Phase II study of lapatinib and capecitabine in second-line treatment for metastatic pancreatic cancer.

PURPOSE: Patients with metastatic, gemcitabine-refractory pancreatic cancer typically have poor survival. Erlotinib, a targeted therapy that inhibits epidermal growth factor receptor (EGFR) activity (overexpressed in 40-60 % of pancreatic cancers), was FDA approved for the treatment of patients with advanced pancreatic cancer. Human epidermal growth factor receptor 2 (HER-2), another member of the ErbB family of growth factor receptor tyrosine kinases, has also been a therapeutic target of interest in pancreatic cancer; HER-2 overexpression is found in 20 % of pancreatic cancers. Lapatinib is a tyrosine kinase inhibitor that binds to both EGFR and HER-2. We conducted a single-arm phase II study to evaluate the combination of lapatinib and capecitabine in the second-line treatment of metastatic, gemcitabine-refractory pancreatic cancer.

METHODS: Seventeen patients with metastatic, unresectable pancreatic cancer whose disease had progressed on first-line gemcitabine-based therapy were selected for this study. Patients were required to have an adequate performance status (ECOG 0-2) and normal hepatic and renal function prior to being enrolled. Patients received lapatinib 1250 mg PO daily 1 h before or after meals, and capecitabine 1000 mg/m(2) PO twice daily on days 1-14 of the 21-day cycle. The primary endpoint was median overall survival (OS), and the secondary endpoints were objective response rate, progression-free survival (PFS) and the safety profile of the combination therapy. Clinical toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0. Radiographic response was evaluated by RECIST criteria.

RESULTS: Clinically, six of the 17 patients treated had disease progression (PD) after two cycles, six of 17 patients had stable disease (SD) and received more than four cycles (SD, range 4-22 cycles). For all patients, median PFS was 2.6 months (95 % CI 1.3-3.8) and median OS was 5.2 months (95 % CI 3.4-9). Treatment-related toxicities were limited to three (17 %) patients developing grade 3 adverse events such as nausea, vomiting, diarrhea and fatigue. When stratifying patients by treatment response, we found a statistically significant difference in median PFS and OS: median PFS was 1.4 months (95 % CI 1.0-1.8) in the PD group versus 4.0 months (95 % CI 1.8-6.3) in the SD group (P value = 0.001). Median OS was 2.9 months (95 % CI 0-7.3) in the PD group versus 8.3 months (95 % CI 0-21.2) in the SD group (P value = 0.023).

CONCLUSIONS: The combination of lapatinib and capecitabine is a tolerable regimen for patients with gemcitabine-refractory pancreatic cancer; however, this observation is based on the small number of patients enrolled in the trial. A subset of the enrolled patients had clinical benefit from treatment. Predictive biomarkers that allow selection of patients that will respond to this regimen should be further investigated.