title: Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors.
abstract: BACKGROUND
  To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology.
  
  
  METHODS
  Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or uterine tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1,500 mg PO daily. The planned sample size was 250 patients with HER2 amplified tumors, with the goal of randomizing 100 patients with stable disease (SD) at week 12 to either lapatinib or placebo. Patients responding after 12 weeks continued on lapatinib; those who progressed were discontinued from study. The primary objectives were response rate after 12 weeks and the percentage of patients who remained progression free 12 weeks after randomization to placebo versus lapatinib. Secondary objectives were duration of response and determination of the incidence of HER2 amplification in multiple tumor types.
  
  
  RESULTS
  A total of 141 patients were screened and 32 patients with HER2 amplified tumors were enrolled. At week 12, 1 (3%) patient had a complete response, 9 (28%) had stable disease, 20 (63%) had progressive disease, and 2 (6%) were unknown. Only 7 patients with SD underwent randomization. The low response rate coupled with slow screening and enrollment led to early study closure.
  
  
  CONCLUSIONS
  Basing trial eligibility on the presence of a genetic target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy is associated with modest activity. The target-specific histology-independent randomized discontinuation design still merits consideration for targets clearly implicated in "oncogene addiction".
authors.affiliation: Mount Sinai Medical Center/Tisch Cancer Institute, 1 Gustave L Levy Place, New York, NY 10029, USA. Matthew.galsky@mssm.edu
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Galsky
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: Marcus
authors.initials: M
authors.lastname: Neubauer
authors.forename: Thomas
authors.initials: T
authors.lastname: Anderson
authors.forename: Mark
authors.initials: M
authors.lastname: Fleming
authors.forename: Yasir
authors.initials: Y
authors.lastname: Nagarwala
authors.forename: Janine M
authors.initials: JM
authors.lastname: Mahoney
authors.forename: Dawn
authors.initials: D
authors.lastname: Midwinter
authors.forename: Linda
authors.initials: L
authors.lastname: Vocila
authors.forename: Tal Z
authors.initials: TZ
authors.lastname: Zaks
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018579:Patient Selection; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human