A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas.
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.
Bekaii-Saab
Tanios
T
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA. Tanios.Bekaii-Saab@osumc.edu
Markowitz
Joseph
J
Prescott
Nichole
N
Sadee
Wolfgang
W
Heerema
Nyla
N
Wei
Lai
L
Dai
Zunyan
Z
Papp
Audrey
A
Campbell
Angela
A
Culler
Kristy
K
Balint
Catherine
C
O'Neil
Bert
B
Lee
Ruey-Min
RM
Zalupski
Mark
M
Dancey
Janet
J
Chen
Helen
H
Grever
Michael
M
Eng
Charis
C
Villalona-Calero
Miguel
M
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
D011799:Quinazolines; D000077341:Lapatinib