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Ann Oncol. 2017 Oct 1;28(10):2377-2385. doi: 10.1093/annonc/mdx286.

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

Khoja L1,2, Day D3,4,5, Wei-Wu Chen T6,7,8, Siu LL3,4, Hansen AR3,4.

Author information

Clinical Development Unit, Early Clinical Development, AstraZeneca UK plc, Melbourn Science Park, Melbourn, Hertfordshire.
Medical Oncology, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
Drug Development Program, Division of Medical Oncology and Haematology, Princess Margaret Cancer Centre, Toronto.
Department of Medicine, University of Toronto, Toronto.
Ontario Institute for Cancer Research (OICR), Toronto, Canada.
Department of Oncology, National Taiwan University Hospital, Taipei.
National Taiwan University Cancer Center, Taipei.
Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.



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 tumour type and ICI class.


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), χ2 tests and multivariable regression models were used to analyse for effect size and associations.


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% versus 10%). All grades colitis (OR 8.7, 95% CI 5.8-12.9), hypophysitis (OR 6.5, 95% CI 3.0-14.3) and rash (OR 2.0, 95% CI 1.8-2.3) were more frequent with CTLA-4 mAbs; whereas pneumonitis (OR 6.4, 95% CI 3.2-12.7), hypothyroidism (OR 4.3, 95% CI 2.9-6.3), arthralgia (OR 3.5, 95% CI 2.6-4.8) and vitiligo (OR 3.5, 95% CI 2.3-5.3) were more common with PD-1 mAbs. Comparison of irAE from the three most studied tumour 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.


CTLA-4 and PD-1 mAbs have distinct irAE profiles. Different immune microenvironments may drive histology-specific irAE patterns. Other tumour-dependent irAE profiles may be identified as data emerge from ICI trials.


immune checkpoint inhibitors; immune-related adverse events

[Indexed for MEDLINE]

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