title: Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial.
abstract: The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). We aimed to compare the efficacy and safety of afatinib and gefitinib in this setting.
  
  
  
  This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed beneficial by the investigator. Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Efficacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug. This ongoing study is registered with ClinicalTrials.gov, number NCT01466660.
  
  
  
  Between Dec 13, 2011, and Aug 8, 2013, 319 patients were randomly assigned (160 to afatinib and 159 to gefitinib). Median follow-up was 27·3 months (IQR 15·3-33·9). Progression-free survival (median 11·0 months [95% CI 10·6-12·9] with afatinib vs 10·9 months [9·1-11·5] with gefitinib; hazard ratio [HR] 0·73 [95% CI 0·57-0·95], p=0·017) and time-to-treatment failure (median 13·7 months [95% CI 11·9-15·0] with afatinib vs 11·5 months [10·1-13·1] with gefitinib; HR 0·73 [95% CI 0·58-0·92], p=0·0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature. The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefitinib) and rash or acne (15 [9%] patients given afatinib vs five [3%] of those given gefitinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefitinib). Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefitinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefitinib group died from drug-related hepatic and renal failure.
  
  
  
  Afatinib significantly improved outcomes in treatment-naive patients with EGFR-mutated NSCLC compared with gefitinib, with a manageable tolerability profile. These data are potentially important for clinical decision making in this patient population.
  
  
  
  Boehringer Ingelheim.
authors.affiliation: Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. Electronic address: kpark@skku.edu.
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.affiliation: National Cancer Centre, Singapore, Singapore.
authors.forename: Eng-Huat
authors.initials: EH
authors.lastname: Tan
authors.affiliation: Princess Alexandra Hospital and Queensland University of Technology, Brisbane, QLD, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: O'Byrne
authors.affiliation: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Chris O'Brien Lifehouse, Camperdown, NSW, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Boyer
authors.affiliation: Key Laboratory of South China, Department of Clinical Oncology, The Chinese University of Hong Kong Sha Tin, Hong Kong.
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.affiliation: McGill University, Montreal, QC, Canada.
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.affiliation: National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Chungbuk National University Hospital, Cheongju, Chungbuk, South Korea.
authors.forename: Ki Hyeong
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Shanghai Chest Hospital, Shanghai, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China; Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing, China.
authors.forename: Yuankai
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Asan Medical Center, Seoul, South Korea.
authors.forename: Sang-We
authors.initials: SW
authors.lastname: Kim
authors.affiliation: BC CancerAgency, Vancouver, BC, Canada.
authors.forename: Janessa
authors.initials: J
authors.lastname: Laskin
authors.affiliation: Seoul National University Hospital, Seoul, South Korea.
authors.forename: Dong-Wan
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Centre François Baclesse, Oncology, Caen, France.
authors.forename: Catherine Dubos
authors.initials: CD
authors.lastname: Arvis
authors.affiliation: Karolinska University Hospital, Solna, Stockholm, Sweden.
authors.forename: Karl
authors.initials: K
authors.lastname: Kölbeck
authors.affiliation: The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Laurie
authors.affiliation: Taipei Veterans General Hospital and National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Tsai
authors.affiliation: Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shahidi
authors.affiliation: Boehringer Ingelheim GmbH, Ingelheim, Germany.
authors.forename: Miyoung
authors.initials: M
authors.lastname: Kim
authors.affiliation: Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK.
authors.forename: Dan
authors.initials: D
authors.lastname: Massey
authors.affiliation: Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Zazulina
authors.affiliation: Hospital Universitario Doce de Octubre and CNIO, Madrid Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Paz-Ares
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; 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 / Q000235:genetics / Q000503:physiopathology; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000077156:Gefitinib; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib