HER2/neu May Not Be an Interesting Target in Biliary Cancers: Results of an Early Phase II Study with Lapatinib

Purpose: Biliary cancers (BCs) respond poorly to chemotherapy. Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and HER2/neu, both implicated in cholan-giocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in BC. Methods: A Fleming phase II design with a single stage of 25 patients 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 and EGFR. Results: Nine patients with BC enrolled in this study. The study was terminated early because of futility. The most common toxicities were nausea and fatigue (78%) and diarrhea (67%). No responses were observed. Of 8 evaluable patients, 4 (50%) had stable disease. Median progression-free survival was 2.6 months (95% CI 1.6-4.4) and median overall survival was 5.1 months (95% CI 2.0-16.5). No somatic mutations in EGFR (exons 18-21) or HER2/neu were found. We did not find evidence of HER2 overexpression. Conclusions: Lapatinib is well tolerated but failed to show activity as a single agent in treating patients with BC. Despite the small patient population, our study is consistent with previous findings, suggesting that targeting HER2/neu does not appear to be an effective therapy for BC.