Critical reappraisal of phase III trials with immune checkpoint inhibitors in non-proportional hazards settings

European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)
Eduardo CastañónAlberto Carmona-Bayonas

Abstract

The dynamic effects of immune checkpoint inhibitors (ICIs) are a challenge when designing and analysing data in non-proportional hazards (PH) scenarios. Herein, we present the risk of making type II errors, affecting pharmacotherapeutic development when methods that assume constant effects are applied. Individual patient data from six clinical trials (KEYNOTE-062/061, IMvigor211, CA184-143 y CheckMate-057/037) were extracted. The most relevant time-varying effects were examined using the Royston-Parmar spline model (RPSM), time-driven analyses and weighted log-rank and Renyi tests. The RPSM yields an appropriate fit in non-PH contexts, enabling dynamic descriptions of the hazard rate, and time-varying differences of overall survival (OS)/progression-free survival. In the KEYNOTE-061, CheckMate-057 and 037 trials, 12-, 18-, and 24-month OS rates were higher with immunotherapy (differences of some 10%) (P-value <0.05). In KEYNOTE-062, CA184-043 and IMvigor-211 trials, OS rate differences were significant for past 20 months. Flemming-Harrington and Renyi tests with late weighting (e.g. with ρ-value = 0 and γ-value = 1) captured the existence of significant differences on all curves. The Cox models and log-rank tests were inefficie...Continue Reading

Citations

Dec 23, 2020·Pharmaceutical Statistics·Dominic Magirr
Dec 30, 2020·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·M C T van ZeijlJ B A G Haanen
Oct 29, 2021·Cancer Investigation·Alberto Carmona-BayonasPavlos Msaouel

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