Efficacy of PD-(L)1 inhibition in the treatment of endometrial cancer across molecular classes: a systematic review and meta-analysis

OBJECTIVE: PD-(L)1 inhibitors have shown benefit in mismatch repair-deficient (MMRd) endometrial cancer. However, their efficacy in mismatch repair-proficient endometrial cancer (comprising POLE-mutated (POLEmut), p53-abnormal (p53abn), and no-specific-molecular-profile (NSMP) molecular classes) remains unclear. This systematic review and meta-analysis evaluated the efficacy of PD-(L)1 inhibitors, as monotherapy or combined with chemotherapy, across the 4 molecular classes. METHODS: Systematic searches were conducted across Embase, PubMed, Cochrane, and Web of Science, with manual searches of reference lists and conference websites. A total of 7 reports on 5 clinical trials were identified, with 3 included in the meta-analysis. Overall survival and progression-free survival were assessed. RESULTS: In patients with primary advanced or recurrent MMRd endometrial cancer (n=215), adding a PD-(L)1 inhibitor to platinum-based chemotherapy significantly improved overall (HR 0.36, 95% CI 0.21 to 0.62) and progression-free survival (HR 0.35, 95% CI 0.23 to 0.53). In patients with p53abn endometrial cancer, no significant benefits in overall (HR 0.91, 95% CI 0.26 to 3.22; n=135) or progression-free survival (HR 0.84, 95% CI 0.41 to 1.70; n=326) were observed, but both were affected by significant heterogeneity. In patients with NSMP endometrial cancer, a significant benefit was observed for progression-free survival (HR 0.73, 95% CI 0.57 to 0.95; n=373), but no overall survival benefit (HR 0.93, 95% CI 0.63 to 1.39; n=242). Insufficient data were available for patients with POLEmut endometrial cancer (n=12), with no events reported in 2 of 3 clinical trials comprising the majority of patients (n=11). CONCLUSIONS: PD-(L)1 inhibition demonstrated significant efficacy in patients with advanced or recurrent MMRd endometrial cancer. In NSMP endometrial cancer, adding a PD-(L)1 inhibitor to platinum-based chemotherapy showed potential benefit, whereas in p53abn endometrial cancer, such benefit was not found. POLEmut endometrial cancer, although rare in recurrent or metastatic settings, was associated with a favorable prognosis, regardless of treatment. These findings underscore the relevance of the molecular classification of endometrial cancer and highlight the importance of prioritizing molecular analyses in clinical trials to guide personalized PD-(L)1 inhibition strategies.