title: Toxicity profile of approved anti-PD-1 monoclonal antibodies in solid tumors: a systematic review and meta-analysis of randomized clinical trials.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Costa
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
authors.forename: Benedito A
authors.initials: BA
authors.lastname: Carneiro
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Agulnik
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.|Northwestern University Department of Preventive Medicine, Chicago, Illinois, USA.
authors.forename: Alfred W
authors.initials: AW
authors.lastname: Rademaker
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
authors.forename: Sachin G
authors.initials: SG
authors.lastname: Pai
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Villaflor
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Cristofanilli
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.|Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects*; D017277:Drug Approval; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000077594:Nivolumab; D016017:Odds Ratio; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C582435:pembrolizumab
keywords: adverse events; anti-PD1 antibodies; hypothyroidism; meta-analysis; pruritus