Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: A systematic review and meta-analysis of randomized clinical trials

Ricardo Costa; Benedito A. Carneiro; Mark Agulnik; Alfred W. Rademaker; Sachin G. Pai; Victoria M. Villaflor; Massimo Cristofanilli; Jeffrey A. Sosman; Francis J. Giles

doi:10.18632/oncotarget.13315

Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: A systematic review and meta-analysis of randomized clinical trials

Ricardo Costa^*, Benedito A. Carneiro, Mark Agulnik, Alfred W. Rademaker, Sachin G. Pai, Victoria M. Villaflor, Massimo Cristofanilli, Jeffrey A. Sosman, Francis J. Giles

^*Corresponding author for this work

Research output: Contribution to journal › Review article › peer-review

85 Scopus citations

Abstract

Purpose: Nivolumab and pembrolizumab are antibodies against the programmed-death-receptor- 1 (PD-1) which are associated with distinct immune related adverse effects (AEs). This meta-analysis of randomized clinical trials aims to summarize current knowledge regarding the toxicity profile of these agents. Methods: PubMed search was conducted in February of 2016. The randomized trials needed to have at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy and a control arm containing no anti-PD-1 therapy. Data were analyzed using random effects meta-analysis for risk ratios. Heterogeneity across studies was analyzed using Q and I² statistics. Results: Nine randomized trials and 5,353 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies. The pooled relative risk (RR) for treatment-related all grade AEs and grade 3/4 AEs was 0.88 (95% CI 0.81-0.95;P=0.002) and 0.39 (95% CI 0.29-0.53; P<0.001) respectively favoring anti-PD-1 therapy versus standard of care approach. The RR of treatment-related death was 0.45 (95% CI 0.19-1.09; P=0.076). Patients treated with PD-1 inhibitors had an increased risk of hyperthyroidism [RR of 3.44 (95% CI 1.98-5.99; P<0.001)] and hypothyroidism [RR of 6.79 (95% CI 3.10-14.84; P<0.001)]. All grade pruritus and vitiligo were also more common among these patients. The pooled absolute risks of pneumonitis and hypophysitis were 2.65% and 0.47% respectively. Conclusion: Approved PD-1 inhibitors are well tolerated, associated with significant low risk of severe treatment-related AEs and increased risk of thyroid dysfunction, pruritus, and vitiligo.

Original language	English (US)
Pages (from-to)	8910-8920
Number of pages	11
Journal	Oncotarget
Volume	8
Issue number	5
DOIs	https://doi.org/10.18632/oncotarget.13315
State	Published - 2017

Keywords

Adverse events
Anti-PD1 antibodies
Hypothyroidism
Meta-analysis
Pruritus

ASJC Scopus subject areas

Oncology

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10.18632/oncotarget.13315

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Costa, Ricardo ; Carneiro, Benedito A. ; Agulnik, Mark ; Rademaker, Alfred W. ; Pai, Sachin G. ; Villaflor, Victoria M. ; Cristofanilli, Massimo ; Sosman, Jeffrey A. ; Giles, Francis J. / Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors : A systematic review and meta-analysis of randomized clinical trials. In: Oncotarget. 2017 ; Vol. 8, No. 5. pp. 8910-8920.

@article{55b72cd528844ed3b03c264324c98b39,

title = "Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: A systematic review and meta-analysis of randomized clinical trials",

