Cadonilimab plus lenvatinib in advanced endometrial cancer: the multicenter single-arm phase II CLEAR-EC trial

Treatment options are limited for women with advanced endometrial cancer after platinum-based chemotherapy. In this single-arm, multicenter phase II CLEAR-EC trial with a safety run-in, we evaluated cadonilimab, a bispecific antibody targeting PD-1 and CTLA-4, plus lenvatinib as second-line or later therapy (ClinicalTrials.gov: NCT05824481). Three patients were enrolled in the safety run-in, followed by 29 additional patients after the recommended phase II dose was established. The primary endpoint was objective response rate; secondary endpoints included progression-free survival, overall survival, duration of response, disease control rate, and safety. Prespecified exploratory analyses assessed circulating tumor DNA in relation to efficacy, with additional post-hoc biomarker analyses. No dose-limiting toxicities occurred, establishing lenvatinib 16 mg once daily plus cadonilimab 10 mg/kg every three weeks as the recommended phase II dose. The trial met its prespecified primary endpoint, with an objective response rate of 40.6% (95% confidence interval, 23.7-59.4). Disease control rate was 81.3% (95% confidence interval, 63.6-92.8), median progression-free survival was 13.8 months, and median overall survival was not reached. Grade ≥3 treatment-related adverse events occurred in 40.6% of patients. Early on-treatment circulating tumor DNA levels were associated with progression-free and overall survival.