Cadonilimab plus lenvatinib in advanced renal cell carcinoma: Interim analysis of a prospective, multi-cohort phase II study.

501 Background: Renal cell carcinoma is a common urological malignancy with poor prognosis in advanced stages, creating a pressing need for effective treatments. Immune checkpoint inhibitors combined with anti-angiogenic targeted therapies have demonstrated synergistic efficacy in advanced RCC. Cadonilimab, a PD-1/CTLA-4 bispecific antibody, and lenvatinib, a multi-target tyrosine kinase inhibitor, form the investigational combination in this study. This trial aims to evaluate the efficacy and safety of this dual blockade in patients with advanced RCC—including both clear cell and non-clear cell subtypes—particularly in those who have progressed on prior immunotherapy or lack standard therapeutic options. Methods: This is a prospective, open-label, multi-cohort phase II trial. The study plans to enroll 46 patients, divided into two cohorts: Cohort 1 consists of patients with ccRCC who have received prior combination therapy of immune checkpoint inhibitors and targeted agents (n=28), and Cohort 2 includes treated or treatment-naïve patients with advanced non-ccRCC (n=18). Patients will receive cadonilimab (10 mg/kg, Q3W) in combination with lenvatinib (12 mg, QD) until disease progression or unacceptable toxicity. The primary endpoint is ORR, with secondary endpoints encompassing DCR, rPFS, OS, quality of life, and safety. Sample size was calculated using a Simon's two-stage design, and efficacy is assessed according to RECIST v1.1 criteria. Results: By Oct 2025, 22 patients enrolled (16 males, 6 females; median age 54). Disease staging included: T1(T1 N0-1 M1) in 2, T2(T2 N0-1 M0-1) in 7, T3(T3 N0-1 M1) in 8, T4(T4 N1 M1) in 1 and Tx(Tx N0-1 M1) in 4 patient. The cohort included 16 cases of ccRCC and 6 cases of non-ccRCC. 5 discontinued (1 lenvatinib intolerance, 4 disease progression). In 15 evaluable patients, the combination regimen demonstrated promising antitumor activity, with an ORR of 33.3% and a DCR of 100.0%. Notably, both the ccRCC subgroup (n=9) and non-ccRCC subgroup (n=6) showed identical ORR of 33.3% and DCR of 100.0%. Median follow-up was 7 months, with a 6-month PFS rate of 66.7%. Treatment-related AEs (proteinuria, hypothyroidism, anemia) were predominantly Grade 1-2 ,72.7%. No SAEs occurred, and although Grade 3 events (hypertension, proteinuria, rare irAEs) required monitoring(22.7%), tolerability was generally good, dose reductions (lenvatinib, n=3; cadonilimab, n=1) did not impact treatment continuity. Conclusions: The Cadonilimab plus Lenvatinib combination regimen demonstrates encouraging antitumor activity and a manageable safety profile in patients with advanced RCC, with promising short-term DCR. These findings support continued patient enrollment and longer-term follow-up to further evaluate survival benefits. Clinical trial information: NCC4708. Tumor treatment efficacy summary. Count Percentage（%） Evaluable Patients 15 100.0 ORR 5 33.3 DCR 15 100.0 PR 5 33.3 SD 10 66.7