Abstract 11: An alternative time-to-event metric that is consistent with tumor response speed and depth, unlike RECIST time to progression
Authors: Johnson Kaitlyn E. , Gomez Axel , Burton Jackson , White Douglas , Chakravarty Arijit , Schmid Annette , Bottino Dean 
Published: August 2020

Abstract
Time to RECIST progression (TTP) is currently used as a surrogate for patient benefit for either accelerated regulatory approval or to study the effects of factors such as drug exposure and drug target expression levels on RECIST progression-free survival (PFS). While the conventional paradigm assumes that increased antitumor effect results in a longer TTP and PFS, we show that this is often not the case due to a fundamental mathematical property of the RECIST definition of disease progression in which faster tumor shrinkage rate (k) can lead to paradoxically shorter TTP (1,2). We investigate under what conditions this paradoxical behavior occurs, what fraction of patients satisfy these conditions, and whether this phenomenon can invert population-level PFS hazard ratio. We use a mathematical model treating tumor burden as decreasing drug-sensitive and increasing drug-resistant cell subpopulations and fit this model to data from several clinical trials with different indications (3). We simulate a more effective treatment and record the resulting TTP. A study-level analysis compares the relationship of speed and depth of response with TTP20 for both the administered “control” and simulated “more effective” drug. Depending on indication, 3-27% of patients are estimated to have a paradoxically inverse relationship between k and TTP. We conclude that while RECIST progression criteria may be useful for decision making in patients, care must be taken in interpreting TTP as a metric of treatment efficacy due to the real possibility that a stronger treatment effect paradoxically results in shorter TTP. We propose and test an alternative benefit metric: the model-projected time that tumor size reaches 120% of baseline (TTB120). Simulated head-to-head studies show that in contrast to TTP, TTB120 is always consistent with patient benefit. We recommend that any alternative metrics with a time-to-event endpoint should consider the directional consistency between speed and depth of response that the endpoint is consistent with patient benefit under any set of patient conditions.
References: 1. Eisenhauer EA et al. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer 2009;45(2):228-47. 2. Johnson K et al. Directional inconsistency between Response Evaluation Criteria in Solid Tumors (RECIST) time to progression and response speed and depth. Eur J Cancer 2019;109:196-203. 3. Project Data Sphere, https://www.projectdatasphere.org/projectdatasphere/html/home; 2018 [accessed 7 September 2018].
Citation Format: Kaitlyn E. Johnson, Axel Gomez, Jackson Burton, Douglas White, Arijit Chakravarty, Annette Schmid, Dean Bottino. An alternative time-to-event metric that is consistent with tumor response speed and depth, unlike RECIST time to progression [abstract]. In: Proceedings of the AACR Special Conference on Advancing Precision Medicine Drug Development: Incorporation of Real-World Data and Other Novel Strategies; Jan 9-12, 2020; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_1):Abstract nr 11.