PMID- 25589191
OWN - NLM
STAT- MEDLINE
DCOM- 20150331
LR  - 20221207
IS  - 1474-5488 (Electronic)
IS  - 1470-2045 (Linking)
VI  - 16
IP  - 2
DP  - 2015 Feb
TI  - Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung 
      adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data 
      from two randomised, phase 3 trials.
PG  - 141-51
LID - S1470-2045(14)71173-8 [pii]
LID - 10.1016/S1470-2045(14)71173-8 [doi]
AB  - BACKGROUND: We aimed to assess the effect of afatinib on overall survival of 
      patients with EGFR mutation-positive lung adenocarcinoma through an analysis of 
      data from two open-label, randomised, phase 3 trials. METHODS: Previously 
      untreated patients with EGFR mutation-positive stage IIIB or IV lung 
      adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These 
      patients were randomly assigned in a 2:1 ratio to receive afatinib or 
      chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin 
      [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, 
      or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature 
      overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) 
      and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with 
      ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. FINDINGS: Median 
      follow-up in LUX-Lung 3 was 41 months (IQR 35-44); 213 (62%) of 345 patients had 
      died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31-37); 246 (68%) of 364 
      patients had died. In LUX-Lung 3, median overall survival was 28.2 months (95% CI 
      24.6-33.6) in the afatinib group and 28.2 months (20.7-33.2) in the 
      pemetrexed-cisplatin group (HR 0.88, 95% CI 0.66-1.17, p=0.39). In LUX-Lung 6, 
      median overall survival was 23.1 months (95% CI 20.4-27.3) in the afatinib group 
      and 23.5 months (18.0-25.6) in the gemcitabine-cisplatin group (HR 0.93, 95% CI 
      0.72-1.22, p=0.61). However, in preplanned analyses, overall survival was 
      significantly longer for patients with del19-positive tumours in the afatinib 
      group than in the chemotherapy group in both trials: in LUX-Lung 3, median 
      overall survival was 33.3 months (95% CI 26.8-41.5) in the afatinib group versus 
      21.1 months (16.3-30.7) in the chemotherapy group (HR 0.54, 95% CI 0.36-0.79, 
      p=0.0015); in LUX-Lung 6, it was 31.4 months (95% CI 24.2-35.3) versus 18.4 
      months (14.6-25.6), respectively (HR 0.64, 95% CI 0.44-0.94, p=0.023). By 
      contrast, there were no significant differences by treatment group for patients 
      with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median 
      overall survival was 27.6 months (19.8-41.7) in the afatinib group versus 40.3 
      months (24.3-not estimable) in the chemotherapy group (HR 1.30, 95% CI 0.80-2.11, 
      p=0.29); in LUX-Lung 6, it was 19.6 months (95% CI 17.0-22.1) versus 24.3 months 
      (19.0-27.0), respectively (HR 1.22, 95% CI 0.81-1.83, p=0.34). In both trials, 
      the most common afatinib-related grade 3-4 adverse events were rash or acne (37 
      [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), 
      diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and 
      stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia 
      (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were 
      the most common chemotherapy-related grade 3-4 adverse events, while in LUX-Lung 
      6, the most common chemotherapy-related grade 3-4 adverse events were neutropenia 
      (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). 
      INTERPRETATION: Although afatinib did not improve overall survival in the whole 
      population of either trial, overall survival was improved with the drug for 
      patients with del19 EGFR mutations. The absence of an effect in patients with 
      Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be 
      distinct from Leu858Arg-positive disease and that these subgroups should be 
      analysed separately in future trials. FUNDING: Boehringer Ingelheim.
CI  - Copyright (c) 2015 Elsevier Ltd. All rights reserved.
FAU - Yang, James Chih-Hsin
AU  - Yang JC
AD  - National Taiwan University Hospital and National Taiwan University, Taipei, 
      Taiwan. Electronic address: chihyang@ntu.edu.tw.
FAU - Wu, Yi-Long
AU  - Wu YL
AD  - Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy 
      of Medical Sciences, Guangzhou, China.
FAU - Schuler, Martin
AU  - Schuler M
AD  - West German Cancer Center, University Hospital Essen, University Duisburg-Essen, 
      Essen, Germany.
FAU - Sebastian, Martin
AU  - Sebastian M
AD  - Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, and 
      University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 
      Germany.
FAU - Popat, Sanjay
AU  - Popat S
AD  - Royal Marsden Hospital, London, UK.
FAU - Yamamoto, Nobuyuki
AU  - Yamamoto N
AD  - Wakayama Medical University, Wakayama, Japan.
FAU - Zhou, Caicun
AU  - Zhou C
AD  - Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
FAU - Hu, Cheng-Ping
AU  - Hu CP
AD  - Xiangya Hospital, Central South University, Changsha, China.
FAU - O'Byrne, Kenneth
AU  - O'Byrne K
AD  - Princess Alexandra Hospital and Queensland University of Technology, Australia.
