Restricted Net Treatment Benefit in oncology

Importance 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 presence of independent right-censoring and can include a pre-specified threshold of minimal clinically relevant difference. Objective 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. Design 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.Main Outcomes and Measures: 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, e.g. 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 and Relevance 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 non-proportional 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.