1. 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
- Author
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Branchoux, S., Sofeu, C.L., Gaudin, A.-F., Kurt, M., Moshyk, A., Italiano, A., Bellera, C., Rondeau, V., Admin, Oskar, Bristol-Myers Squibb [Rueil-Malmaison], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, Bristol-Myers Squibb [Princeton], Institut Bergonié [Bordeaux], UNICANCER, and Bristol-Myers Squibb
- Subjects
Cancer Research ,Time to next treatment ,Advanced melanoma ,Ipilimumab ,Immune checkpoint inhibitors ,Nivolumab ,Clinical Trials, Phase III as Topic ,Oncology ,Surrogate endpoint ,[SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Overall survival ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,Melanoma ,Biomarkers ,Original Research - 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 (R2trial) 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 R2trial 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., Highlights • This is the first study to assess the surrogacy properties of TNT-D for OS in immune checkpoint inhibitor-treated patients. • TNT-D is a clinically relevant, pragmatic and often measurable endpoint that reflects the result of a therapeutic decision. • TNT-D appears to be a promising SE for OS in advanced melanoma patients treated with immune checkpoint inhibitors.
- Published
- 2021