Restricted Net Treatment Benefit in oncology

Max Piffoux; Brice Ozenne; Mickaël De Backer; Marc Buyse; Jean-Christophe Chiem; Julien Péron

doi:10.1016/j.jclinepi.2024.111340

Restricted Net Treatment Benefit in oncology

J Clin Epidemiol. 2024 Apr 1:170:111340. doi: 10.1016/j.jclinepi.2024.111340. Online ahead of print.

Authors

Max Piffoux¹, Brice Ozenne², Mickaël De Backer³, Marc Buyse⁴, Jean-Christophe Chiem³, Julien Péron⁵

Affiliations

¹ Medical Oncology, Hospices Civils de Lyon, CITOHL, Lyon, France; Direction de la Recherche Clinique et de l'Innovation, Centre Léon Bérard, Lyon, France; Laboratoire MSC Matière et Systèmes Complexes, Université de Paris, CNRS UMR 7057, 75006 Paris, France. Electronic address: max.piffoux@cri-paris.org.
² Neurobiology Research Unit and BrainDrugs, Copenhagen University Hospital, Rigshospitalet, 6-8 Inge Lehmanns Vej, 2100 Copenhagen, Denmark; Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark.
³ International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium.
⁴ International Drug Development Institute (IDDI), Louvain-la-Neuve, Belgium; I-BioStat, University of Hasselt, Hasselt, Belgium.
⁵ Hospices Civils de Lyon, Oncology Department, Pierre-Bénite, France; Université de Lyon, Université Lyon 1, Reshape Laboratory INSERM U1290, Lyon, France.

PMID: 38570079
DOI: 10.1016/j.jclinepi.2024.111340

Abstract

Objectives: The restricted Net Treatment Benefit (rNTB) is a clinically meaningful and tractable estimand of the overall treatment effect assessed in randomized trials when at least one survival endpoint with time restriction is used. Its interpretation does not rely on parametric assumptions such as proportional hazards, can be estimated without bias even in the presence of independent right-censoring, and can include a prespecified threshold of minimal clinically relevant difference. To demonstrate that the rNTB, corresponding to the NTB during a predefined time interval, is a meaningful and adaptable measure of treatment effect in clinical trials.

Methods: In this simulation study, we tested the impact on the rNTB value, estimation, and power of several factors including the presence of a delayed treatment effect, minimal clinically relevant difference threshold value, restriction time value, and the inclusion of both efficacy and toxicity in the rNTB definition. The impact of right censoring on rNTB was assessed in terms of bias. rNTB-derived statistical tests and log rank (LR) tests were compared in terms of power.

Results: RNTB estimates are unbiased even in case of right-censoring. rNTB may be used to estimate the benefit/risk ratio of a new treatment, for example, taking into account both survival and toxicity and include several prioritized outcomes. The estimated rNTB is much easier to interpret in this context compared to NTB in the presence of censoring since the latter is intrinsically dependent on the follow-up duration. Including toxicity increases the test power when the experimental treatment is less toxic. rNTB-derived test power increases when the experimental treatment is associated with longer survival and lower toxicity and might increase in the presence of a cure rate or a delayed treatment effect. Case applications on the PRODIGE, Checkmate-066, and Checkmate-067 trials are provided.

Conclusions: RNTB is an interesting alternative to describe and test the treatment's effect in a clear and understandable way in case of restriction, particularly in scenarios with nonproportional hazards or when trying to balance benefit and safety. It can be tuned to take into consideration short- or long-term survival differences and one or more prioritized outcomes.

Keywords: Clinical trial; Generalized pairwise comparisons; Immunotherapy; Nonproportional hazard; Restriction; Toxicity.