A Multi-Institutional Phase II Study of the Efficacy and Tolerability of Lapatinib in Patients with Advanced Hepatocellular Carcinomas

被引:92
作者
Bekaii-Saab, Tanios [1 ,2 ]
Markowitz, Joseph [1 ]
Prescott, Nichole [4 ,5 ]
Sadee, Wolfgang [2 ]
Heerema, Nyla [1 ]
Wei, Lai [3 ]
Dai, Zunyan [2 ]
Papp, Audrey [2 ]
Campbell, Angela [1 ]
Culler, Kristy [1 ]
Balint, Catherine [1 ]
O'Neil, Bert [8 ]
Lee, Ruey-min [9 ]
Zalupski, Mark [10 ]
Dancey, Janet [11 ]
Chen, Helen [11 ]
Grever, Michael [1 ,2 ]
Eng, Charis [4 ,5 ,6 ,7 ]
Villalona-Calero, Miguel [1 ,2 ]
机构
[1] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA
[2] Ohio State Univ, Dept Pharmacol, Columbus, OH 43210 USA
[3] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA
[4] Cleveland Clin, Genom Med Inst, Cleveland, OH 44106 USA
[5] Cleveland Clin, Taussig Canc Inst, Cleveland, OH 44106 USA
[6] Case Western Reserve Univ, Sch Med, Dept Genet, Cleveland, OH 44106 USA
[7] Case Western Reserve Univ, Sch Med, CASE Comprehens Canc Ctr, Cleveland, OH 44106 USA
[8] Univ N Carolina, Chapel Hill, NC USA
[9] Virginia Commonwealth Univ, Richmond, VA USA
[10] Univ Michigan, Ann Arbor, MI 48109 USA
[11] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA
关键词
GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; PTEN EXPRESSION; CLINICAL-TRIALS; SORAFENIB; ERLOTINIB; ADRIAMYCIN; THERAPY; OVEREXPRESSION; HER-2/NEU;
D O I
10.1158/1078-0432.CCR-09-0465
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 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. (Clin Cancer Res 2009;15(18):5895-901)
引用
收藏
页码:5895 / 5901
页数:7
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