title: Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a phase II trial in patients with advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have had a significant impact on non-small-cell lung cancer (NSCLC) outcomes, particularly for patients with EGFR mutations. Resistance emerges after 9 to 12 months, primarily mediated by the T790M resistance mutation. We studied neratinib, an irreversible pan-ErbB TKI that may overcome T790M.
  
  
  METHODS
  Patients with advanced NSCLC underwent EGFR sequencing of available tumor tissue at enrollment. Those with > or = 12 weeks of prior TKI therapy were placed in arm A if they were EGFR mutation positive or arm B if they were wild-type. Arm C included TKI-naïve patients with adenocarcinoma and light smoking histories (< or = 20 pack-years). All patients received daily oral neratinib, initially at 320 mg but subsequently reduced to 240 mg because of excessive diarrhea. The primary end point was objective response rate (RR).
  
  
  RESULTS
  One-hundred sixty-seven patients were treated: 91 in arm A, 48 in arm B, and 28 in arm C. Diarrhea was the most common toxicity; grade 3 incidence was 50% at 320 mg but improved to 25% after dose reduction. The RR was 3% in arm A and zero in arms B and C. No patients with known T790M responded. Notably, three of four patients with an exon 18 G719X EGFR mutation had a partial response and the fourth had stable disease lasting 40 weeks.
  
  
  CONCLUSIONS
  Neratinib had low activity in patients with prior benefit from TKIs and in TKI-naïve patients, potentially because of insufficient bioavailability from diarrhea-imposed dose limitation. Responses were seen in patients with the rare G719X EGFR mutation, highlighting the importance of obtaining comprehensive genetic information on trials of targeted agents.
authors.affiliation: Massachusetts General Hospital Cancer Center and Dana-Farber Cancer Center, Harvard Medical School, Boston, MA 02114, USA. LVSequist@partners.org
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lynch
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.forename: Kwok K
authors.initials: KK
authors.lastname: Wong
authors.forename: Barbara
authors.initials: B
authors.lastname: Gitlitz
authors.forename: Keith
authors.initials: K
authors.lastname: Eaton
authors.forename: Charles
authors.initials: C
authors.lastname: Zacharchuk
authors.forename: Amy
authors.initials: A
authors.lastname: Freyman
authors.forename: Christine
authors.initials: C
authors.lastname: Powell
authors.forename: Revathi
authors.initials: R
authors.lastname: Ananthakrishnan
authors.forename: Susan
authors.initials: S
authors.lastname: Quinn
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D006801:Humans; D007390:International Agencies; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011446:Prospective Studies; D011804:Quinolines / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D015996:Survival Rate; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D066246:ErbB Receptors; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C487932:neratinib