title: Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors.
abstract: OBJECTIVE
  Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy.
  
  
  METHODS
  Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state.
  
  
  RESULTS
  Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non-small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting > or = 6 months.
  
  
  CONCLUSIONS
  Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.
authors.affiliation: Drug Development Unit, the Royal Marsden National Health Service Foundation Trust, and The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Yap
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal
authors.forename: Jan
authors.initials: J
authors.lastname: Adam
authors.forename: Peter
authors.initials: P
authors.lastname: Stephens
authors.forename: James
authors.initials: J
authors.lastname: Spicer
authors.forename: Heather
authors.initials: H
authors.lastname: Shaw
authors.forename: Jooern
authors.initials: J
authors.lastname: Ang
authors.forename: Graham
authors.initials: G
authors.lastname: Temple
authors.forename: Susan
authors.initials: S
authors.lastname: Bell
authors.forename: Mehdi
authors.initials: M
authors.lastname: Shahidi
authors.forename: Martina
authors.initials: M
authors.lastname: Uttenreuther-Fischer
authors.forename: Peter
authors.initials: P
authors.lastname: Stopfer
authors.forename: Andrew
authors.initials: A
authors.lastname: Futreal
authors.forename: Hilary
authors.initials: H
authors.lastname: Calvert
authors.forename: Johann S
authors.initials: JS
authors.lastname: de Bono
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
mesh_terms: D000328:Adult; D000077716:Afatinib; D000368:Aged; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage* / Q000009:adverse effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000077716:Afatinib; D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human