title: Risk of Treatment-Related Toxicities from EGFR Tyrosine Kinase Inhibitors: A Meta-analysis of Clinical Trials of Gefitinib, Erlotinib, and Afatinib in Advanced EGFR-Mutated Non-Small Cell Lung Cancer.
abstract: Gefitinib, erlotinib, and afatinib are tyrosine kinase inhibitors (TKIs) used for treatment of advanced EGFR-mutated NSCLC. Estimating differences in toxicity between these EGFR TKIs is important for personalizing treatment.
  
  
  
  We performed a meta-analysis of randomized trials that compared EGFR TKI therapy against chemotherapy or placebo. We extracted data from the EGFR TKI arm for indirect comparisons to estimate the relative risk for toxic death, grade 3 to 4 (G3/4) adverse events (AEs), and discontinuation of treatment because of AE for each EGFR TKI.
  
  
  
  Sixteen trials included 2535 patients with mutated or wild-type EGFR. Toxic deaths were rare (1.7%), with pneumonitis being most frequent cause and no significant differences between EGFR TKIs. Overall, 40% of patients experienced G3/4 AEs. The risk for G3/4 AEs was lower with gefitinib (29.1%) than with erlotinib (54.1%) or afatinib (42.1%) (p < 0.01). Discontinuation of treatment because of AEs occurred in 7.7% of patients, with no significant differences between EGFR TKIs. Diarrhea (in 53.3% of cases) and rash (in 66.5%) were the most frequent AEs. The risk for rash was higher with afatinib (84.8%) than with erlotinib (62.0%) or gefitinib (62.0%) (p < 0.01). The risk for diarrhea was higher with afatinib (91.7%) than with erlotinib (42.4%) or gefitinib (44.4%) (p < 0.01). The risk for increased liver enzyme levels was higher with gefitinib (61.7%) than with erlotinib (17.8%) or afatinib (20.1%) (p < 0.01). A risk-benefit contour was used to assess the trade-off between efficacy and toxicity for different EGFR TKIs.
  
  
  
  EGFR TKIs are well tolerated, with less than 10% of patients discontinuing treatment because of AEs. The profile of and risk for toxicities vary between EGFR TKIs and can be used to inform the selection of treatment.
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, Australia; Department of Medical Oncology, Liverpool Hospital, Sydney, Australia.
authors.forename: Pei Ni
authors.initials: PN
authors.lastname: Ding
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, Australia; School of Medicine, The University of Notre Dame, Sydney, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Lord
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, Australia.
authors.forename: Val
authors.initials: V
authors.lastname: Gebski
authors.affiliation: Cancer Care Centre, St. George Hospital, Sydney, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Links
authors.affiliation: Department of Medical Oncology, Liverpool Hospital, Sydney, Australia.
authors.forename: Victoria
authors.initials: V
authors.lastname: Bray
authors.affiliation: Albert Einstein College of Medicine, Jacobi Medical Center, New York, New York.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gralla
authors.affiliation: Graduate Institute of Oncology, National Taiwan University and Department of Oncology, National Taiwan University Hospital, Taipei, Republic of China.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.affiliation: National Health and Medical Research Council Clinical Trials Centre, The University of Sydney, Sydney, Australia; Cancer Care Centre, St. George Hospital, Sydney, Australia. Electronic address: chee.lee@ctc.usyd.edu.au.
authors.forename: Chee Khoon
authors.initials: CK
authors.lastname: Lee
mesh_terms: D000077716:Afatinib; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced* / Q000175:diagnosis; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011799:Quinazolines / Q000008:administration & dosage; D012307:Risk Factors; D015996:Survival Rate
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: EGFR mutation; Meta-analysis; NSCLC; Tyrosine kinase inhibitors