A prospective, multi-center, phase Ib/II trial of first-line cadonilimab plus axitinib in advanced non–clear cell renal cell carcinoma.

4501 Background: Non-clear cell renal cell carcinoma (nccRCC) is a rare and heterogeneous disease with limited treatment evidence. Patients with nccRCC generally respond less favorably to systemic immunotherapy than those with clear cell RCC. However,current evidence for the treatment of nccRCC remains limited,underscoring the need for new strategies. Cadonilimab,a bispecific PD-1/CTLA-4 antibody,has shown antitumor activity in various solid tumors, but its efficacy in RCC remains unknown. Here, we report initial results from a phase Ib/Il trial of cadonilimab plus axitinib in advanced nccRCC. Methods: This open-label, multi-center, single-arm, phase Ib/Il trial included patients with metastatic or unresectable treatment-naive nccRCC, regardless of PD-L1 status, to receive cadonilimab plus axitinib 5mg b.i.d. In phasel,a 3+3 dose-escalation design was adopted,starting at 10 mg/kg Q3W of cadonilimab with axitinib to evaluate safety. In phase Il, an additional 31 patients were enrolled at the recommended phase ll dose (RP2D). The primary endpoints were safety assessment in phase Ib and objective response rate (ORR) by RECIST v1.1 in phase Il. Results: As of October 1,2025, A total of 37 patients was enrolled (Phase Ib:n=6;Phase ll: n=31), with a median follow-up duration of 14.4 months. In phase Ib, no DLTs were observed. AEs were reported in 100.0% (6/6) of cases. Grade≥3 treatment-related adverse events (TRAEs) occurred in 66.7% (4/6) of cases,including proteinuria, hypertriglyceridemia, myasthenia gravis, diarrhea and alanine aminotransferase increased. The RP2D for cadolinimab was 10 mg/kg. For secondary endpoints, ORR was 50% (2/4) and DCR was 100% (6/6). In phase Il, the ORR was 51.6%(16/31). DCR was 96.8% (30/31). AEs were reported in100.0% of cases. Grade≥3 treatment-related adverse events (TRAEs) occurred in 58.1% (18/31) of cases. All AEs were expected and manageable. The median PFS was 16.7 (95%Cl,11.8-NR). The median OS was NR at the data cutoff. For the total cohort, the median PFS was 17.3(95%Cl,12.1-NR). The median OS was NR at the data cutoff. Conclusions: Cadonilimab combined with axitinib demonstrated encouraging efficacy and tolerability as first-line therapy in advanced nccRCC across subtypes in this multi-center phase Ib/II study. Clinical trial information: NCT05808608 . Summary of efficacy analysis and tumor response review per RECIST v1.1. Phase Ib Phase II Total cohort Objective response rate, n(%) 2 (50) 16 (51.6) 18 (51.4%) Disease control rate, n(%) 6 (100) 30 (96.8) 36 (97.2%) mPFS (95%CI) months NR (17.3, NR) 16.7 (11.8-NR) 17.3 (12.1-NR) mOS (95%CI), months NR (NR, NR) NR (NR, NR) NR (NR, NR)