VORSIN-RCC: Vorolanib plus sintilimab for advanced renal cell carcinoma after failure of prior immune checkpoint inhibitors-based combination therapy.
Authors: Yu Shen, Xingming Zhang, Xinyuan Wei, Jiayu Liang, Guangxi Sun, Junjie Zhao, Haoyang Liu, Junru Chen, Xu Hu, Yuntian Chen, Jin Yao, Ni Chen, Ling Nie, Peng Zhang, Xiang Li, Qiang Wei, Pengfei Shen, Jiyan Liu, Zhenhua Liu, Hao Zeng
Journal: Journal of Clinical Oncology (2025)

TPS616 Background: Despite substantial advances in therapy over the past 20 years, the median progression-free survival (mPFS) for advanced RCC patients treated with first-line tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) remains around 20 months (Motzer RJ et al., NEJM 2021, Choueiri TK et al., NEJM 2021). Moreover, subsequent treatments post-first-line progression exhibit inadequate efficacy. A phase Ib/II single-arm trial achieved a high objective response rate (ORR) with lenvatinib plus pembrolizumab in patients post-ICI progression (Lee CH et al., Lancet Oncol 2021). However, other trials showed that ICIs did not benefit advanced RCC patients who have progressed after receiving ICIs (Pal SK et al., Lancet 2023, Choueiri TK, et al., Lancet 2024). The failures of previous ICI re-challenges may be related to the limited efficacy of PD-L1 blockade (atezolizumab) in RCC and the reduced dosage of tivozanib, whose efficacy is closely related to its blood concentration. So we designed a trial to assess the efficacy and safety of the full-dose TKI vorolanib, with favorable safety profiles, combined with the PD-1 inhibitor sintilimab in advanced RCC patients who have failed prior immune combination therapy. Methods: VORSIN-RCC is a prospective, multicenter, single-arm, phase II study enrolling patients with pathologically confirmed RCC. It includes individuals with metastatic or stage IV disease (2017 AJCC 8th edition TNM staging system) who have progressed on prior targeted combination immunotherapy, dual checkpoint inhibitor therapy, or immune monotherapy. Based on historical data, the mPFS for advanced RCC patients previously treated with immune-based combination therapy is approximately 7.96 months for targeted therapy alone and 10.6 to 12.2 months for combined targeted and immunotherapy. Using these figures, with a reference mPFS (m 0 ) of 7.96 months and a desired mPFS (m 1 ) of 11.2 months, the sample size was calculated for a 24-month enrollment period and a total trial duration of 36 months. A one-sided significance level (α) of 0.05, power of 0.8018, dropout rate of 10%, and a Weibull distribution shape parameter (k) of 1 were used. The sample size was determined using PASS software with a one-sample log-rank test estimation method, resulting in an expected sample size of 67 patients for this study. Enrolled patients will receive oral vorolanib tablets (200 mg/day) combined with intravenous sintilimab (400 mg every 3 weeks). The primary endpoint is PFS. Secondary endpoints include ORR, overall survival (OS), adverse events (AEs), disease control rate (DCR), duration of response (DoR), patient quality of life (QoL), and pain score. Both ORR and DCR are assessed using RECIST 1.1 and imRECIST criteria. This study is actively recruiting. Research Sponsor: Hao Zeng. Clinical trial information: NCT06523049 .