Predictors of overall survival in advanced biliary tract cancer in the phase 3 TOPAZ-1 study

INTRODUCTION TOPAZ-1 (NCT03875235) was the first large, phase 3 study to show that combining durvalumab, an immune checkpoint inhibitor, with gemcitabine and cisplatin (GemCis) could improve overall survival (OS) versus GemCis alone, the prior standard of care (SoC), in advanced biliary tract cancers (aBTCs).1 At the pre-planned interim analysis of TOPAZ-1 [primary analysis, data cut-off (DCO) August 11, 20211], durvalumab plus GemCis showed a significant improvement in OS versus placebo plus GemCis, with no additional toxicity observed. An updated analysis (6-month follow-up; DCO February 25, 2022) further confirmed the favorable benefit-risk profile.2 Based on the findings from TOPAZ-1, durvalumab plus GemCis has become a SoC for aBTCs. However, the factors prognostic for OS in aBTCs, or those predictive of survival following immune checkpoint inhibitor treatment, remain poorly defined.3,4 Although several patient-related and disease-related factors have been identified as potentially prognostic for survival benefit in aBTCs, none have been definitively confirmed.5 This post-hoc analysis aimed to assess patient-related and disease-related factors, and evaluate their potential prognostic or predictive value, in participants with aBTCs treated with durvalumab plus GemCis versus placebo plus GemCis in TOPAZ-1. METHODS The design and eligibility criteria of TOPAZ-1 have been described previously1 and are summarized in the Supplemental Digital Content, https://links.lww.com/HC9/C208. The DCO for this analysis was February 25, 2022. A list of potential prognostic factors for OS was compiled through a literature search of articles published between January 01, 2022, and March 14, 2024, and included pre-specified factors from the original TOPAZ-1 study. These factors were evaluated for their potential to predict OS benefit following treatment with durvalumab plus GemCis versus placebo plus GemCis, in participants of the TOPAZ-1 study.1 Analyses were based on the full analysis set (FAS), with additional prognostic sensitivity analyses conducted using both the FAS and the complete case set (CCS; excluding participants with ≥1 missing clinical or laboratory measurement). Detailed methods are provided in the Supplemental Digital Content, https://links.lww.com/HC9/C208. RESULTS A total of 685 participants were randomized to durvalumab plus GemCis (n = 341) or placebo plus GemCis (n = 344) and comprised the FAS; the CCS comprised 205 and 211 participants, respectively. Baseline demographics, disease characteristics, clinical factors, and laboratory factors were generally balanced across treatment groups and data sets (Supplemental Table S1, https://links.lww.com/HC9/C208). The OS HR for durvalumab plus GemCis versus placebo plus GemCis, adjusted for stratification factors only, was 0.76 (95% CI: 0.64–0.91)2 in the FAS and 0.74 (95% CI: 0.59–0.93) in the CCS. The following factors were identified as potentially prognostic for OS in the FAS: neutrophil-to-lymphocyte ratio (NLR), cancer antigen 19-9 (CA 19-9), disease status (initially unresectable vs. recurrent), primary tumor location, lactate dehydrogenase, albumin, carcinoembryonic antigen (CEA), and total bilirubin (Supplemental Table S2, https://links.lww.com/HC9/C208). After adjusting for these factors, the OS HR was 0.70 (95% CI: 0.56–0.88). The results of the sensitivity analyses based on the FAS and CCS are reported in Supplemental Table S2, https://links.lww.com/HC9/C208. In the predictive analysis, OS HRs for durvalumab plus GemCis versus placebo plus GemCis were