A phase II study of lapatinib and capecitabine in first-line treatment of metastatic pancreatic cancer (ICORG 08- 39).

Abstract

315 Background: The combination of capecitabine plus erlotinib in gemcitabine-refractory advanced pancreatic cancer patients has proved beneficial in terms of median survival duration, objective radiological response rate and decrease in tumour marker levels from baseline. In the phase I study of capecitabine and lapatinib carried out in advanced solid tumors, the optimal tolerated regimen was determined to be lapatinib 1,250 mg plus capecitabine 2,000 mg/m2/day. At these dose levels, the combination was well tolerated with few grade 3 toxicities and no grade 4 toxicity. Our preclinical work suggested synergistic activity of capecitabine and lapatinib in pancreatic cancer. We initiated a study of this combination in the first-line therapy of metastatic pancreas cancer. Methods: This was a single-arm multicenter study in patients with chemotherapy-naive metastatic pancreatic cancer. The primary endpoint was overall survival. The study was designed as a Simons two-stage optimal design and was divided into two stages. The first stage was to recruit up to 12 patients. If at least seven of these patients survived for at least six months, then a further 20 patients would be enrolled into the study. If six or fewer of the initial 12 patients met the specified study survival criteria, the study would be halted. Treatment was to be administered until disease progression or until withdrawal from the study due to unacceptable toxicity or other reasons. Clinical and laboratory parameters were assessed to evaluate disease response and toxicity of therapy. The study patients received lapatinib 1,250 mg/day, plus capecitabine 2000 mg/m2/day on days 1-14 every 21 days. Results: Nine patients were enrolled. Seven of these patients did not achieve the interim protocol response requirement of survival for at least 6 months, to allow for the study to continue to the second cohort of patients. Median overall survival from first dose was 4 months. Median time on treatment was 2 months. There were no objective responses. There were no unexpected toxicities. Conclusions: The addition of lapatinib to capecitabine does not improve overall survival in the first-line treatment of advanced pancreatic cancer patients. [Table: see text]

EGFR and HER2 inhibition in pancreatic cancer

“…A phase II trial of lapatinib and gemcitabine revealed that this combination may not be effective in pancreatic cancer [34]. Phase II clinical trials investigating the combination of lapatinib and capecitabine for second-line treatment of metastatic pancreatic cancer are currently on-going (ClinicalTrials.gov, NCT00881621) [35]; however, it has been found that this combination does not improve the overall survival in the first-line treatment of advanced pancreatic cancer patients [36]. Many studies show that EGFR is over-expressed in pancreatic cancer [12], our IHC results are in agreement, whereby EGFR was over-expressed in 44 % of pancreatic tumours with significant correlation to adenocarcinoma tumour type (p0 0.04).…”

Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer

“…Median PFS in our trial was 65 days with an OS of 6.9 month, which is similar to single-agent capecitabine ( Cartwright et al , 2002 ). In a recent study, published in abstract form ( McDermott et al , 2011 ) capecitabine in combination with lapatinib, a small molecule, tyrosine kinase inhibitor of epidermal growth factor receptor and HER2 showed disappointing antitumour activity with an OS of 4 months. Our study showed an median OS of 6.9 months, but taken together capecitabine in combination with anti-HER2 therapy does not seem to significantly improve treatment results in comparison with historical capecitabine monotherapy (mean OS 6.0 months; Cartwright et al , 2002 ).…”

Current Perspectives and Future Trends of Systemic Therapy in Advanced Pancreatic Carcinoma

“…More recently, preliminary results of a single arm phase II trial evaluating the combination of capecitabine and lapatinib as firstline treatment in advanced pancreatic cancer have been presented. Survival of 6 months was not reached in 7 of the 9 enrolled patients, and none of them obtained objective responses (McDermott et al, 2011). This data led to the premature termination of the study.…”