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Meta-Analysis
. 2017 Jan 31;8(5):8910-8920.
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  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 , Francis J Giles  1   2
Affiliations
Meta-Analysis

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

Ricardo Costa et al. Oncotarget. .

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.

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Conflict of interest statement

CONFLICTS OF INTEREST

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.

Figures

Figure 1
Figure 1. Study flow diagram
Figure 2
Figure 2. Forest plots of relative risks of all grade AEs (A) and grade 3&4 AEs (B)
Abbreviations: Adverse events (AEs), immunotherapy therapy treatment arm (ITX), and control arm (CTX).
See this image and copyright information in PMC

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