title: Phase II study of afatinib, an irreversible ErbB family blocker, in demographically and genotypically defined lung adenocarcinoma.
abstract: OBJECTIVE
  Afatinib, an oral irreversible ErbB family blocker, has demonstrated efficacy in patients with epidermal growth factor receptor (EGFR) mutation-positive advanced lung adenocarcinoma. Other potential biomarkers predicting response to afatinib, such as human epidermal growth factor receptor-2 (HER2) mutations and EGFR gene amplification, have not been validated yet. This phase II study investigated whether afatinib conferred clinical benefit in cohorts of adenocarcinoma patients with: (1) EGFR mutation and failing on erlotinib/gefitinib; or (2) increased copy number of EGFR by fluorescence in situ hybridization (FISH); or (3) HER2 mutation.
  
  
  METHODS
  Patients started daily afatinib 50mg monotherapy. Upon disease progression, patients could continue, at the investigator's discretion, afatinib (40mg) with the addition of paclitaxel (80mg/m(2) weekly for 3 weeks/4-week cycle). Endpoints included confirmed objective response (OR), progression-free survival (PFS), disease control, and safety.
  
  
  RESULTS
  Of 41 patients treated (cohort 1: n=32; cohort 2: n=2; cohort 3: n=7), 33 received afatinib monotherapy; eight subsequently received afatinib plus paclitaxel. With afatinib monotherapy, one patient achieved a confirmed OR (partial response [PR]; cohort 2). Two further patients achieved unconfirmed PRs (one each in cohort 1 and cohort 3). Disease control was achieved by 17/32 (53%), 2/2 (100%) and 5/7 (71%) patients in cohorts 1, 2 and 3, respectively. In patients receiving combination therapy (median PFS: 6.7 weeks), one (cohort 3) had confirmed PR of 41.9 weeks. The most common afatinib-related adverse events were diarrhea (95%) and rash/acne (80%).
  
  
  CONCLUSIONS
  Afatinib demonstrated signs of clinical activity in heavily pretreated patients with activating HER2 or EGFR mutations or EGFR FISH-positive tumors.
authors: Medical Oncology, Oncologisch Centrum, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Electronic address: jacques.degreve@uzbrussel.be.
authors: Jacques
authors: J
authors: De Grève
authors: Institut Catala d'Oncologia, Hospital Germans Trias I Pujol, Universitat Autònoma de Barcelona, Departament de Medicina, Badalona, Spain. Electronic address: mmoran@iconcologia.net.
authors: Teresa
authors: T
authors: Moran
authors: Centre Hospitalier Chrétien, Liège, Belgium. Electronic address: marie-pascale.graas@chc.be.
authors: Marie-Pascale
authors: MP
authors: Graas
authors: ZNA Middelheim Hospital, Antwerp, Belgium. Electronic address: danny.galdermans@pandora.be.
authors: Daniella
authors: D
authors: Galdermans
authors: Clinique et Maternité Sainte-Elisabeth, Medical Oncology, Namur, Belgium. Electronic address: peter.vuylsteke@cmsenamur.be.
authors: Peter
authors: P
authors: Vuylsteke
authors: Grand Hospital de Charleroi, Oncologie-Hématologie, Grand Rue 3, Charleroi 6000, Belgium. Electronic address: jean_luc.canon@ghdc.be.
authors: Jean-Luc
authors: JL
authors: Canon
authors: Medical Oncology, Oncologisch Centrum, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Electronic address: denis.schallier@uzbrussel.be.
authors: Denis
authors: D
authors: Schallier
authors: Medical Oncology, Oncologisch Centrum, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Electronic address: lore.decoster@uzbrussel.be.
authors: Lore
authors: L
authors: Decoster
authors: Medical Oncology, Oncologisch Centrum, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Electronic address: Erik.Teugels@uzbrussel.be.
authors: Erik
authors: E
authors: Teugels
authors: Boehringer Ingelheim, Ltd., Bracknell, Berkshire, UK. Electronic address: dan.massey.ext@boehringer-ingelheim.com.
authors: Dan
authors: D
authors: Massey
authors: Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA. Electronic address: vikram.chand@boehringer-ingelheim.com.
authors: Vikram K
authors: VK
authors: Chand
authors: Respiratory Oncology Unit, Department of Pulmonology, University Hospitals KU Leuven, Leuven, Belgium. Electronic address: johan.vansteenkiste@uz.kuleuven.ac.be.
authors: Johan
authors: J
authors: Vansteenkiste
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality; D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D000077716:Afatinib; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human
keywords: Afatinib; EGFR; ErbB; HER2; Non-small cell lung cancer; Paclitaxel