Phase II study assessing tolerability, efficacy, and biomarkers for durvalumab (D) ± tremelimumab (T) and gemcitabine/cisplatin (GemCis) in chemo-naïve advanced biliary tract cancer (aBTC).

4520 Background: In aBTC, GemCis is the standard of care as 1 st -line treatment. Immunotherapies have shown early promising efficacy in some BTC patients (pts). We assessed D (anti-PD-L1) ± T (anti-CTLA-4) and GemCis in 1L BTC pts, including an extensive biomarker analysis (NCT03046862). Methods: Pts were first enrolled in the biomarker cohort (BMC) to receive 1 cycle of Gem 1000 mg/m 2 + Cis 25 mg/m 2 on D1 & D8, followed by GemCis + D 1120 mg and T 75 mg, Q3W until disease progression (PD). Subsequent pts were allocated to GemCis + D (3 combo cohort [3C]) or GemCis + D+T (4 combo cohort [4C]) until PD. In all cohorts, tumor biopsies were obtained pre-treatment, after 1 cycle, and at PD. Blood samples for ctDNA were obtained every cycle. Results: 121 pts were enrolled. Median follow-up durations were 28.5 months (m; 95% CI, 26.5-30.5), 11.3 m (95% CI, 9.1-13.5), and 11.9m (95% CI, 8.4-15.4) in the BMC, 3C, and 4C arms, respectively. Efficacy data are shown (Table). The most common adverse events (AEs, any grade) were neutropenia (54.5%), nausea (59.5%), and pruritus (55.44%). The most common grade 3/4 AEs were neutropenia (50.4%), anemia (35.5%), and thrombocytopenia (16.5%). In the BMC cohort, frequent mutations were found in DNA damage repair, cell cycle regulation, and genome instability genes (eg, ATM, BRCA2, POLE, MSH2, CDKN2A). Distinct somatic variants were detected in responders vs non-responders. Baseline tissue TMB did not correlate with PFS or OS. Reductions in ctDNA variant allele frequency (VAF) were more prominent among responders during early D+T cycles. ctDNA VAF on C3, D1 was significantly correlated with ORR ( P< 0.015). Pretreatment PD-L1 expression was not associated with efficacy, but PD-L1 expression after 1 st GemCis cycle trended with improved PFS. Conclusions: These are the first clinical data of D±T plus chemotherapy in chemo-naïve aBTC pts. The addition of immunotherapy to chemotherapy was tolerable and showed very promising efficacy. Biomarker analyses show early signs of markers associated with response. The combination of GemCis + D is being investigated in the Phase 3 TOPAZ-1 trial (NCT03875235). Clinical trial information: NCT03046862 . [Table: see text]