title: 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.
abstract: 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.
  
  
  RESULTS
  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%]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Boehringer Ingelheim.
authors.affiliation: National Taiwan University Hospital and National Taiwan University, Taipei, Taiwan. Electronic address: chihyang@ntu.edu.tw.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.affiliation: Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China.
authors.forename: Yi-Long
authors.initials: YL
authors.lastname: Wu
authors.affiliation: West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schuler
authors.affiliation: Johann Wolfgang Goethe University Medical Center, Frankfurt am Main, and University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Sebastian
authors.affiliation: Royal Marsden Hospital, London, UK.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Popat
authors.affiliation: Wakayama Medical University, Wakayama, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Shanghai Pulmonary Hospital, Tongji University, Shanghai, China.
authors.forename: Caicun
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Cheng-Ping
authors.initials: CP
authors.lastname: Hu
authors.affiliation: Princess Alexandra Hospital and Queensland University of Technology, Australia.
authors.forename: Kenneth
authors.initials: K
authors.lastname: O'Byrne
authors.affiliation: Jiangsu Province Cancer Hospital, Nanjing, Jiangsu, China.
authors.forename: Jifeng
authors.initials: J
authors.lastname: Feng
authors.affiliation: Shanghai Lung Tumor Clinical Medical Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Yunnan Tumor Hospital (The Third Affiliated Hospital of Kunming Medical University), Kunming, Yunnan Province, China.
authors.forename: Yunchao
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Prince of Songkla University, Songkhla, Thailand.
authors.forename: Sarayut L
authors.initials: SL
authors.lastname: Geater
authors.affiliation: Department of Internal Medicine, Konkuk University Medical Center, Seoul, South Korea.
authors.forename: Kye Young
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Tsai
authors.affiliation: FSBI "N N Blokhin Russian Cancer Research Centre", Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Vera
authors.initials: V
authors.lastname: Gorbunova
authors.affiliation: McGill University, Montreal, Canada.
authors.forename: Vera
authors.initials: V
authors.lastname: Hirsh
authors.affiliation: Institut de Cancérologie de l'Ouest-site René Gauducheau, Nantes, France.
authors.forename: Jaafar
authors.initials: J
authors.lastname: Bennouna
authors.affiliation: Pavlov State Medical University, St Petersburg, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Orlov
authors.affiliation: State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Tony
authors.initials: T
authors.lastname: Mok
authors.affiliation: Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Boyer
authors.affiliation: National Cheng Kung University Hospital, Tainan, Taiwan.
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.affiliation: Chungbuk National University Hospital, Cheongju, South Korea.
authors.forename: Ki Hyeong
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.
authors.forename: Terufumi
authors.initials: T
authors.lastname: Kato
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: Mehdi
authors.initials: M
authors.lastname: Shahidi
authors.affiliation: Boehringer Ingelheim Ltd UK, Bracknell, Berkshire, UK.
authors.forename: Victoria
authors.initials: V
authors.lastname: Zazulina
authors.affiliation: Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D000068437:Pemetrexed; D011379:Prognosis; D011799:Quinazolines / Q000627:therapeutic use*; D015996:Survival Rate; D000093542:Gemcitabine
chemical_list: D005971:Glutamates; D011799:Quinazolines; D000068437:Pemetrexed; D003841:Deoxycytidine; D000077716:Afatinib; D006147:Guanine; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin; D000093542:Gemcitabine