• Yucai Wang, Shouhao Zhou, Fang Yang, Xinyue Qi, Xin Wang, Xiaoxiang Guan, Chan Shen, Narjust Duma, Jesus Vera Aguilera, Ashish Chintakuntlawar, Katharine A Price, Julian R Molina, Lance C Pagliaro, Thorvardur R Halfdanarson, Axel Grothey, Svetomir N Markovic, Grzegorz S Nowakowski, Stephen M Ansell, and Michael L Wang.
• Division of Hematology, Mayo Clinic, Rochester, Minnesota.
• JAMA Oncol. 2019 Jul 1; 5 (7): 1008-1019.

ImportanceProgrammed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice.ObjectiveTo evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types.Data SourcesPubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018.Study SelectionPublished clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included.Data Extraction And SynthesisTrial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis.Main Outcomes And MeasuresIncidences of treatment-related adverse events and differences between different drugs and cancer types.ResultsThis systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54).Conclusions And RelevanceDifferent PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.

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