FAU - Feng, Jifeng
AU  - Feng J
AD  - Jiangsu Province Cancer Hospital, Nanjing, Jiangsu, China.
FAU - Lu, Shun
AU  - Lu S
AD  - Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai 
      Jiao Tong University, Shanghai, China.
FAU - Huang, Yunchao
AU  - Huang Y
AD  - Yunnan Tumor Hospital (The Third Affiliated Hospital of Kunming Medical 
      University), Kunming, Yunnan Province, China.
FAU - Geater, Sarayut L
AU  - Geater SL
AD  - Prince of Songkla University, Songkhla, Thailand.
FAU - Lee, Kye Young
AU  - Lee KY
AD  - Department of Internal Medicine, Konkuk University Medical Center, Seoul, South 
      Korea.
FAU - Tsai, Chun-Ming
AU  - Tsai CM
AD  - Taipei Veterans General Hospital, Taipei, Taiwan.
FAU - Gorbunova, Vera
AU  - Gorbunova V
AD  - FSBI "N N Blokhin Russian Cancer Research Centre", Russian Academy of Medical 
      Sciences, Moscow, Russia.
FAU - Hirsh, Vera
AU  - Hirsh V
AD  - McGill University, Montreal, Canada.
FAU - Bennouna, Jaafar
AU  - Bennouna J
AD  - Institut de Cancerologie de l'Ouest-site Rene Gauducheau, Nantes, France.
FAU - Orlov, Sergey
AU  - Orlov S
AD  - Pavlov State Medical University, St Petersburg, Russia.
FAU - Mok, Tony
AU  - Mok T
AD  - State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese 
      University of Hong Kong, Hong Kong, China.
FAU - Boyer, Michael
AU  - Boyer M
AD  - Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
FAU - Su, Wu-Chou
AU  - Su WC
AD  - National Cheng Kung University Hospital, Tainan, Taiwan.
FAU - Lee, Ki Hyeong
AU  - Lee KH
AD  - Chungbuk National University Hospital, Cheongju, South Korea.
FAU - Kato, Terufumi
AU  - Kato T
AD  - Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.
FAU - Massey, Dan
AU  - Massey D
AD  - Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK.
FAU - Shahidi, Mehdi
AU  - Shahidi M
AD  - Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK.
FAU - Zazulina, Victoria
AU  - Zazulina V
AD  - Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK.
FAU - Sequist, Lecia V
AU  - Sequist LV
AD  - Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT00949650
SI  - ClinicalTrials.gov/NCT01121393
PT  - Clinical Trial, Phase III
PT  - Comparative Study
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20150112
PL  - England
TA  - Lancet Oncol
JT  - The Lancet. Oncology
JID - 100957246
RN  - 0 (Glutamates)
RN  - 0 (Quinazolines)
RN  - 04Q9AIZ7NO (Pemetrexed)
RN  - 0W860991D6 (Deoxycytidine)
RN  - 41UD74L59M (Afatinib)
RN  - 5Z93L87A1R (Guanine)
RN  - EC 2.7.10.1 (EGFR protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - Q20Q21Q62J (Cisplatin)
RN  - 0 (Gemcitabine)
SB  - IM
CIN - Lancet Oncol. 2015 Feb;16(2):118-9. doi: 10.1016/S1470-2045(14)71196-9. PMID: 
      25589190
CIN - Nat Rev Clin Oncol. 2015 Mar;12(3):127. doi: 10.1038/nrclinonc.2015.9. PMID: 
      25622977
MH  - Adenocarcinoma/*drug therapy/genetics/mortality/pathology
MH  - Adult
MH  - Afatinib
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use
MH  - Cisplatin/administration & dosage
MH  - Deoxycytidine/administration & dosage/analogs & derivatives
MH  - ErbB Receptors/antagonists & inhibitors/*genetics
MH  - Female
MH  - Follow-Up Studies
MH  - Glutamates/administration & dosage
MH  - Guanine/administration & dosage/analogs & derivatives
MH  - Humans
MH  - Lung Neoplasms/*drug therapy/genetics/mortality/pathology
MH  - Male
MH  - Middle Aged
MH  - Mutation/*genetics
MH  - Neoplasm Staging
MH  - Pemetrexed
MH  - Prognosis
MH  - Quinazolines/*therapeutic use
MH  - Survival Rate
MH  - Gemcitabine
EDAT- 2015/01/16 06:00
MHDA- 2015/04/01 06:00
CRDT- 2015/01/16 06:00
PHST- 2015/01/16 06:00 [entrez]
PHST- 2015/01/16 06:00 [pubmed]
PHST- 2015/04/01 06:00 [medline]
AID - S1470-2045(14)71173-8 [pii]
AID - 10.1016/S1470-2045(14)71173-8 [doi]
PST - ppublish
SO  - Lancet Oncol. 2015 Feb;16(2):141-51. doi: 10.1016/S1470-2045(14)71173-8. Epub 
      2015 Jan 12.