title: Safety and Tolerability of PD-1/PD-L1 Inhibitors Compared with Chemotherapy in Patients with Advanced Cancer: A Meta-Analysis.
abstract: Compared with chemotherapy, significant improvement in survival outcomes with the programmed death receptor-1 (PD-1) inhibitors nivolumab and pembrolizumab and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab has been shown in several types of advanced solid tumors. We conducted a systematic review and meta-analysis to compare safety and tolerability between PD-1/PD-L1 inhibitors and chemotherapy.
  
  
  
  PubMed and American Society of Clinical Oncology (ASCO) databases were searched 1966 to September 2016. Eligible studies included randomized controlled trials (RCTs) comparing single-agent U.S. Food and Drug Administration-approved PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, or atezolizumab) with chemotherapy in cancer patients reporting any all-grade (1-4) or high-grade (3-4) adverse events (AEs), all- or high-grade treatment-related symptoms, hematologic toxicities and immune-related AEs, treatment discontinuation due to toxicities, or treatment-related deaths. The summary incidence, relative risk, and 95% confidence intervals were calculated.
  
  
  
  A total of 3,450 patients from 7 RCTs were included in the meta-analysis: 4 nivolumab, 2 pembrolizumab, and 1 atezolizumab trials. The underlying malignancies included were non-small cell lung cancer (4 trials) and melanoma (3 trials). Compared with chemotherapy, the PD-1/PD-L1 inhibitors had a significantly lower risk of all- and high-grade fatigue, sensory neuropathy, diarrhea and hematologic toxicities, all-grade anorexia, nausea, and constipation, any all- and high-grade AEs, and treatment discontinuation. There was an increased risk of all-grade rash, pruritus, colitis, aminotransferase elevations, hypothyroidism, and hyperthyroidism, and all- and high-grade pneumonitis with PD1/PD-L1 inhibitors.
  
  
  
  PD-1/PD-L1 inhibitors are overall better tolerated than chemotherapy. Our results provide further evidence supporting the favorable risk/benefit ratio for PD-1/PD-L1 inhibitors.The Oncologist2017;22:470-479 IMPLICATIONS FOR PRACTICE: We conducted a systematic review and meta-analysis to compare summary toxicity endpoints and clinically relevant adverse events between programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors and chemotherapy. PD1/PD-L1 inhibitors were associated with a lower risk of treatment-related symptoms (fatigue, anorexia, nausea, diarrhea, constipation, and sensory neuropathy) but a higher risk of immune-related adverse events (AEs). Summary toxicity endpoints favor PD1/PD-L1 inhibitors (any all- and high-grade AEs and treatment discontinuation). PD1/PD-L1 inhibitors are overall better tolerated than chemotherapy. In addition to efficacy data from trials, our findings provide useful information for clinicians for well-balanced discussions with their patients on the risks and benefits of treatment options for advanced cancer.
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA Tomohiro.Nishijima@unchealth.unc.edu.
authors.forename: Tomohiro F
authors.initials: TF
authors.lastname: Nishijima
authors.affiliation: Division of Oncology, Rambam Health Care Campus, Haifa, Israel.
authors.forename: Shlomit S
authors.initials: SS
authors.lastname: Shachar
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
authors.forename: Kirsten A
authors.initials: KA
authors.lastname: Nyrop
authors.affiliation: UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina, USA.
authors.forename: Hyman B
authors.initials: HB
authors.lastname: Muss
mesh_terms: D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000473:pathology*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; C000594389:atezolizumab; C582435:pembrolizumab
keywords: Chemotherapy; Meta‐analysis; PD‐1/PD‐L1 inhibitor; Systematic review; Toxicity