Tumor- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review.

Abstract

Background:Immune checkpoint inhibitor (ICI) monoclonal antibodies (mAbs) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) or its ligand (PD-L1) produce unique toxicity profiles. The objective of this review was to identify patterns and incidence of immune related adverse events (irAE) based on tumor type and ICI class.Methods:MEDLINE, EMBASE and COCHRANE databases were searched to identify prospective monotherapy trials of ICIs from 2003 to November 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR), chi-squared tests and multivariable regression models were used to analyze for effect size and associations.Results:We identified 48 trials (6938 patients), including 26 CTLA-4, 17 PD-1, 2 PD-L1 trials, and 3 studies tested both CTLA-4 and PD-1. Grade 3/4 irAE were more common with CTLA-4 mAbs compared with PD-1 (31% vs 10%). All grades colitis (OR 8.7, CI 5.8-12.9), hypophysitis (6.5, 3.0-14.3) and rash (2.0, 1.8-2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (6.4, 3.2-12.7), hypothyroidism (4.3, 2.9-6.3), arthralgia (3.5, 2.6-4.8) and vitiligo (3.5, 2.3-5.3) were more common with PD-1 mAbs. Comparison of irAE from the 3 most studied tumor types in PD-1 mAbs trials [melanoma (n = 2048), non-small cell lung cancer (n = 1030) and renal cell carcinoma (n = 573)] showed melanoma patients had a higher frequency of gastrointestinal and skin irAE and lower frequency of pneumonitis.Conclusions:CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumor-dependent irAE profiles may be identified as data emerge from ICI trials.

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