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

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, Michael L. Wang

Research output: Contribution to journalReview article

19 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)1008-1019
Number of pages12
JournalJAMA Oncology
Volume5
Issue number7
DOIs
StatePublished - Jul 1 2019

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CD274 Antigen
Meta-Analysis
Clinical Trials
Incidence
Odds Ratio
Therapeutics
Fatigue
Neoplasms
Cell Death
Information Storage and Retrieval
Hyperthyroidism
Pruritus
Aspartate Aminotransferases
Hypothyroidism
Drug-Related Side Effects and Adverse Reactions
PubMed
Pharmaceutical Preparations
Names
Anemia
Diarrhea

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Wang, Yucai ; Zhou, Shouhao ; Yang, Fang ; Qi, Xinyue ; Wang, Xin ; Guan, Xiaoxiang ; Shen, Chan ; Duma, Narjust ; Vera Aguilera, Jesus ; Chintakuntlawar, Ashish ; Price, Katharine A. ; Molina, Julian R. ; Pagliaro, Lance C. ; Halfdanarson, Thorvardur R. ; Grothey, Axel ; Markovic, Svetomir N. ; Nowakowski, Grzegorz S. ; Ansell, Stephen M. ; Wang, Michael L. / Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials : A Systematic Review and Meta-analysis. In: JAMA Oncology. 2019 ; Vol. 5, No. 7. pp. 1008-1019.
@article{df7e699c6a7a4002b318b6f2ef758637,
title = "Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis",
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 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.",
author = "Yucai Wang and Shouhao Zhou and Fang Yang and Xinyue Qi and Xin Wang and Xiaoxiang Guan and Chan Shen and Narjust Duma and {Vera Aguilera}, Jesus and Ashish Chintakuntlawar and Price, {Katharine A.} and Molina, {Julian R.} and Pagliaro, {Lance C.} and Halfdanarson, {Thorvardur R.} and Axel Grothey and Markovic, {Svetomir N.} and Nowakowski, {Grzegorz S.} and Ansell, {Stephen M.} and Wang, {Michael L.}",
year = "2019",
month = "7",
day = "1",
doi = "10.1001/jamaoncol.2019.0393",
language = "English (US)",
volume = "5",
pages = "1008--1019",
journal = "JAMA oncology",
issn = "2374-2437",
publisher = "American Medical Association",
number = "7",

}

Wang, Y, Zhou, S, Yang, F, Qi, X, Wang, X, Guan, X, Shen, C, Duma, N, Vera Aguilera, J, Chintakuntlawar, A, Price, KA, Molina, JR, Pagliaro, LC, Halfdanarson, TR, Grothey, A, Markovic, SN, Nowakowski, GS, Ansell, SM & Wang, ML 2019, 'Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-analysis', JAMA Oncology, vol. 5, no. 7, pp. 1008-1019. https://doi.org/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. / Wang, Yucai; Zhou, Shouhao; Yang, Fang; Qi, Xinyue; Wang, Xin; Guan, Xiaoxiang; Shen, Chan; Duma, Narjust; Vera Aguilera, Jesus; Chintakuntlawar, Ashish; Price, Katharine A.; Molina, Julian R.; Pagliaro, Lance C.; Halfdanarson, Thorvardur R.; Grothey, Axel; Markovic, Svetomir N.; Nowakowski, Grzegorz S.; Ansell, Stephen M.; Wang, Michael L.

In: JAMA Oncology, Vol. 5, No. 7, 01.07.2019, p. 1008-1019.

Research output: Contribution to journalReview article

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.

PY - 2019/7/1

Y1 - 2019/7/1

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

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JO - JAMA oncology

JF - JAMA oncology

SN - 2374-2437

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