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Cited by 123Cancer Immunotherapy and BiomarkersPharmacovigilance and Adverse Drug ReactionsImmunotherapy and Immune Responses

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

Open access
Costa, Ricardo, Carneiro, Benedito A., Agulnik, Mark, Rademaker, Alfred W., Pai, Sachin G., Villaflor, Victoria M., Cristofanilli, Massimo, Sosman, Jeffrey A. +1 more·2017·Oncotarget
DOI 10.18632/oncotarget.13315PMC PMC5352453
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Abstract

// Ricardo Costa 1,2 , Benedito A. Carneiro 1,2 , Mark Agulnik 1,2 , Alfred W. Rademaker 2,3 , Sachin G. Pai 1,2 , Victoria M. Villaflor 1,2 , Massimo Cristofanilli 1,2 , Jeffrey A. Sosman 1,2 and Francis J. Giles 1,2 1 Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA 2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA 3 Northwestern University Department of Preventive Medicine, Chicago, Illinois, USA Correspondence to: Ricardo Costa, email: // Keywords : anti-PD1 antibodies; adverse events; meta-analysis; hypothyroidism; pruritus Received : September 20, 2016 Accepted : October 13, 2016 Published : November 11, 2016 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 I 2 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.

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  • Autoimmune thyroiditis is caused by monoclonal antibodies to programmed cell death-1 receptor (nivolumab and pembrolizumab) and to cytotoxic T lymphocyte-associated antigen-4 (ipilimumab, tremelimumab).

    “Autoimmune thyroiditis is also caused by monoclonal Ab to programmed cell death-1 receptor (nivolumab and pembrolizumab), and Ab to cytotoxic T lymphocyte-associated antigen-4 (ipilimumab, tremelimumab) (27, 37–39).”

    From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [39]

  • Anti-CTLA-4 antibodies and anti-PD-1 antibodies induce autoimmune hypophysitis, with rates of 0-17.4% for ipilimumab, 0-2.6% for tremelimumab, 0-0.9% for nivolumab, and 0-1.2% for pembrolizumab.

    “Anti-CTLA-4 Ab and anti-PD-1 Ab induce autoimmune hypophysitis (27, 37–39), with rates of 0–17.4% (ipilimumab), 0–2.6% (tremelimumab), 0–0.9% (nivolumab), and 0–1.2% (pembrolizumab) (38).”

    From L-T4 therapy in the presence of pharmacological interferents (2020) · cites this paper as [39]

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Authors
Costa, R., Carneiro, B. A., Agulnik, M., Rademaker, A. W., Pai, S. G., Villaflor, V. M., Cristofanilli, M., Sosman, J. A., & Giles, F. J.
Affiliations
Northwestern University (US)
Corresponding author
Costa, Ricardo
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2016-11-11
Volume
8
Issue
5
Pages
8910-8920
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.13315
PMC
PMC5352453
OpenAlex
W2554828182
Cited by
123
References
43
Citations by year
2026: 3 · 2025: 6 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 10 · 2020: 18 · 2019: 20 · 2018: 18 · 2017: 30
FWCI
2.28
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (P30CA060553)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
anti-PD-1 monoclonal antibody, nivolumab, pembrolizumab, immune-related adverse events, immune checkpoint inhibitors, solid tumors, hypothyroidism, pruritus, non-relapse mortality, treatment toxicity, immune-related pneumonitis, immune-related colitis, immune-related endocrinopathy, immune-related dermatitis, immune-related encephalitis
MeSH terms
Antineoplastic Agents, Immunological, Nivolumab, Antibodies, Monoclonal, Humans, Neoplasms, Risk Factors, Odds Ratio, Randomized Controlled Trials as Topic, Treatment Outcome, Drug Approval, Risk Assessment, Programmed Cell Death 1 Receptor, Antibodies, Monoclonal, Humanized

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