Cancer Therapy: Clinical 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 ≥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 andmedian 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. (Clin Cancer Res 2009;15(18):5895–901) The annual mortality rate of hepatocellular carcinoma (HCC) is similar to its annual incidence, indicating a poor prognosis (1). The increasing incidence in the United States can be largely attributed to the increase in hepatitis C (HCV; ref. 1). Most patients with HCC have advanced disease at the time of diagnosis with no satisfactory treatment available (2–10). The current standard of care in advanced HCC is sorafenib, an agent recently approved by the Food and Drug Administration based on a survival advantage versus placebo (11). Potential targets for anticancer therapy in HCC include the epidermal growth factor receptor (EGFR) and HER2/NEU (EGFR2 or ERBB2), both overexpressed in HCC and directly implicated in hepatocarcinogenesis. Previous investigations indicate that EGFR is actively expressed in human HCC cells (in up to 85%), and epidermal growth factor is required for the growth of those cells (12). A recent study showed that the EGFR inhibitor gefitinib inhibits the growth of orthotopically implanted HCC tumor in the liver of mice (13). In human studies, EGFR inhibition was found to increase survival in a number of malignancies, although levels of EGFR expression did not correlate with outcome (14–16). The literature contains conflicting data regarding HER2/NEU expression and its significance in HCC. Several studies have shown that HER2/NEU is rarely overexpressed in HCC and may not play a role in this Authors' Affiliations: The Ohio State University Comprehensive Cancer Center, Department of Pharmacology, and Center of Biostatistics, The Ohio State University, Columbus, Ohio; Genomic Medicine Institute and Taussig Cancer Institute, Cleveland Clinic and Department of Genetics and CASE Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; University of North Carolina, Chapel Hill, North Carolina; Virginia Commonwealth University, Richmond, Virginia; University of Michigan, Ann Arbor, Michigan; and Cancer Therapy Evaluation Program/National Cancer Institute, Bethesda, Maryland Received 2/23/09; revised 7/7/09; accepted 7/18/09; publishedOnlineFirst 9/8/09. Grant support: U01-CA76576, NO1-CM62207, and TRF SAIC BOA 24XS106. The costs of publication of this article were defrayed in part by the payment of page charges. This articlemust therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: T. Bekaii-Saab and J. Markowitz contributed equally to this work. Requests for reprints: Tanios Bekaii-Saab, The Ohio State University Comprehensive Cancer Center, B421 Starling Loving Hall, 320 West 10th Avenue, Columbus, OH, 43210. Phone: 614-293-9863; Fax: 614-293-7529; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0465 5895 Clin Cancer Res 2009;15(18) September 15, 2009 www.aacrjournals.org Research. on April 14, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst September 8, 2009; DOI: 10.1158/1078-0432.CCR-09-0465