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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

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

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Oncotarget. 2017; 8:8910-8920. https://doi.org/10.18632/oncotarget.13315

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Abstract

Ricardo Costa1,2, Benedito A. Carneiro1,2, Mark Agulnik1,2, Alfred W. Rademaker2,3, Sachin G. Pai1,2, Victoria M. Villaflor1,2, Massimo Cristofanilli1,2, Jeffrey A. Sosman 1,2 and Francis J. Giles1,2

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 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.


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