TY - JOUR
T1 - Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials
T2 - A Systematic Review and Meta-analysis
AU - Wang, Yucai
AU - Zhou, Shouhao
AU - Yang, Fang
AU - Qi, Xinyue
AU - Wang, Xin
AU - Guan, Xiaoxiang
AU - Shen, Chan
AU - Duma, Narjust
AU - Vera Aguilera, Jesus
AU - Chintakuntlawar, Ashish
AU - Price, Katharine A.
AU - Molina, Julian R.
AU - Pagliaro, Lance C.
AU - Halfdanarson, Thorvardur R.
AU - Grothey, Axel
AU - Markovic, Svetomir N.
AU - Nowakowski, Grzegorz S.
AU - Ansell, Stephen M.
AU - Wang, Michael L.
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2019 American Medical Association. All rights reserved.
PY - 2019/7
Y1 - 2019/7
N2 - 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 20128 patients; 12 277 (66.0%) of 18610 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.
AB - 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 20128 patients; 12 277 (66.0%) of 18610 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.
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U2 - 10.1001/jamaoncol.2019.0393
DO - 10.1001/jamaoncol.2019.0393
M3 - Review article
C2 - 31021376
AN - SCOPUS:85065336828
SN - 2374-2437
VL - 5
SP - 1008
EP - 1019
JO - JAMA Oncology
JF - JAMA Oncology
IS - 7
ER -