title: Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.
abstract: BACKGROUND
  Afatinib, an irreversible ErbB-family blocker, has shown preclinical activity when tested in EGFR mutant models with mutations that confer resistance to EGFR tyrosine-kinase inhibitors. We aimed to assess its efficacy in patients with advanced lung adenocarcinoma with previous treatment failure on EGFR tyrosine-kinase inhibitors.
  
  
  METHODS
  In this phase 2b/3 trial, we enrolled patients with stage IIIB or IV adenocarcinoma and an Eastern Cooperative Oncology Group performance (ECOG) performance score of 0-2 who had received one or two previous chemotherapy regimens and had disease progression after at least 12 weeks of treatment with erlotinib or gefitinib. We used a computer-generated sequence to randomly allocate patients (2:1) to either afatinib (50 mg per day) or placebo; all patients received best supportive care. Randomisation was done in blocks of three and was stratified by sex and baseline ECOG performance status (0-1 vs 2). Investigators, patients, and the trial sponsor were masked to treatment assignment. The primary endpoint was overall survival (from date of randomisation to death), analysed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00656136.
  
  
  RESULTS
  Between May 26, 2008, and Sept 21, 2009, we identified 697 patients, 585 of whom were randomly allocated to treatment (390 to afatinib, 195 to placebo). Median overall survival was 10·8 months (95% CI 10·0-12·0) in the afatinib group and 12·0 months (10·2-14·3) in the placebo group (hazard ratio 1·08, 95% CI 0·86-1·35; p=0·74). Median progression-free survival was longer in the afatinib group (3·3 months, 95% CI 2·79-4·40) than it was in the placebo group (1·1 months, 0·95-1·68; hazard ratio 0·38, 95% CI 0·31-0·48; p<0·0001). No complete responses to treatment were noted; 29 (7%) patients had a partial response in the afatinib group, as did one patient in the placebo group. Subsequent cancer treatment was given to 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group. The most common adverse events in the afatinib group were diarrhoea (339 [87%] of 390 patients; 66 [17%] were grade 3) and rash or acne (305 [78%] patients; 56 [14%] were grade 3). These events occurred less often in the placebo group (18 [9%] of 195 patients had diarrhoea; 31 [16%] had rash or acne), all being grade 1 or 2. Drug-related serious adverse events occurred in 39 (10%) patients in the afatinib group and one (<1%) patient in the placebo group. We recorded two possibly treatment-related deaths in the afatinib group.
  
  
  CONCLUSIONS
  Although we recorded no benefit in terms of overall survival with afatinib (which might have been affected by cancer treatments given after progression in both groups), our findings for progression-free survival and response to treatment suggest that afatinib could be of some benefit to patients with advanced lung adenocarcinoma who have failed at least 12 weeks of previous EGFR tyrosine-kinase inhibitor treatment.
  
  
  BACKGROUND
  Boehringer Ingelheim Inc.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York City, NY, USA; Weill Cornell Medical College, New York City, NY, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.forename: Jacques
authors.initials: J
authors.lastname: Cadranel
authors.forename: Yuh-Min
authors.initials: YM
authors.lastname: Chen
authors.forename: Keunchil
authors.initials: K
authors.lastname: Park
authors.forename: Sang-We
authors.initials: SW
authors.lastname: Kim
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.forename: Mengzhao
authors.initials: M
authors.lastname: Wang
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
authors.forename: Lucio
authors.initials: L
authors.lastname: Crino
authors.forename: Eng-Huat
authors.initials: EH
authors.lastname: Tan
authors.forename: Tsu-Yi
authors.initials: TY
authors.lastname: Chao
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shahidi
authors.forename: Xiuyu Julie
authors.initials: XJ
authors.lastname: Cong
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lorence
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D004311:Double-Blind Method; D000069347:Erlotinib Hydrochloride; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib