Interim results from the phase 3 ENGOT-en11/GOG-3053/KEYNOTE-B21 trial indicate that adjuvant pembrolizumab (Keytruda) combined with chemotherapy did not significantly improve disease-free survival (DFS) in patients with newly diagnosed, high-risk endometrial cancer compared to chemotherapy alone. The study, presented at the ESMO Congress 2024, however, suggests a clinically meaningful benefit in the subgroup of patients whose tumors were mismatch repair deficient (dMMR).
Lack of DFS Improvement in Overall Population
At a median follow-up of 23.9 months, the intent-to-treat (ITT) population showed no significant difference in median DFS between the pembrolizumab and placebo arms (HR, 1.02; 95% CI, 0.79-1.32; P = .570). The 2-year DFS rates were 75% and 76% in the pembrolizumab and placebo arms, respectively.
Clinically Meaningful Benefit in dMMR Subgroup
In patients with dMMR tumors (n = 281), the median DFS was not reached with pembrolizumab compared to the placebo arm (HR, 0.31; 95% CI, 0.14-0.69). The 2-year DFS rates were 92% and 80%, respectively, indicating a substantial benefit in this subgroup.
Dr. Toon Van Gorp, a gynecologist oncologist at UZ Leuven, noted, "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."
No Benefit in pMMR Subgroup
For 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). The 2-year DFS rates were 69% and 75%, respectively, showing no benefit from the addition of pembrolizumab.
Trial Design and Patient Population
The phase 3 trial randomized 1095 patients with newly diagnosed, high-risk endometrial cancer following surgery to receive either adjuvant pembrolizumab at 200 mg (n = 545) or placebo (n = 550) every 3 weeks for 6 cycles, combined with carboplatin and paclitaxel. 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 had to be at least 18 years old with histologically confirmed high-risk endometrial cancer or carcinosarcoma post-surgery with curative intent and no postoperative evidence of disease. High-risk criteria included specific FIGO stages and histological characteristics.
Safety Profile
Any-grade adverse effects (AEs) occurred in all patients in 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 were also more common in the pembrolizumab arm (42%) compared to the placebo arm (24%). There were no treatment-related deaths.
Current Treatment Landscape
Currently, systemic chemotherapy with or without radiation is the standard adjuvant treatment for patients with high-risk endometrial cancer, with 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.
