Clinicopathologic features and outcomes of patients with microsatellite instability-high endometrial cancer treated with pembrolizumab in Japan: the KCOG-G1902S/1903S study.

OBJECTIVE

To characterize clinicopathologic features of microsatellite instability-high (MSI-high) gynecologic malignancies in Japan and evaluate outcomes of pembrolizumab in MSI-high endometrial cancer, including an exploratory assessment of MLH1 promoter methylation and obesity.

METHODS

Gynecologic malignancies undergoing routine MSI testing at 11 institutions were registered (KCOG-G1902S). Clinicopathologic data of MSI-high cases were collected from medical records. Patients with MSI-high endometrial cancer treated with pembrolizumab were prospectively followed (KCOG-G1903S). MLH1 promoter methylation was assessed in tumors with MLH1 loss, and exploratory analyses evaluated outcomes according to MLH1 methylation status and body mass index (BMI).

RESULTS

Among 529 tumors tested, 56 (10.6%) were MSI-high, most arising in the endometrium (52/251; 20.7%). MSI-high tumors from other organs were predominantly endometrioid. All MSI-high tumors showed mismatch repair protein loss on immunohistochemistry; 41/56 (73.2%) demonstrated PMS2 and/or MLH1 loss. Pembrolizumab was administered to 25 patients with MSI-high endometrial cancer. The objective response rate was 48% (12/25), with median progression-free survival (PFS) of 21.2 months and overall survival of 58.1 months. MLH1 promoter methylation was detected in 17/18 tumors with MLH1 loss. In exploratory analyses, patients with at least one favorable factor (absence of MLH1 methylation and/or BMI ≥30 kg/m²) had higher response rates (77.8% vs. 31.3%, p=0.041) and longer PFS (p=0.039).

CONCLUSION

MSI-high gynecologic malignancies arise predominantly in the endometrium. Pembrolizumab demonstrated durable activity in MSI-high endometrial cancer. MLH1 promoter methylation status, and possibly obesity, may provide clinically relevant insights into the heterogeneity of pembrolizumab response. These findings are exploratory and require validation in larger cohorts.