Open-label, single-arm, phase II trial to investigate the efficacy of sitravatinib plus tislelizumab combination as a second-line treatment for advanced biliary tract cancer

Background & Aims Immune checkpoint inhibitors (ICIs) combined with cytotoxic chemotherapy are now the standard first-line treatment for advanced biliary tract cancer (BTC). With this evolving landscape, therapeutic options using ICIs after first-line failure are urgently needed. Anti-angiogenic agents may enhance anti-tumor immunity by increasing tumor antigen presentation and promoting lymphocyte infiltration and migration. We aimed to evaluate the efficacy of sitravatinib plus tislelizumab as second-line therapy for advanced BTC. Methods In this open-label, single-arm, phase II trial, patients were enrolled regardless of prior ICI treatment history. The primary endpoint was disease control rate. Key secondary endpoints included objective response rate, progression-free survival, overall survival, safety, and biomarker analyses (NCT04727996). Results A total of 43 patients were enrolled. The median follow-up was 10.5 months (95% CI 7.03-15.6). Nine patients had previously received ICI therapy. The disease control rate was 65.1% (95% CI 50.3–78.0), and the objective response rate was 18.6% (95% CI 9.2–32.1). Median progression-free and overall survival were 4.93 months (95% CI 3.10–8.87) and 10.3 months (95% CI 6.67–18.2), respectively. Anti-tumor activity was observed regardless of prior ICI exposure. The most common treatment-related adverse events were associated with sitravatinib and were predominantly grade 1–2. In exploratory analyses, patients with homologous recombination deficiency (HRD), detected by baseline tissue next-generation sequencing (frequency 18.5%), showed better outcomes than those without HRD. Responders displayed higher inflammatory signaling in baseline and on-treatment tumor tissue compared with non-responders. Conclusions Sitravatinib plus tislelizumab demonstrated meaningful efficacy and an acceptable safety profile as second-line therapy for advanced BTC. HRD-based patient selection may provide a promising strategy for optimizing treatment in this setting. Clinicaltrials.gov Identifier NCT04727996 Impact and Implications The results of this multi-center, open-label, phase II study suggest that immunotherapy and anti-angiogenic agent combination treatment has a promising efficacy and safety as second-line treatment for patients with advanced biliary tract cancer. Furthermore, the presence of homologous recombination deficiency detected on tumor next-generation sequencing may select patients who have benefit from this combination, which supports further research exploring immunotherapy with anti-angiogenics combination strategy in this setting. Clinicaltrials.gov Identifier NCT04727996.