Approximately 25%-30% of patients with endometrial cancer have mismatch repair-deficient (dMMR) tumours.1,2 These tumours are characterised by an inflamed phenotype and show a high neoantigen load, a high number of tumour infiltrating lymphocytes and a frequent overexpression of PD-1 and PD-L1.3 In patients with recurrent or advanced dMMR endometrial cancer, first-line treatment with the combination of immunotherapy and chemotherapy resulted in improved survival outcomes compared to chemotherapy alone in patients with dMMR or MSI-H tumours.4-6 In the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study, adjuvant pembrolizumab plus chemotherapy did not improve disease-free survival (DFS) compared to placebo plus chemotherapy in all-comers with newly diagnosed high-risk endometrial cancer after curative-intent surgery.7 A prespecified subgroup analysis was performed in patients with dMMR tumours.8
The phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study enrolled 1,532 patients with newly diagnosed, high-risk endometrial cancer after surgery with curative intent. These patients were randomised to receive pembrolizumab (200 mg) or placebo every 3 weeks for 6 cycles added to 4-6 cycles of carboplatin-paclitaxel, followed by pembrolizumab (400 mg) or placebo every 6 weeks for 6 cycles. Patients received radiotherapy at investigator discretion. The primary endpoints were investigator-assessed DFS and overall survival in the intention-to-treat population. The current analysis is a protocol-prespecified subgroup analysis of patients with dMMR tumours, for which no formal hypothesis testing was performed.
A total of 281 patients had dMMR tumours (pembrolizumab N= 141, placebo N = 140). Baseline patient and tumour characteristics were well-balanced between groups. The majority of patients were PD-L1-positive (91.5%), were TMB-high (87.9%), and had stage III disease (74.7%). At a median follow-up of 24.6 months, three investigator-assessed recurrences occurred in the pembrolizumab group and 23 in the placebo group. Median investigator-assessed DFS was not reached in either group (HR[95% CI]: 0.31[0.14-0.69]). Two-year DFS rates were 92.4% and 80.2% in the pembrolizumab and placebo groups, respectively. Data on overall survival are still immature (3.6% maturity). Grade ≥3 adverse events occurred in 78.6% and 66.4% of the patients in the pembrolizumab and placebo groups, respectively. No treatment-related grade 5 adverse events occurred.
This preplanned subgroup analysis suggests that pembrolizumab plus chemotherapy improves DFS compared to chemotherapy alone in patients with dMMR endometrial tumours following surgery with curative intent.
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