abstract = "Purpose: Nivolumab and pembrolizumab are antibodies against the programmed-death-receptor- 1 (PD-1) which are associated with distinct immune related adverse effects (AEs). This meta-analysis of randomized clinical trials aims to summarize current knowledge regarding the toxicity profile of these agents. Methods: PubMed search was conducted in February of 2016. The randomized trials needed to have at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy and a control arm containing no anti-PD-1 therapy. Data were analyzed using random effects meta-analysis for risk ratios. Heterogeneity across studies was analyzed using Q and I2 statistics. Results: Nine randomized trials and 5,353 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies. The pooled relative risk (RR) for treatment-related all grade AEs and grade 3/4 AEs was 0.88 (95% CI 0.81-0.95;P=0.002) and 0.39 (95% CI 0.29-0.53; P<0.001) respectively favoring anti-PD-1 therapy versus standard of care approach. The RR of treatment-related death was 0.45 (95% CI 0.19-1.09; P=0.076). Patients treated with PD-1 inhibitors had an increased risk of hyperthyroidism [RR of 3.44 (95% CI 1.98-5.99; P<0.001)] and hypothyroidism [RR of 6.79 (95% CI 3.10-14.84; P<0.001)]. All grade pruritus and vitiligo were also more common among these patients. The pooled absolute risks of pneumonitis and hypophysitis were 2.65% and 0.47% respectively. Conclusion: Approved PD-1 inhibitors are well tolerated, associated with significant low risk of severe treatment-related AEs and increased risk of thyroid dysfunction, pruritus, and vitiligo.",

keywords = "Adverse events, Anti-PD1 antibodies, Hypothyroidism, Meta-analysis, Pruritus",

author = "Ricardo Costa and Carneiro, {Benedito A.} and Mark Agulnik and Rademaker, {Alfred W.} and Pai, {Sachin G.} and Villaflor, {Victoria M.} and Massimo Cristofanilli and Sosman, {Jeffrey A.} and Giles, {Francis J.}",

note = "Funding Information: Ricardo Costa M.D., M.Sc.: In the past 2 years the author had research project funded, in whole or in part, by Bristol Myers Squibb. Benedito A. Carneiro M.D., M.Sc.: In the past 2 years the author had research project funded, in whole or in part, by Bristol Myers Squibb. Mark Agulnik M.D.: none. Alfred W. Rademaker: none. Sachin G. Pai M.D.: none. Victoria A. Villaflor M.D.: In the past 2 years the author had research project funded, in whole or in part, by Celgene and Norvatis. Massimo Cristofanilli M.D.: none. Jeffrey A. Sosman M.D.: In the past 2 years the author received Honoraria from Novartis, Merck, Array, Genentech and had research project funded, in whole or in part, by BMV pharma. Francis J. Giles M.D.: In the past 2 years the author received honoraria from Novartis and had research project funded, in whole or in part, by Bristol Myers Squibb, AbbVie and MedImmune. Publisher Copyright: {\textcopyright} 2017 Impact Journals LLC. All rights reserved.",

year = "2017",

doi = "10.18632/oncotarget.13315",

language = "English (US)",

volume = "8",

pages = "8910--8920",

journal = "Oncotarget",

issn = "1949-2553",

publisher = "Impact Journals",

number = "5",

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Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors : A systematic review and meta-analysis of randomized clinical trials. / Costa, Ricardo; Carneiro, Benedito A.; Agulnik, Mark; Rademaker, Alfred W.; Pai, Sachin G.; Villaflor, Victoria M.; Cristofanilli, Massimo; Sosman, Jeffrey A.; Giles, Francis J.

In: Oncotarget, Vol. 8, No. 5, 2017, p. 8910-8920.

Research output: Contribution to journal › Review article › peer-review

TY - JOUR

T1 - Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors

T2 - A systematic review and meta-analysis of randomized clinical trials

AU - Costa, Ricardo

AU - Carneiro, Benedito A.

AU - Agulnik, Mark

AU - Rademaker, Alfred W.

AU - Pai, Sachin G.

AU - Villaflor, Victoria M.

AU - Cristofanilli, Massimo

AU - Sosman, Jeffrey A.

AU - Giles, Francis J.

N1 - Funding Information: Ricardo Costa M.D., M.Sc.: In the past 2 years the author had research project funded, in whole or in part, by Bristol Myers Squibb. Benedito A. Carneiro M.D., M.Sc.: In the past 2 years the author had research project funded, in whole or in part, by Bristol Myers Squibb. Mark Agulnik M.D.: none. Alfred W. Rademaker: none. Sachin G. Pai M.D.: none. Victoria A. Villaflor M.D.: In the past 2 years the author had research project funded, in whole or in part, by Celgene and Norvatis. Massimo Cristofanilli M.D.: none. Jeffrey A. Sosman M.D.: In the past 2 years the author received Honoraria from Novartis, Merck, Array, Genentech and had research project funded, in whole or in part, by BMV pharma. Francis J. Giles M.D.: In the past 2 years the author received honoraria from Novartis and had research project funded, in whole or in part, by Bristol Myers Squibb, AbbVie and MedImmune. Publisher Copyright: © 2017 Impact Journals LLC. All rights reserved.

