Interim data from the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 trial indicates that postsurgical pembrolizumab combined with chemotherapy, with or without radiation, did not significantly improve disease-free survival (DFS) in the overall high-risk endometrial cancer population. However, a notable trend toward improved DFS was observed in a specific subgroup of patients with mismatch repair deficient (dMMR) tumors.
The study, presented at the 2024 European Society for Medical Oncology (ESMO) Congress, revealed that in the intent-to-treat (ITT) population, the median DFS was not reached in either the pembrolizumab or placebo arms (HR, 1.02; 95% CI, 0.79-1.32; P = .570) after a median follow-up of 23.9 months. The 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo arms, respectively.
dMMR Subgroup Shows Benefit
In patients with dMMR tumors (n = 281), the median DFS was not reached with pembrolizumab (95% CI, NR-NR) compared to placebo (95% CI, 29.5-NR), demonstrating a hazard ratio of 0.31 (95% CI, 0.14-0.69). The 2-year DFS rates in this subgroup were 92% with pembrolizumab and 80% with placebo. Conversely, in patients with mismatch repair proficient (pMMR) tumors, the median DFS was not reached in either arm (HR, 1.20; 95% CI, 0.91-1.57), with 2-year DFS rates of 69% and 75%, respectively.
Dr. Toon Van Gorp, a gynecologist oncologist at UZ Leuven, highlighted the clinical significance of these findings, stating, "The subgroup analysis by MMR status suggests a clinically meaningful benefit in DFS for the dMMR subgroup—which is about 25% of the population—a biomarker population well established to have a high [tumor mutational burden] and an inflamed phenotype with elevated PD-L1 expression."
Trial Design and Patient Population
The ENGOT-en11/GOG-3053/KEYNOTE-B21 trial randomized 1095 newly diagnosed patients with high-risk endometrial cancer post-surgery to receive either pembrolizumab at 200 mg (n = 545) or placebo (n = 550) every 3 weeks for 6 cycles, in addition to carboplatin (AUC 5 or 6) and paclitaxel (175 mg/m2) every 3 weeks for 4 or 6 cycles. This was followed by pembrolizumab at 400 mg or placebo every 6 weeks for 6 cycles. Radiation therapy and/or cisplatin were administered at the investigator’s discretion.
Eligible patients were at least 18 years old with newly diagnosed, histologically confirmed high-risk endometrial cancer or carcinosarcoma post-surgery with curative intent and no postoperative evidence of disease. High-risk criteria included FIGO (2009) surgical stage I/II of non-endometrioid histology with myometrial invasion, FIGO (2009) surgical stage I/II of any histology with p53/ TP53 abnormalities with myometrial invasion, or FIGO (2009) stage III/IVA of any histology.
The co-primary endpoints of the trial were investigator-assessed DFS and overall survival (OS) in the ITT population.
Safety Profile
Any-grade adverse effects (AEs) occurred in all patients across both arms. Grade 3 or higher AEs were more frequent in the pembrolizumab arm (71%) compared to the placebo arm (63%). Treatment discontinuation rates were 24% and 16% in the pembrolizumab and placebo arms, respectively. Immune-related AEs and infusion reactions occurred in 42% of pembrolizumab-treated patients, leading to treatment discontinuation in 6% and death in 1 patient. In the placebo arm, these rates were 24%, 4%, and 0%, respectively. No treatment-related deaths occurred.
Common AEs (≥25%) in the pembrolizumab and placebo arms included alopecia (63%; 65%), anemia (52%; 52%), nausea (44%; 48%), diarrhea (40%; 38%), and decreased neutrophil count (35%; 32%).
Current Treatment Landscape
Currently, systemic chemotherapy with or without radiation is the standard adjuvant treatment for high-risk endometrial cancer, yielding 5-year DFS rates between 58% and 65%. Pembrolizumab plus chemotherapy is already approved as a frontline treatment for advanced or recurrent endometrial cancer, irrespective of MMR status, based on data demonstrating a reduced risk of disease progression or death.
