 78.6% of patients on pembrolizumab experienced grade ≥3 adverse events (AEs) compared to 66.4% in the placebo group. AEs led to death in 2.1% of pembrolizumab patients and 0.7% of placebo patients, with no deaths attributed to treatment. These results suggest pembrolizumab offers a significant benefit in DFS for patients with dMMR tumors while also highlighting safety concerns.

In the intention-to-treat population, no difference in DFS was observed between treatment groups. However, a prespecified subgroup analysis indicated that adding pembrolizumab to adjuvant carboplatin-paclitaxel may improve DFS in patients with high-risk dMMR tumors. These tumors have biological features that make them more immunogenic, enhancing treatment benefits compared to proficient mismatch repair (pMMR) tumors. The safety profile for the combination therapy was manageable, with no significant quality of life differences. Ongoing studies aim to further evaluate outcomes in patients with dMMR tumors, indicating promising potential for pembrolizumab in this subgroup.

Reference

Slomovitz BM, Cibula D, Lv W, et al. Pembrolizumab or placebo plus adjuvant chemotherapy with or without radiotherapy for newly diagnosed, high-risk endometrial cancer: results in mismatch repair-deficient tumors. J Clin Oncol. 2024;101200JCO2401887. doi: 10.1200/JCO-24-01887