Mauro, Ezequiel; de Castro, Tiago; Zeitlhoefler, Marcus; Hackshaw, Allan; Lee, MinJae; Meyer, Tim; Singal, Amit G; Mauro, Ezequiel; de Castro, Tiago; Zeitlhoefler, Marcus; Hackshaw, Allan; Lee, MinJae; Meyer, Tim; Singal, Amit G; Llovet, Josep M; - view fewer (2025) Strategies to address non-proportional hazards between survival curves - Lessons from phase III trials in hepatocellular carcinoma. Journal of Hepatology 10.1016/j.jhep.2025.08.042. (In press).

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Abstract

BACKGROUND AND AIMS: Non-proportional hazards (NPH) can cause discrepancies between interim (IA) and final analyses (FA) in randomized clinical trials (RCT) in hepatocellular carcinoma (HCC). We analyzed the impact of NPH in pivotal HCC trials and proposed strategies for a robust analysis. METHODS: Pivotal phase III HCC RCTs (2008-2024) were selected. The Grambsch-Therneau test assessed proportional hazards. For NPH, we proposed an optimal IA timing (twice the estimated median of primary endpoint in the control group) or event size (≥60%). MaxCombo test, restricted mean survival time (rRMST) and piecewise HR (pHR) were used in the NPH scenario. RESULTS: NPH was present in 4/20 (20%) phase III trials in HCC, all involving immunotherapies, and displayed 3 patterns: 1) diminishing effects, 2) delayed effects, and 3) crossing hazards. Two RCTs (IMbrave050, LEAP-012) reported positive IA results with diminishing effects. In IMbrave050, discrepancies were observed when comparing IA and FA using MaxCombo analysis (p=0.02 and p=0.33, respectively), rRMST at 12 and 36 months [1.11 (p<0.001) and 1.08 (p=0.08), respectively] and pHR prior/after 12 months [0.59 (95%CI 0.43-0.73) and 1.12 (95%CI 0.88-1.37)]. In LEAP-012, consistently results at both 12 and 24 months were observed (MaxCombo test p<0.001) and rRMST [1.20 (p<0.001) and 1.27 (p<0.001)]. HIMALAYA and Checkmate 9DW reported positive results, which were confirmed by MaxCombo test. HIMALAYA showed delayed effects [rRMST at 12 and 36 months: 1.04 (p=0.13) and 1.15 (p=0.004)], while CheckMate 9DW displayed crossing hazards [rRMST at 12 and 36 months: 0.95 (p=0.07) and 1.12 (p=0.03)]. CONCLUSION: NPH caused discrepancies in IMbrave050’s interim and subsequent efficacy analyses. Robust IA requires a minimum follow-up duration or number of events before prematurely stopping an RCT with NPH. IMPACT AND IMPLICATIONS: Non-proportional hazards (NPH) impact phase III RCTs in hepatocellular carcinoma (HCC), particularly in immunotherapy trials, potentially causing discrepancies between the interim and final analyses. In fact, halting trials at the interim analysis can be premature when NPH is present. Thus, we propose a framework to ensure study maturity based on follow-up duration and event accruals to optimize interim analyses in the presence of NPH. Whenever NPH is identified, distinct statistical tools should be used to assess reliable differences between arms (MaxCombo) and to assess the effect size [restricted mean survival time (RMST) and piecewise hazard ratios (pHR)] for regulatory decisions and clinical guidance. Implementing these strategies can improve trial design, and better support decision-making for HCC management.

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