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Int J Cancer. 2019 Aug 1;145(3):639-648. doi: 10.1002/ijc.32132. Epub 2019 Feb 4.

A systematic review of adverse events in randomized trials assessing immune checkpoint inhibitors.

Arnaud-Coffin P1,2,3, Maillet D1,2, Gan HK4,5,6, Stelmes JJ7, You B1,2,3, Dalle S2,3,8, Péron J1,2,3,9,10.

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Department of Medical Oncology, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Pierre-Bénite, France.
Department of ImmuCare (Immunology Cancer Research), Institut de Cancérologie des Hospices Civils de Lyon, Lyon, France.
Faculté de Médecine Lyon-Sud, Lyon 1 University, EMR 3738, Oullins, France.
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.
School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia.
Department of Medicine, Melbourne University, Melbourne, VIC, Australia.
Department of Radiation Oncology, University Hospital of Zurich, Zürich, Switzerland.
Department of Dermatology, Hospices Civils de Lyon, Pierre-Bénite, France.
Department of Statistics unit, Hospices Civils de Lyon, Pierre-Bénite, France.
CNRS, UMR 5558 Biometry and Evolutionary Biology Laboratory, Université Lyon 1, Villeurbanne, France.


The advent of immune checkpoint-inhibitors (CPI) has transformed treatment for several cancer types. This review was performed to assess the rate of adverse events (AEs) associated with the use of CPI, alone or in combinations. A review of AEs reporting quality was also performed. All publications of Randomized Clinical Trials (RCTs) assessing CPI published before December 2017 were included. To investigate the quality of AEs reporting, a set of items was defined based on the 2004 CONSORT harms extension statement. Rates of Grade 5, serious, and study-withdrawal related AEs were collected in each treatment category. Specific immune related AEs (irAEs) were also collected when available. Pooled estimates of adverse event rates were calculated by using generalized linear mixed model. A total of 35 RCTs including 16,485 patients were included. The overall quality of AEs reporting was satisfactory, but items pertaining to methods of data collection and analysis were infrequently reported. Grade ≥ 3 AEs were reported for 14% (95% CI 12-16) of patients treated with PD(L)-1 inhibitors, 34% (95% CI 27-42) of patients treated with CTLA-4 inhibitors, 55% (95% CI 51-59) of patients on CPI combinations and 46% (95% CI 40-53) of patients on immunotherapy-chemotherapy combination. The profile of irAEs was different among the treatment categories. The use of CPI, especially in combination, is associated with significant rates of Grade ≥ 3 AEs. Healthcare planning should anticipate the expected high number of patients presenting with irAEs in the future.


adverse event; immune checkpoint inhibitors; immune toxicity; quality control; systematic review


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