Interim analysis of vorolanib combined with cadonilimab in previously untreated patients with advanced renal cell carcinoma.

Abstract

499 Background: Targeted therapy combined with immunotherapy is the first-line standard for advanced renal cell carcinoma (aRCC). Anti-angiogenic agents plus PD-1/PD-L1 inhibitors significantly improve progression-free survival, while ~40% of patients show suboptimal response. Vorolanib, a novel tyrosine kinase inhibitor, and cadonilimab is a PD-1/CTLA-4 bispecific antibody. Vorolanib has demonstrated OS benefit and safety as monotherapy or combined with everolimus in later-line settings. This combination has shown potential in other cancers but has not been evaluated in aRCC. This study evaluates their efficacy and safety as 1L treatment for aRCC and explores circulating CTCs as predictive biomarkers. Methods: This single-arm, multicenter trial enrolled patients with untreated aRCC or recurrence >6 months after prior (neo)adjuvant therapy. The study includes Phase I dose escalation and Phase II expansion. Phase I used a 3+3 design (vorolanib 200 mg QD, cadonilimab 10 mg/kg Q3W IV) with 3 + 3 Dose De-escalation Design based on dose-limiting toxicities. Phase II plans to enroll 37 patients treated at the recommended dose(Q3W) until progression or intolerable toxicity. Primary endpoint is ORR, secondary endpoints include PFS, OS, DCR, DoR, 12-month PFS rate, 12/24-month OS rates, safety and quality of life. The exploratory endpoint is CTC clearance and its association with treatment efficacy. Results: By Oct 2025, 15 patients enrolled (12 males, 3 females; median age 60). Disease staging included: T1b in 2, T2 in 5, T3 in 7, and T4 in 1 patient.6 discontinued (3 liver dysfunction, 1 infusion reaction, 2 brain metastases). Among 15 patients, 11 underwent efficacy assessment: 5 achieved PR and 6 had SD, resulting in an ORR of 45.5% and DCR of 100%. Median follow-up was 3.7 months, with a 6-month PFS rate of 85.71%. No SAEs were reported. Treatment-related AEs (abnormal liver function, elevated urinary protein) were mostly grade 1–2, 53.3%. The incidence of common AEs (liver function, elevated urine protein, diarrhea, hypertension) did not show increase compared to other 1L targeted-immunotherapy combination. Dose reductions were minimal (vorolanib: 2; cadonilimab: 1) and did not affect subsequent treatment. Among 8 with ≥2 CTC tests, 7 showed a consistent and significant decrease in CTCs and PD-L1+ CTCs from baseline. ORR was associated with CTCs and PD-L1+ CTCs reduction. Conclusions: The combination of vorolanib and cadonilimab represents a 1L treatment option for aRCC, demonstrating a high ORR and favorable tolerability. Further large-scale studies are warranted to validate OS, PFS, and long-term safety. PD-L1+ CTCs show potential as predictive biomarkers for treatment efficacy. Clinical trial information: NCT06577961 . Correlation analysis of circulating blood CTCs. Spearman's ρ Pearson's r CTC Change vs. Efficacy 0.435 0.476 PD-L1+ CTC Change vs. Efficacy 0.417 0.513 PD-L1+ Proportion vs. Efficacy 0.786 0.702