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 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.