Quantification of dose dependence and frequency of checkpoint inhibitor immune-mediated adverse events: A Bayesian model-based meta-analysis.

Abstract

83 Background: Immune checkpoint inhibitors (ICIs) are associated with immune-mediated adverse events (imAEs). The objective of this study was to use a Bayesian model-based meta-analysis to quantify dose dependence and compare imAE frequencies for PD-1, PD-L1 and CTLA-4 inhibitor monotherapies and their combinations. Methods: We searched PubMed, TrialTrove, ASCO and ESMO databases and retrieved relevant ICI safety data. In order to quantitatively compare safety across doses and drugs against a given target, we converted the various dose regimens used into drug exposures derived from pharmacokinetic models; we also normalized exposures by the corresponding drug potency. We performed a Bayesian meta-analysis for Grades 3&4 of treatment related (trAE) and immune-mediated (imAE) adverse events. Results: A total of 149 articles were identified, covering 35,559 patients in 197 dosing cohorts treated with ICI therapies. For PD-1 and PD-L1 inhibitor monotherapies, no dose dependence of AEs was found; Grades 3&4 trAE rates for anti PD-L1 vs. anti PD-1 were, respectively, 12% and 15%. The AE rates for the different ICI drugs and organ classes were estimated. Dose dependence was found for anti CTLA-4 monotherapies, for total trAEs of Grades 3/4, gastrointestinal and hepatic imAEs. Dose dependence was found and quantified for anti CTLA-4 in combination with anti PD-1 with respect to total trAEs of Grades 3/4 trAEs and imAEs per gastrointestinal and hepatic organ groups. We found that combination of anti PD-L1 agents with anti CTLA-4 exhibited lower AE rates, as compared to anti PD-1 combined with anti CTLA-4. Conclusions: We introduced a novel meta-analysis methodology and used it to quantify and compare AE rates across ICI agents. Significant AE rate dose dependencies were observed for CTLA-4 inhibitors, either as monotherapy or used in combinations. Patients naive to anti-cancer therapies exhibited higher AE rates vs. previously treated patients. AE rates for CTLA-4 + PD-1 inhibitor combination regimens were supra-additive vs. the respective monotherapies. AE rates for anti PD-L1 agents were lower vs. anti PD-1, both in monotherapy and combinations with CTLA-4.