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 Joseph Giles

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

65 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 languageEnglish (US)
Pages (from-to)8910-8920
Number of pages11
JournalOncotarget
Volume8
Issue number5
DOIs
StatePublished - 2017

Keywords

  • Adverse events
  • Anti-PD1 antibodies
  • Hypothyroidism
  • Meta-analysis
  • Pruritus

ASJC Scopus subject areas

  • Oncology

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