A phase 2 randomized, open-label, multicentre study of sintilimab and anlotinib in combination with gemcitabine plus cisplatin (GemCis) as first-line therapy in patients (pts) with advanced biliary tract cancer (BTC): SAGC.

4015 Background: BTC has a higher incidence in China rather than worldwide, with extremely poor prognosis, and the efficacy of standard first-line therapy is rather limited. TOPAZ-1 study suggested the immune check-point inhibitor plus chemotherapy as first line in advanced BTC significantly improved OS and PFS with manageable safety, but the median OS was just 12.8 months. SAGC is the first randomized controlled phase 2 trial to evaluate immune check-point inhibitor plus antiangiogenic targeted drug plus chemotherapy in advanced BTC as first-line treatment. Methods: Overall 80 advanced BTC were randomized 1:1 to receive sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) in combination with GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles, followed by sintilimab (200mg every 3 weeks [Q3W]) and anlotinib (10mg po qd, Days 1-14 Q3W) (SAGC group) or GemCis (Gem 1000 mg/m2 and Cis 25 mg/m2 on Days 1 and 8 Q3W) for up to 8 cycles until disease progression or unacceptable toxicity (GC group). The primary objective was to assess the progression-free survival (PFS). Secondary endpoints included, objective response rate (ORR), overall survival (OS) and safety. Next generation sequencing (NGS) was performed on pre-treatment available tumor tissue in 58 patients to screen dominant patients of the therapy. Results: At the time of the final data cutoff (Sep. 22,2022), median follow-up was 13.4 mo, and 65/80 pts (81.3%) had discontinued tx. The confirmed median PFS was 8.6 months for SAGC group vs. 6.2 months for GC group (HR 0·37, p < 0.01) and ORR was 52.8% for SAGC group vs. 29.4% for GC group. Grade 3/4 treatment-related adverse events (TRAEs) occurred in 77.5% of pts receiving sintilimab plus anlotinib plus GemCis and 40% of pts receiving GemCis. The results from NGS suggested that patients with TMB-H and ARID1A-WT may benefit more from combination therapy. Conclusions: In pts with advanced BTC, sintilimab plus anlotinib plus GemCis significantly improved PFS and ORR vs GemCis with manageable safety, indicating sintilimab plus anlotinib plus GemCis may be a new first-line standard of care regimen. Clinical trial information: NCT04300959 .