Phase II study of sitravatinib in combination with tislelizumab in patients with advanced biliary tract cancer who have failed to at least 1 prior systemic treatment.

4018Background: In first line of advanced biliary tract cancer (BTC), immune-checkpoint inhibitor (ICI) in combination with cytotoxic chemotherapy is now standard of care supported by TOPAZ-1 and KN-966 studies. With this landscape, new drug development using ICI in second or later line setting is urgent unmet medical needs area. Anti-angiogenic agent induced improved anti-tumor immune responses by increasing tumor antigen presentation and promoting lymphocyte infiltration and migration. Methods: This study is an open-label, phase 2 trial to investigate the efficacy of sitravatinib and tislelizumab (PD1 inhibitor) combination treatment for 2L advanced BTC. Patients who received prior ICI could be enrolled. All patients received sitravatinib 120mg orally once daily in combination with tislelizumab 200mg intravenously once every 3 weeks until disease progression, unacceptable toxicity. The primary endpoint was disease control rate (DCR), with key secondary endpoints including overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Tissue biopsies were conducted three times in total: screening, the first response evaluation, and disease progression. Blood samples were collected every cycles. (NCT04727996) Results: A total of 43 patients were enrolled. Data-cut off was on July 31, 2023. Median follow-up was 10.5months (95% Confidence interval (CI), 7.03-15.6). 9 patients had received prior ICI. This study met primary endpoint as a DCR of 65.1% in all population. ORR was 20.5% in unselected per-protocol population, and PFS was 4.93 months (95% CI, 3.10-8.87). OS was 10.3months (95% CI, 6.67-18.2). Similar efficacy was observed regardless of prior ICI exposure. The most common treatment-related adverse events (AEs) were sitravatinib-related; hand-foot syndrome (any grade 60.5%, grade 3/4 0%), hypertension (any grade 34.9%, grade 3/4 11.6%). Immune-related AEs (irAEs) were 46.5%, with most irAEs being grade 1-2. In exploratory analysis, patients with homologous recombination deficiency (HRD) detected by baseline tissue NGS (frequency 18.5%) showed higher ORR (60% vs 13.6%), longer PFS (not reached vs 4.87 months) and OS (21.1 vs 8.57 months) than patients without HRD. HRD detected by circulating tumor DNA had a complementary role for patient selection. RNA sequencing showed upregulation in inflammatory signal and downregulation in angiogenesis signal between screening and on-treatment tumor tissue. Responders showed higher inflammatory signaling at baseline and on-treatment tumor tissue compared to non-responders. Conclusions: Sitravatinib/tiselizumab combination as 2L therapy in patients with advanced BTC demonstrated meaningful efficacy and an acceptable safety profile. Especially, patient selection using HRD biomarker might be a promising strategy in this setting. Clinical trial information: NCT04727996.