A subgroup analysis from the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 trial revealed that adjuvant pembrolizumab (Keytruda) combined with chemotherapy, with or without radiation, significantly improved disease-free survival (DFS) in patients with mismatch repair deficient (dMMR) newly diagnosed high-risk endometrial cancer. The findings, presented at the 2024 European Society for Medical Oncology Congress (ESMO), suggest a targeted benefit for this specific patient population, which constitutes approximately 25% of endometrial cancer cases.
The study randomized 1095 patients with newly diagnosed high-risk endometrial cancer following surgery to receive either pembrolizumab (200 mg every 3 weeks for 6 cycles, followed by 400 mg every 6 weeks for 6 cycles) or placebo, in addition to chemotherapy (carboplatin and paclitaxel). Radiation therapy and/or cisplatin were administered at the investigator’s discretion. The primary endpoint was investigator-assessed DFS in the intent-to-treat (ITT) population.
Efficacy in dMMR Subgroup
While the overall ITT population did not show a significant difference in DFS (HR, 1.02; 95% CI, 0.79-1.32; P = .570), the dMMR subgroup (n = 281) experienced a notable improvement. The median DFS was not reached in the pembrolizumab arm compared to the placebo arm (HR, 0.31; 95% CI, 0.14-0.69). The 2-year DFS rates were 92% and 80% in the pembrolizumab and placebo arms, respectively. In contrast, patients with mismatch repair proficient (pMMR) tumors did not show a significant DFS benefit (HR, 1.20; 95% CI, 0.91-1.57).
"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," said lead study author Dr. Toon Van Gorp, a gynecologist oncologist at UZ Leuven in Belgium.
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 previous data demonstrating a reduced risk of disease progression or death (pMMR: HR, 0.54; 95% CI, 0.41-0.71; dMMR: HR, 0.30; 95% CI, 0.19-0.48).
Safety Profile
Adverse events (AEs) of any grade occurred in all patients in both arms, with grade 3 or higher AEs reported in 71% of patients on the pembrolizumab arm and 63% on the placebo arm. 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. Common AEs included alopecia, anemia, nausea, and diarrhea. The safety profile was consistent with the known effects of checkpoint inhibitors.
Patient Eligibility and Trial Design
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. Patients with prior radiation or systemic therapy were excluded.
Stratification factors included MMR status (pMMR vs dMMR), planned radiation (chemo-EBRT vs EBRT vs no EBRT), histology (endometrioid vs non-endometrioid), and FIGO (2009) surgical stage (I/II vs III/IVA) within the pMMR subgroup. The coprimary endpoints were investigator-assessed DFS and overall survival (OS) in the ITT population. OS data were immature at the time of the interim analysis.
