Time to next treatment or death as a candidate surrogate endpoint for overall survival in advanced melanoma patients treated with immune checkpoint inhibitors: an insight from the phase III CheckMate 067 trial

Abstract

Background Time to next treatment or death (TNT-D) may be a patient-relevant endpoint in patients treated with immune checkpoint inhibitors. This study investigated TNT-D as a surrogate endpoint (SE) for overall survival (OS) in previously untreated advanced melanoma patients. Methods Patient-level data from the 60-month results of the CheckMate 067 randomised, controlled trial were used. Analyses were carried out for nivolumab monotherapy or nivolumab with ipilimumab versus ipilimumab monotherapy. The SE 1-step validation method based on a joint frailty-copula model was used where the country of enrolment was applied to define clusters. Kendall's τ and the coefficient of determination (R 2 trial ) were estimated for respective measurements of association at the individual and cluster levels. The surrogate threshold effect, the maximum threshold hazard ratio for TNT-D that would translate into OS benefit, was estimated. A leave-one-out cross-validation analysis was carried out to evaluate model robustness. Results Fifteen clusters of data were generated from 945 patients. For both nivolumab-containing arms, the association between TNT-D and OS was deemed acceptable at the individual level (Kendall's τ > 0.60) and strong at the cluster level, with R 2 trial fairly close to 1, with narrow confidence intervals. The estimated surrogate threshold effects were 0.61 for nivolumab versus ipilimumab and 0.49 for nivolimub + ipilimumab versus ipilimumab. Cross-validation results showed minimum variation of the correlation measures and satisfactory predictive accuracy for the model. Conclusion Results suggest that TNT-D may be a valuable SE in previously untreated advanced melanoma patients treated with immune checkpoint inhibitors. Surrogacy analyses considering multiple randomised controlled trials are warranted for confirming these findings.