Background: ICIs targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1) and its ligand (PD-L1) produce a unique profile of toxicities driven by T cell tissue infiltration. The objective of this SR was to identify patterns and incidence of irAEs based on tumor type and ICI class. Methods: A SR was performed in MEDLINE, EMBASE and COCHRANE databases to identify prospective trials investigating single agent ICIs up to Nov 2015. Paired reviewers selected studies for inclusion and extracted data. Odds ratio (OR) with 95% confidence interval (CI) was used to quantify the effect of variables on the incidence of irAEs and contingency table p values were calculated using the chi-squared test. Results: We identified 48 clinical trials with a total of 6872 patients (pts), including 27 CTLA-4, 17 PD-1, 2 CTLA-4 vs PD-1 and 2 PD-L1 monoclonal antibody (mAb) trials. Nine were phase III and 39 were phase I/II trials. Grade 3/4 irAEs were more common with CTLA-4 mAbs compared with PD-1 mAbs (31% vs 10%). All grades colitis (OR 8.7, 95% CI 5.8-12.9), hypophysitis (6.5, 3.0-14.3) and rash (2.0, 1.8-2.3) were more common 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 irAEs from the 3 most studied tumor types in PD-1 mAbs trials [melanoma (n = 2048), non-small cell lung cancer (NSCLC, n = 1030) and renal cell carcinoma (RCC, n = 573)] showed that melanoma pts had a higher frequency of gastrointestinal and skin irAEs and lower frequency of pneumonitis (Table). Conclusions: We demonstrated that CTLA-4 and PD-1 mAbs have distinct irAE profiles presumably by checkpoint-specific immune modulation. Different immune microenvironments may drive histology-specific irAE patterns. Other tumor-dependent irAE profiles may be identified as data emerge from ICI trials.