Phase Ⅱ Study of Combined Sintilimab and Anlotinib with Gemcitabine plus Cisplatin in Advanced Biliary Tract Cancer: Efficacy, Safety and Optimize Dose

Abstract Background: The prognosis of biliary tract cancer (BTC) is poor, with limited efficacy of first-line chemotherapy. SAGC is a randomized, controlled, phase 2 trial evaluating the efficacy of sintilimab (an anti-PD-1 inhibitor) and anlotinib (an anti-angiogenic VEGF-targeted agent) combined with standard chemotherapy as a first-line treatment in advanced BTC. Methods: Eighty eligible patients with unresectable, locally advanced, or metastatic BTC were randomized 1:1 to SAGC group (n = 40) to receive sintilimab (200 mg) and anlotinib (initial 10 mg, then adjusted for 8 mg on days 1-14) plus GC (gemcitabine 1,000 mg/m² and cisplatin 25 mg/m² on days 1 and 8) every 3 weeks for up to 8 cycles, followed by sintilimab and anlotinib until disease progression or unacceptable toxicity or to GC group (n = 40), respectively. The primary endpoint was progression-free survival (PFS). The secondary endpoints included the objective response rate (ORR), overall survival (OS), and safety. The AKT/YAP-induced tumor-bearing mice model was established to study effect of anlotinib on the tumor immune microenvironment at varying doses (low-dose: 3 mg/kg, high-dose: 6 mg/kg). Results: The median follow-up was 13.4 months, and 77 of the 80 patients (96.3%) discontinued treatment. The median PFS was 8.5 months (SAGC group) and 6.2 months (GC group) (hazard ratio: 0.47 [95% CI, 0.22–0.64], P = 0.003). The ORR for the SAGC and GC groups were 51.4% and 29.4%, respectively. Overall, grade 3/4 treatment-related adverse events occurred in 75.0% (30/40) and 43.6% (17/39) of cases in the SAGC and GC groups, respectively. A post hoc analysis shown that patients in SAGC group who received 8mg (22 patients) of anlotinib daily had a higher ORR (54.5% vs. 38.8%) compared to those received 10mg (18 patients), and there was a trend towards an OS benefit (HR: 0.49 [95% CI, 0.14–1.18], P = 0.055). In vivo, the combination of low-dose anlotinib with anti-PD-1 resulted in heightened vascular pericyte coverage, improved vascular perfusion, enhanced cytotoxicity of activated T cells, and increased secretion of effector cytokines when compared to high-dose anlotinib. Conclusion: Sintilimab and anlotinib in addition to gemcitabine plus cisplatin treatment in patients with advanced BTC significantly improved PFS and had a manageable safety profile, and the survival benefit of anlotinib 8mg group is more superior. Low‐dose anlotinib plus anti–PD-1 immune therapy may synergistically improve the antitumor response with reducing adverse effects in vivo. Trial registration number ClinicalTrials.gov Identifier: NCT04300959.