Outcomes by primary tumour location in patients with advanced biliary tract cancer treated with durvalumab or placebo plus gemcitabine and cisplatin in the phase 3 TOPAZ-1 study

Abstract

Background: The double-blind, phase 3 TOPAZ-1 study (NCT03875235) evaluated the efficacy and safety of durvalumab plus gemcitabine and cisplatin (GemCis) as first-line treatment for patients with advanced biliary tract cancer (BTC; Oh D-Y et al. J Clin Oncol 2022;40[suppl 4]. Abs 378). Durvalumab plus GemCis significantly improved overall survival (OS) versus placebo plus GemCis and represents a potential new first- line treatment option. In BTC, primary tumour location (intrahepatic or extrahepatic cholangiocarcinoma [IHCC/EHCC], or gallbladder cancer [GBC]) may impact risk fac- tors, prognoses, and response to treatment. Methods: The aim of this exploratory subgroup analysis of TOPAZ-1 was to assess efficacy outcomes, OS, progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) per RECIST v1.1, by primary tumour location in pa- tients receiving durvalumab versus placebo. Patients with BTC were randomised 1:1 to receive durvalumab (1500 mg) or placebo on Day 1 Q3W, plus gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on Day 1 and 8 Q3W, for up to 8 cycles, followed by durvalumab or placebo monotherapy until disease progression, unacceptable toxicity or other discontinuation criteria were met. Randomisation was stratified by disease status (initially unresectable vs recurrent) and primary tumour location (IHCC vs EHCC vs GBC). Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for OS and PFS using a Cox proportional hazards model, and odds ratios (ORs) and 95% CIs for ORR were calculated using the Cochran-Mantel Haenszel test. Results: Patient numbers with IHCC, EHCC and GBC were balanced between treatment arms; more patients had IHCC than EHCC or GBC (durvalumab: n¼190, n¼66, n¼85; placebo: n¼193, n¼65, n¼86, respectively). HRs for OS favoured durvalumab: HR was 0.76 (95% CI, 0.58-0.98) for IHCC, 0.76 (95% CI, 0.49-1.19) for EHCC, and 0.94 (95% CI, 0.65-1.37) for GBC. To aid in understanding the higher HR in GBC, regional analysis was performed: the OS HR for GBC in Asia was 0.82 (95% CI, 0.48-1.40) and in Europe plus North America (non-Asian countries minus South America) was 0.78 (95% CI, 0.44-1.37). PFS HR was 0.79 (95% CI, 0.64-0.99) for IHCC, 0.52 (95% CI, 0.35-0.78) for EHCC, and 0.90 (95% CI, 0.65-1.24) for GBC. ORR favoured durvalumab in IHCC (24.7% vs 15.5%; OR, 1.79; 95% CI, 1.07-2.97), EHCC (28.8% vs 15.6%; OR, 2.18; 95% CI, 0.92-5.16) and GBC (29.4% vs 27.9%; OR, 1.08; 95% CI, 0.55-2.09). Percentages of responders with a DoR of at least 9 and 12 months were higher with durvalumab versus placebo for all tumour locations (9-month: IHCC 28.3% vs 24.0%, EHCC 43.3% vs 23.3%, GBC 33.2% vs 27.5%; 12-month: IHCC 18.9% vs 12.0%, EHCC 43.3% vs 23.3%, GBC 27.6% vs 16.5%). Conclusions: In TOPAZ-1, the addition of durvalumab to GemCis appeared to improve efficacy outcomes (not formally tested for subgroup comparisons) for patients with IHCC, EHCC and GBC. Though the magnitude of efficacy improvement varied slightly between primary tumour locations, the benefit of durvalumab was observed consistently. These findings support durvalumab plus GemCis as a treatment option for BTC, irrespective of primary tumour location.