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Meta-Analysis
. 2019 Jul 1;5(7):1008-1019.
doi: 10.1001/jamaoncol.2019.0393.

Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis

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Free PMC article
Meta-Analysis

Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis

Yucai Wang et al. JAMA Oncol. .
Free PMC article

Abstract

Importance: Programmed 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.

Objective: To 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 sources: PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018.

Study selection: Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included.

Data extraction and synthesis: Trial 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 measures: Incidences of treatment-related adverse events and differences between different drugs and cancer types.

Results: This 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 relevance: Different 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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Halfdanarson reported grants from Ipsen, Agios, ArQule, and Thermo Fisher Scientific as well as other from Advanced Accelerator Applications outside the submitted work. Dr Grothey reported grants and nonfinancial support from Bayer, Genentech, and ARRAY as well as grants from Boston Biomedical and Daiichi outside the submitted work. Dr Nowakowski reported grants from Celgene, Morphosys, Bayer, Genetech, Curis, and Nanostring outside the submitted work. Dr Ansell reported other from Bristol-Myers Squibb and Merck outside the submitted work. Dr M. L. Wang reported grants, personal fees, and nonfinancial support from Janssen, AstraZeneca, AcertaPharma, and Celgene; grants and nonfinancial support from Pharmacyclics; grants from BeiGene, Kite Pharma, Juno Therapeutics, and Oncternal; nonfinancial support from MoreHealth and Pulse Biosciences; and personal fees and nonfinancial support from PeerView Institute for Medical Education and OMI outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Flow Diagram of the Study Selection Process
Figure 2.
Figure 2.. Incidences of the Most Common Adverse Events and Immune-Related Adverse Events (irAEs)
A, Incidences of the most common all-grade adverse events. B, Incidences of the most common grade 3 or higher adverse events. C, Incidences of the most common all-grade irAEs. D, Incidences of the most common grade 3 or higher irAEs. Vertical lines in A and C indicate the overall mean incidence of all-grade adverse events (1.66%). Vertical lines in B and D indicate the overall mean incidence of grade 3 or higher adverse events (0.11%). Values to the left of the line are lower than the mean, to the right, higher. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; GGT, γ-glutamyltransferase.
Figure 3.
Figure 3.. Mean Incidences of Adverse Events by Cancer Type
A, Mean incidences of all grade adverse events by cancer type; vertical line indicates the overall mean incidence of all-grade adverse events (1.66%). B, Mean incidences of grade 3 or higher adverse events by cancer type. The vertical line indicates the overall mean incidence of grade 3 or higher adverse events (0.11%). For both panels, values to the left of the line are lower than the mean, to the right, higher.
Figure 4.
Figure 4.. Mean Incidences of Adverse Events by Drug Type
A, Mean incidences of all-grade adverse events by drug and dose; vertical line indicates the overall mean incidence of all-grade adverse events (1.66%). B, Mean incidences of grade 3 or higher adverse events by drug and dose. C, Comparisons of mean incidences of adverse events between different drugs. The vertical line indicates the overall mean incidence of grade 3 or higher adverse events (0.11%). For A and B, values to the left of the line are lower than mean, to the right, higher. For C, values to the left of the line are higher for second drug in the comparison, to the right, for first drug in comparison. PD-1 indicates programmed cell death; PD-L1, programmed cell death ligand 1.

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