Sintilimab and anlotinib with gemcitabine plus cisplatin in advanced biliary tract cancer: SAGC a randomized phase 2 trial
Jingjing Li, Shurui Zhou, Xiaoqing Xu, Qinhong Zheng, Fabiao Zhang, Cong Luo, Da Li, Xing Sun, Zhe Han, Wei Wu, Junrong Yan, Yang Shao, Yuhua Zhang, Bingchen Wu, Qing Wei, Xinbao Wang, Yiwen Zhou, Weijing Sun, Qi Xu, Jieer Ying
Abstract
Biliary tract cancer (BTC) has a poor prognosis with limited treatment options. This phase 2 trial randomized 80 patients with unresectable/metastatic BTC 1:1 to sintilimab, anlotinib, and gemcitabine/cisplatin (SAGC) or chemotherapy alone (GC). At 13.4-month median follow-up, SAGC significantly improved median progression-free survival (8.5 vs. 6.3 months; HR 0.48, 95% CI 0.22–0.64, p = 0.005) and objective response rate (51.4% vs. 29.4%), with higher grade 3/4 adverse events (75.0% vs. 43.6%). Post hoc analysis showed enhanced efficacy with anlotinib 8 mg versus 10 mg (ORR 54.5% vs. 38.8%). In AKT/YAP tumor models, low-dose anlotinib (3 mg/kg) combined with sintilimab improved vascular perfusion, T-cell cytotoxicity, and cytokine secretion compared to high-dose (6 mg/kg). These findings demonstrate improved efficacy and manageable toxicity with SAGC, particularly at the 8 mg anlotinib dose, suggesting low-dose regimens may optimize antitumor response while mitigating adverse effects. Trial registration number ClinicalTrials.gov Identifier: NCT04300959. Limited improvement of systemic therapy has been achieved in first line treatment for advanced Biliary tract cancer (BTC). In this randomized phase 2 trial on BTC, the combination of sintilimab, anlotinib, and gemcitabine/cisplatin demonstrated an improvement in progression - free survival (PFS) and objective response rate (ORR) while reducing the risk of disease progression compared to chemotherapy monotherapy.