PMID- 22452896
OWN - NLM
STAT- MEDLINE
DCOM- 20120626
LR  - 20220419
IS  - 1474-5488 (Electronic)
IS  - 1470-2045 (Linking)
VI  - 13
IP  - 5
DP  - 2012 May
TI  - 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.
PG  - 528-38
LID - 10.1016/S1470-2045(12)70087-6 [doi]
AB  - 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Boehringer Ingelheim Inc.
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Miller, Vincent A
AU  - Miller VA
AD  - Memorial Sloan-Kettering Cancer Center, New York City, NY, USA; Weill Cornell 
      Medical College, New York City, NY, USA.
FAU - Hirsh, Vera
AU  - Hirsh V
FAU - Cadranel, Jacques
AU  - Cadranel J
FAU - Chen, Yuh-Min
AU  - Chen YM
FAU - Park, Keunchil
AU  - Park K
FAU - Kim, Sang-We
AU  - Kim SW
FAU - Zhou, Caicun
AU  - Zhou C
FAU - Su, Wu-Chou
AU  - Su WC
FAU - Wang, Mengzhao
AU  - Wang M
FAU - Sun, Yan
AU  - Sun Y
FAU - Heo, Dae Seog
AU  - Heo DS
FAU - Crino, Lucio
AU  - Crino L
FAU - Tan, Eng-Huat
AU  - Tan EH
FAU - Chao, Tsu-Yi
AU  - Chao TY
FAU - Shahidi, Mehdi
AU  - Shahidi M
FAU - Cong, Xiuyu Julie
AU  - Cong XJ
FAU - Lorence, Robert M
AU  - Lorence RM
FAU - Yang, James Chih-Hsin
AU  - Yang JC
LA  - eng
SI  - ClinicalTrials.gov/NCT00656136
PT  - Clinical Trial, Phase II
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20120326
PL  - England
TA  - Lancet Oncol
JT  - The Lancet. Oncology
JID - 100957246
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Quinazolines)
RN  - 41UD74L59M (Afatinib)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - S65743JHBS (Gefitinib)
SB  - IM
EIN - Lancet Oncol. 2012 May;13(5):e186
CIN - Lancet Oncol. 2012 May;13(5):442-3. doi: 10.1016/S1470-2045(12)70124-9. PMID: 
      22452893
MH  - Adenocarcinoma/*drug therapy/secondary
MH  - Adult
MH  - Afatinib
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/*therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
MH  - Double-Blind Method
MH  - Erlotinib Hydrochloride
MH  - Female
MH  - Gefitinib
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/secondary
MH  - Male
MH  - Middle Aged
MH  - Protein Kinase Inhibitors/therapeutic use
MH  - Quinazolines/*therapeutic use
EDAT- 2012/03/29 06:00
MHDA- 2012/06/27 06:00
CRDT- 2012/03/29 06:00
PHST- 2012/03/29 06:00 [entrez]
PHST- 2012/03/29 06:00 [pubmed]
PHST- 2012/06/27 06:00 [medline]
AID - S1470-2045(12)70087-6 [pii]
AID - 10.1016/S1470-2045(12)70087-6 [doi]
PST - ppublish
SO  - Lancet Oncol. 2012 May;13(5):528-38. doi: 10.1016/S1470-2045(12)70087-6. Epub 
      2012 Mar 26.