PY - 2017

Y1 - 2017

N2 - Purpose: Nivolumab and pembrolizumab are antibodies against the programmed-death-receptor- 1 (PD-1) which are associated with distinct immune related adverse effects (AEs). This meta-analysis of randomized clinical trials aims to summarize current knowledge regarding the toxicity profile of these agents. Methods: PubMed search was conducted in February of 2016. The randomized trials needed to have at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy and a control arm containing no anti-PD-1 therapy. Data were analyzed using random effects meta-analysis for risk ratios. Heterogeneity across studies was analyzed using Q and I2 statistics. Results: Nine randomized trials and 5,353 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies. The pooled relative risk (RR) for treatment-related all grade AEs and grade 3/4 AEs was 0.88 (95% CI 0.81-0.95;P=0.002) and 0.39 (95% CI 0.29-0.53; P<0.001) respectively favoring anti-PD-1 therapy versus standard of care approach. The RR of treatment-related death was 0.45 (95% CI 0.19-1.09; P=0.076). Patients treated with PD-1 inhibitors had an increased risk of hyperthyroidism [RR of 3.44 (95% CI 1.98-5.99; P<0.001)] and hypothyroidism [RR of 6.79 (95% CI 3.10-14.84; P<0.001)]. All grade pruritus and vitiligo were also more common among these patients. The pooled absolute risks of pneumonitis and hypophysitis were 2.65% and 0.47% respectively. Conclusion: Approved PD-1 inhibitors are well tolerated, associated with significant low risk of severe treatment-related AEs and increased risk of thyroid dysfunction, pruritus, and vitiligo.

AB - Purpose: Nivolumab and pembrolizumab are antibodies against the programmed-death-receptor- 1 (PD-1) which are associated with distinct immune related adverse effects (AEs). This meta-analysis of randomized clinical trials aims to summarize current knowledge regarding the toxicity profile of these agents. Methods: PubMed search was conducted in February of 2016. The randomized trials needed to have at least one of the study arms consisting of nivolumab or pembrolizumab monotherapy and a control arm containing no anti-PD-1 therapy. Data were analyzed using random effects meta-analysis for risk ratios. Heterogeneity across studies was analyzed using Q and I2 statistics. Results: Nine randomized trials and 5,353 patients were included in our meta-analysis. There was evidence of significant heterogeneity between studies. The pooled relative risk (RR) for treatment-related all grade AEs and grade 3/4 AEs was 0.88 (95% CI 0.81-0.95;P=0.002) and 0.39 (95% CI 0.29-0.53; P<0.001) respectively favoring anti-PD-1 therapy versus standard of care approach. The RR of treatment-related death was 0.45 (95% CI 0.19-1.09; P=0.076). Patients treated with PD-1 inhibitors had an increased risk of hyperthyroidism [RR of 3.44 (95% CI 1.98-5.99; P<0.001)] and hypothyroidism [RR of 6.79 (95% CI 3.10-14.84; P<0.001)]. All grade pruritus and vitiligo were also more common among these patients. The pooled absolute risks of pneumonitis and hypophysitis were 2.65% and 0.47% respectively. Conclusion: Approved PD-1 inhibitors are well tolerated, associated with significant low risk of severe treatment-related AEs and increased risk of thyroid dysfunction, pruritus, and vitiligo.

KW - Adverse events

KW - Anti-PD1 antibodies

KW - Hypothyroidism

KW - Meta-analysis

KW - Pruritus

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DO - 10.18632/oncotarget.13315

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JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

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Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: A systematic review and meta-analysis of randomized clinical trials

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