Comparing Survival for Different CAR Ts: Need for Addressing Bias Due to Differences in the Pre-Infusion Period

▪ Introduction Patients with relapsed/refractory large B-cell lymphoma (RR-LBCL) treated with salvage chemotherapy have a poor prognosis, with a median survival of 6.3 months (Crump 2017). Given the recent approval of chimeric antigen receptor T-cell therapies (CAR T) for patients with RR-LBCL, efforts to demonstrate the comparative effectiveness of different CAR Ts are imminent. In the absence of head-to-head trials, such an assessment will likely be based on indirect or between-trial comparisons of reported survival estimates. Due to differences in the multi-step manufacturing process preceding the infusion of CAR T cells, the duration of the pre-infusion period, which accounts for time from leukapheresis to infusion, may vary across CAR Ts. This variability may be associated with differences in the prognostic characteristics of patients who endure the pre-infusion period. As such, comparisons of reported survival among these selected patients with the different CAR Ts evaluated in different trials may be biased. Estimating the comparative effects of CAR T therapies on survival requires careful attention to these potential differences and the use of thoughtful analytic approaches to address bias. We aimed to review current methodological approaches used to address bias related to time-to-treatment initiation and assess their potential utility in comparative analyses of CAR T based on between-trial comparisons. Methods A targeted literature review was performed to identify studies that used methods to adjust for bias related to time-to-treatment initiation when estimating relative treatment effects regarding survival outcomes between interventions in oncology. Relevant studies published in English from 2008 onwards were identified by searching the Medical Literature Analysis and Retrieval System Online (MEDLINE) and Excerpta Medica dataBASE (EMBASE). In addition, manual searches of the reference lists of the identified studies were performed. Studies that provided the most recent application of a proposed method were selected for inclusion. Results We identified several manuscripts that utilized methods to address survival or survival treatment selection bias (STSB) in observational studies where the classification of “treated” individuals required them to have survived until treatment initiation, and individuals who died early without the opportunity to get treatment were classified as “untreated”. The identified methods to adjust for the over-estimation