Abstract LB-306: A Phase II study of the efficacy and tolerability of Lapatinib in patients with advanced hepatocellular carcinomas.

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Abstract Background: Hepatocellular carcinoma (HCC) is on the rise in the US and the rest of the world. HCC responds poorly to systemic chemotherapy. EGFR 1 and 2 are both overexpressed in HCC. We reported that HER2/NEU (EGFR2) somatic mutations in HCC may predict response to EGFR-targeted agents. Lapatinib is an oral inhibitor of EGFR and HER2/NEU with evidence of activity in a number of tumor types. This trial was designed to determine the efficacy of lapatinib in HCC patients. Methods: A Fleming phase II design resulting in a single stage of 25 patients was utilized with a 90% power to detect a true response rate >20%. Adequate hematologic, renal and hepatic function were required. Eligible pts included Child’s A or favorable B group and ECOG PS of 0-1. One prior treatment regimen was allowed. Lapatinib dose was 1,500 mg/d orally without interruption. One cycle was 28 days and radiological assessment was done every 8 weeks. Tumor and blood specimens were analyzed for expression of EGFR/EGFRP, HER2/NEU/CEP17, status of downstream signal pathway molecules (including PTEN, P-Akt, cyclin D, p27 and p70S6K, p53 and others) and correlated to response. Results: 26 pts with HCC were accrued with the following characteristics: Males (17 pts), ECOG PS 0/1 (12/14 pts), median age of 58 yrs (range 29-83). A median of 2 cycles were administered (range 1-12). The most common toxicities were: diarrhea (69%) and nausea ( 54% ). Grade 3/4 toxicities were noted in 3 patients including diarrhea, rash and acute renal failure. There was no evidence of cardiac dysfunction. In 25 patients with HCC, no objective responses were observed. However, 8 (31%) patients had stable disease (SD) including 2 (7.6%) with SD lasting > 6 months. Survival data is being analyzed. The overall goal of correlative studies underway is to attempt to understand the molecular biology of this tumor and guide directed therapy for subsets of patients with hepatocellular carcinoma that may benefit from EGFR inhibition. Tissue and blood specimens were available on >95% of patients. No mutations in EGFR (exons 18-21) were found, consistent with our previous findings, although three single nucleotide polymorphisms (SNP) were found that correlate with SNPs in the NCBI SNP database. We did not find evidence of HER2/NEU somatic mutations. HER2/NEU copy number may be elevated in one patient with stable disease using FISH and is currently being confirmed by IHC staining. Studies are currently underway to assess the expression of EGFR/EGFR-P protein expression and the genes that regulate the cell cycle and apoptosis, which are either downstream of or cross-talk with the EGFR signaling pathway. KRAS mutational status is also underway as it is hypothesized that KRAS mutations will correlate with resistance to EGFR directed-treatment. Conclusions: Lapatinib is well-tolerated and may have some activity, mainly stabilization of disease, in HCC. Source of support: NCI-NO1-CM-62207.