title: Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): a phase 2 trial.
abstract: BACKGROUND
  Afatinib is an irreversible ErbB-family blocker with preclinical activity in non-small-cell lung cancer (NSCLC) with EGFR mutations. We aimed to assess the efficacy of afatinib in patients with lung adenocarcinoma and EGFR mutations.
  
  
  METHODS
  In this phase 2 study, we enrolled patients from 30 centres in Taiwan and the USA with lung adenocarcinoma (stage IIIb with pleural effusion or stage IV) with EGFR mutations, who had no more than one previous chemotherapy regimen for advanced disease, an Eastern Cooperative Oncology Group performance status of 0-2, and no previous treatment with EGFR tyrosine-kinase inhibitors. We tested two afatinib starting doses: 50 mg daily and subsequently 40 mg daily, introduced to establish whether tolerability could be improved with retention of anti-tumour activity. The primary endpoint was the proportion of patients with a confirmed objective response (complete response or partial response), on the basis of Response Evaluation Criteria in Solid Tumors 1.0 (independent review). This study is registered with ClinicalTrials.gov, number NCT00525148.
  
  
  RESULTS
  129 patients were treated with afatinib, 99 with a starting dose of 50 mg and 30 with a starting dose of 40 mg. 79 (61%) of 129 patients had an objective response (two complete responses, 77 partial responses). 70 (66%) of the 106 patients with the two common activating EGFR mutations (deletion 19 or L858R) had an objective response, as did nine (39%) of 23 patients with less common mutations. Similar proportions of patients had an objective response when analysed by starting dose (18 [60%] of 30 patients at 40 mg vs 61 [62%] of 99 patients at 50 mg). Of the two most common adverse events (diarrhoea and rash or acne), grade 3 events were more common in patients receiving a 50 mg starting dose (22 [22%] of 99 patients for diarrhoea and 28 [28%] of 99 patients for rash or acne) than they were in those receiving a 40 mg starting dose (two [7%] of 30 patients for both diarrhoea and rash or acne); possibly treatment-related serious adverse events were also less common in patients receiving a 40 mg starting dose (two of 30 patients vs 14 of 99 patients). We recorded one possibly drug-related death (interstitial lung disease).
  
  
  CONCLUSIONS
  Afatinib shows activity in the treatment of patients with advanced lung adenocarcinoma with EGFR mutations, especially in patients with deletion 19 or L858R mutations. The efficacy of afatinib 40 mg should be compared with chemotherapy or other EGFR tyrosine-kinase inhibitors in EGFR-mutation-positive NSCLC.
  
  
  BACKGROUND
  Boehringer Ingelheim Inc.
authors.affiliation: Graduate Institute of Oncology and Cancer Research Centre, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: James Chih-Hsin
authors.initials: JC
authors.lastname: Yang
authors.forename: Jin-Yuan
authors.initials: JY
authors.lastname: Shih
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.forename: Te-Chun
authors.initials: TC
authors.lastname: Hsia
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Tsai
authors.forename: Sai-Hong Ignatius
authors.initials: SH
authors.lastname: Ou
authors.forename: Chung-Jen
authors.initials: CJ
authors.lastname: Yu
authors.forename: Gee-Chen
authors.initials: GC
authors.lastname: Chang
authors.forename: Ching-Liang
authors.initials: CL
authors.lastname: Ho
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Arkadiusz Z
authors.initials: AZ
authors.lastname: Dudek
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: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077716:Afatinib; D066246:ErbB Receptors