Title: The time to progression ratio in molecular tumor trials Authors:  Tobias Terzer - German Cancer Research Center (Germany)
Axel Benner - Deutsches Krebsforschungszentrum Heidelberg (Germany)
Dominic Edelmann - German Cancer Research Center (Germany) [presenting]
Abstract: The time to progression ratio (TTPr) is a novel endpoint in Phase I/II oncology trials, which is frequently applied to evaluate the efficacy of molecularly targeted treatments in late-stage patients. The general idea of the design is that a patient serves as their control. To calculate the TTPr for an individual, the time to progression (TTP) under the experimental targeted treatment is divided by the last TTP under standard treatment. The person is considered a responder if the TTPr exceeds a specific value (typically 1.3). Subsequently, a binomial test is performed, investigating if the proportion of responders is significantly higher than a certain threshold (typically 15\%). The current practice for the TTPr is critically examined. Using elementary calculations and simulations, numerous shortcomings of the current methodology are pointed out. Notably, the applied threshold values will often lead to even if the experimental treatment is harmful. On the other hand, the approach features little power when the thresholds are specified correctly. To remedy these shortcomings, the aim is to propose an alternative methodology using a Cox model or accelerated failure time (AFT) model for clustered time-to-event data. It is shown that this methodology outperforms the current approach in terms of power using a comprehensive simulation study.