title: Phase 2 trial of afatinib, an ErbB family blocker, in solid tumors genetically screened for target activation.
abstract: BACKGROUND
  The efficacy of afatinib, an irreversible ErbB Family Blocker, was evaluated in patients who had 1 of 4 categories of solid tumors with epidermal growth factor receptor/human epidermal growth factor receptor 2 (EGFR/HER2) gene amplification or EGFR-activating mutations.
  
  
  METHODS
  Patients with previously treated but ErbB inhibitor-naive esophagogastric, biliary tract, urothelial tract, or gynecologic cancers (lung cancers were excluded) harboring EGFR/HER2 gene amplification or high polysomy were identified by fluorescence in situ hybridization (FISH). Tumors were also screened for EGFR mutations. The primary endpoint was the objective response rate; secondary endpoints included the clinical benefit rate, pharmacokinetics, and safety.
  
  
  RESULTS
  Of 385 prescreened patients, 38 had FISH-positive tumors (10 with EGFR amplification and 29 with HER2 amplification or high polysomy [1 tumor had EGFR/HER2 high polysomy]; none had EGFR-activating mutations), and 20 patients received treatment with afatinib 50 mg daily. The objective response rate was 5% (1 of 20 patients), and the best objective response included 1 complete response. Eight patients experienced stable disease. The most frequently reported adverse events were diarrhea, rash, and decreased appetite. The trial closed early because of slow recruitment.
  
  
  CONCLUSIONS
  Single-agent afatinib activity was limited, yet encouraging, in selected tumors that were screened prospectively for target activation. The implementation of a biomarker-driven approach using a low-frequency biomarker for patient selection across multiple tumor types can be challenging.
authors.affiliation: Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Eunice L
authors.initials: EL
authors.lastname: Kwak
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: Seth M
authors.initials: SM
authors.lastname: Cohen
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Becerra
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Wen-Fang
authors.initials: WF
authors.lastname: Cheng
authors.forename: Wu-Chou
authors.initials: WC
authors.lastname: Su
authors.forename: Meghan
authors.initials: M
authors.lastname: Robohn
authors.forename: Florence
authors.initials: F
authors.lastname: Le Maulf
authors.forename: Maximilian T
authors.initials: MT
authors.lastname: Lobmeyer
authors.forename: Vikram K
authors.initials: VK
authors.lastname: Chand
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D011446:Prospective Studies; D011799:Quinazolines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000077716:Afatinib; D066246:ErbB Receptors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: EGFR; EGFR-activating mutations; ErbB Family Blocker; HER2; afatinib; epidermal growth factor receptor; gene amplification; human epidermal growth factor receptor 2; solid tumors