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
METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
References
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