title: A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC) is on the rise worldwide. HCC responds poorly to chemotherapy. Lapatinib is an inhibitor of epidermal growth factor receptor and HER2/NEU both implicated in hepatocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in HCC.
  
  
  METHODS
  A Fleming phase II design with a single stage of 25 patients with a 90% power to exclude a true response rate of <10% and detect a true response rate of > or =30% was used. The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/NEU/CEP17 and status of downstream signal pathway proteins.
  
  
  RESULTS
  Twenty-six patients with HCC enrolled on this study. Nineteen percent had one prior therapy. Most common toxicities were diarrhea (73%), nausea (54%), and rash (42%). No objective responses were observed. Ten (40%) patients had stable disease as their best response including six (23%) with stable disease lasting >120 days. Median progression-free survival was 1.9 months and median overall survival was 12.6 months. Patients who developed a rash had a borderline statistically significant longer survival. Tissue and blood specimens were available on >90% of patients. No somatic mutations in EGFR (exons 18-21) were found. In contrast to our previous findings, we did not find evidence of HER2/NEU somatic mutations. PTEN, P-AKT, and P70S6K expression did not correlate with survival.
  
  
  CONCLUSIONS
  Lapatinib is well-tolerated but seems to benefit only a subgroup of patients for whom predictive molecular or clinical characteristics are not yet fully defined.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA. Tanios.Bekaii-Saab@osumc.edu
authors.forename: Tanios
authors.initials: T
authors.lastname: Bekaii-Saab
authors.forename: Joseph
authors.initials: J
authors.lastname: Markowitz
authors.forename: Nichole
authors.initials: N
authors.lastname: Prescott
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sadee
authors.forename: Nyla
authors.initials: N
authors.lastname: Heerema
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.forename: Zunyan
authors.initials: Z
authors.lastname: Dai
authors.forename: Audrey
authors.initials: A
authors.lastname: Papp
authors.forename: Angela
authors.initials: A
authors.lastname: Campbell
authors.forename: Kristy
authors.initials: K
authors.lastname: Culler
authors.forename: Catherine
authors.initials: C
authors.lastname: Balint
authors.forename: Bert
authors.initials: B
authors.lastname: O'Neil
authors.forename: Ruey-Min
authors.initials: RM
authors.lastname: Lee
authors.forename: Mark
authors.initials: M
authors.lastname: Zalupski
authors.forename: Janet
authors.initials: J
authors.lastname: Dancey
authors.forename: Helen
authors.initials: H
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Grever
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
authors.forename: Miguel
authors.initials: M
authors.lastname: Villalona-Calero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D000077341:Lapatinib; D008113:Liver Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011237:Predictive Value of Tests; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: D011799:Quinazolines; D000077341:Lapatinib