title: Targeting HER2 aberrations as actionable drivers in lung cancers: phase II trial of the pan-HER tyrosine kinase inhibitor dacomitinib in patients with HER2-mutant or amplified tumors.
abstract: BACKGROUND
  HER2 mutations and amplifications have been identified as oncogenic drivers in lung cancers. Dacomitinib, an irreversible inhibitor of HER2, EGFR (HER1), and HER4 tyrosine kinases, has demonstrated activity in cell-line models with HER2 exon 20 insertions or amplifications. Here, we studied dacomitinib in patients with HER2-mutant or amplified lung cancers.
  
  
  METHODS
  As a prespecified cohort of a phase II study, we included patients with stage IIIB/IV lung cancers with HER2 mutations or amplification. We gave oral dacomitinib at 30-45 mg daily in 28-day cycles. End points included partial response rate, overall survival, and toxicity.
  
  
  RESULTS
  We enrolled 30 patients with HER2-mutant (n = 26, all in exon 20 including 25 insertions and 1 missense mutation) or HER2-amplified lung cancers (n = 4). Three of 26 patients with tumors harboring HER2 exon 20 mutations [12%; 95% confidence interval (CI) 2% to 30%] had partial responses lasting 3+, 11, and 14 months. No partial responses occurred in four patients with tumors with HER2 amplifications. The median overall survival was 9 months from the start of dacomitinib (95% CI 7-21 months) for patients with HER2 mutations and ranged from 5 to 22 months with amplifications. Treatment-related toxicities included diarrhea (90%; grade 3/4: 20%/3%), dermatitis (73%; grade 3/4: 3%/0%), and fatigue (57%; grade 3/4: 3%/0%). One patient died on study likely due to an interaction of dacomitinib with mirtazapine.
  
  
  CONCLUSIONS
  Dacomitinib produced objective responses in patients with lung cancers with specific HER2 exon 20 insertions. This observation validates HER2 exon 20 insertions as actionable targets and justifies further study of HER2-targeted agents in specific HER2-driven lung cancers.
  
  
  BACKGROUND
  NCT00818441.
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York krism@mskcc.org.
authors.forename: M G
authors.initials: MG
authors.lastname: Kris
authors.affiliation: Department of Medical Oncology, University of Colorado Denver, Aurora.
authors.forename: D R
authors.initials: DR
authors.lastname: Camidge
authors.affiliation: Lombardi Cancer Center, Georgetown University, Washington, USA.
authors.forename: G
authors.initials: G
authors.lastname: Giaccone
authors.affiliation: Department of Thoracic Oncology, Aichi Cancer Center, Chikusa-ku Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hida
authors.affiliation: Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York.
authors.forename: B T
authors.initials: BT
authors.lastname: Li
authors.affiliation: Pfizer Oncology, Pfizer, Inc., New York.
authors.forename: J
authors.initials: J
authors.lastname: O'Connell
authors.affiliation: Translational Oncology, Pfizer, Inc., Groton, USA.
authors.forename: I
authors.initials: I
authors.lastname: Taylor
authors.affiliation: Pfizer (China) Research & Development Co. Ltd, Pfizer, Inc., Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Molecular Diagnostics Service, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York.
authors.forename: M E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Pfizer Oncology, Pfizer, Inc., San Diego.
authors.forename: Z
authors.initials: Z
authors.lastname: Goldberg
authors.affiliation: Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Jänne
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000284:Administration, Oral; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D052999:Quinazolinones / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015996:Survival Rate
chemical_list: D052999:Quinazolinones; D018719:Erb-b2 Receptor Tyrosine Kinases; C525726:dacomitinib; C508053:ERBB2 protein, human
keywords: HER2 amplification; HER2 mutations; dacomitinib; lung cancers; tyrosine kinase inhibitors