Model-based meta-analysis of safety for immune checkpoint inhibitor combinations and monotherapy.

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89 Background: Immune checkpoint inhibitors (ICIs) have shown efficacy across multiple cancer types; however, ICIs are also associated with immune-mediated (im) adverse events (AEs) especially when used in combination. Methods: Published safety data from 35 melanoma and non-small cell lung cancer clinical trials was normalized for drug exposure using drug concentrations at 50% inhibition (IC50). Pharmacokinetic models from FDA, EMEA, and our own model were used to compare AEs across 4 ICIs: anti-PD-1 (nivolumab, pembrolizumab) and anti-CTLA-4 (ipilumumab, tremelimumab). Data was analyzed by ICI target and organ class (ie, GI, skin, liver, lung, and endocrine). To test dependence of AE rate (%) on drug dose dependence (DD) we calculated mean AE rates for low and high halves of the dose range, and used Pearson’s χ2-squared test for statistical significance (SS) ( p< 0.05). Results: We found AEs to be DD for anti-CTLA-4 monotherapies and anti-CTLA-4 + anti-PD-1 combinations, whereas DD was not SS for anti-PD-1 monotherapies (Table). For anti-CTLA-4 drugs DD was SS for GI, hepatic, skin, and endocrine AEs. In combination, there was DD upon anti-CTLA-4, but data were insufficient to confirm SS. For PD-1 drugs there was no significant DD found. Conclusions: For anti-PD-1 therapy, no DD for Grade 3/4 AEs was found across organ classes. However, for anti-CTLA-4 therapies, DD was SS for GI, skin, hepatic, and endocrine im AEs. Although not all data were sufficient to confirm SS, dose intensity of anti-CTLA-4 may be an important determinant of AEs, when co-administered with anti-PD-1. [Table: see text]