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).

Abstract

4520 Background: In aBTC, GemCis is the standard of care as 1st-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/m2 + Cis 25 mg/m2 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 1st 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]

Immunotherapy in Advanced Biliary Tract Cancers

“…Median DOR was 8.5 months and median OS was 10.1 months (95% CI: 6.2–11.4). Durvalumab and tremelimumab were also tested in combination with CISGEM in a phase 2 study that included 121 BTC patients in first-line, 45 treated with CISGEM and durvalumab and 46 with CISGEM, durvalumab and tremelimumab (30 patients also received this quadruplet therapy in a biomarker cohort) [ 62 ]. Median ORR was 50.0%, 73.3% and 73.4% in the biomarker, triplet and quadruplet cohort, respectively, with DCR of 96.7%, 100% and 97.8% and median DOR of 11.0, 9.8, and 9.1 months.…”

Current Progress and Future Perspectives of Immune Checkpoint Inhibitors in Biliary Tract Cancer

“…PD-L1 expression after the first GemCis cycle, rather than baseline expression, trended with improved PFS. 32 Results from another recruiting study (NCT02834013) on dual ICIs combination after multiline therapies for advanced BTC are awaited. BTC is rather heterogeneous according to the different anatomical and molecular subtypes.…”

“…With more extensive research, combined therapy has proven to be more efficient than monotherapy, and seems to be the future direction for this form of treatment. [28][29][30][31][32]34,[36][37][38][39][40][41] Nevertheless, the ideal combination partner, whether chemotherapy, molecular targeted therapy, or radiotherapy, needs to be evaluated, and which one is the best is still a matter of ongoing research. The proper dose, duration, and the sequence should be evaluated to obtain the maximum clinical benefits with limited toxicity.…”

Current Status and Future Perspectives of Perioperative Therapy for Resectable Biliary Tract Cancer: A Multidisciplinary Review

“…Triplet chemotherapy, such as GemCis plus nab-paclitaxel or S-1-irinotecan–oxaliplatin, have shown high response rates (40–50%) in single-arm studies, and these regimens may be as effective as neoadjuvant therapy [ 54 , 55 ]. A recent single-arm phase 2 study showed promising efficacy outcomes with durvalumab, anti-PD-L1 antibody, and GemCis for patients with unresectable or metastatic BTC, and this regimen is now under investigation (DEBATE: NCT04308174) as neoadjuvant therapy for resectable BTC ( Table 3 ) [ 56 ].…”