Erlotinib Plus Gemcitabine Compared With Gemcitabine Alone in Patients With Advanced Pancreatic Cancer: A Phase III Trial of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival. RESULTS: A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% CI, 0.69 to 0.99; P = .038, adjusted for stratification factors; median 6.24 months v 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P = .023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; P = .004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2. CONCLUSION: To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.

Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models.

PURPOSE: We looked at the value of three preclinical cancer models, the in vitro human cell line, the human xenograft, and the murine allograft, to examine whether they are reliable in predicting clinical utility. EXPERIMENTAL DESIGN: Thirty-one cytotoxic cancer drugs were selected. Literature was searched for drug activity in Phase II trials, human xenograft, and mouse allografts in breast, non-small cell lung, ovary, and colon cancers. Data from the National Cancer Institute Human Tumor Cell Line Screen were used to calculate drug in vitro preclinical activity for each cancer type. Phase II activity versus preclinical activity scatter plot and correlation analysis was conducted for each model, by tumor type (disease-oriented approach), using one tumor type as a predictor of overall activity in the other three tumor types combined (compound-oriented approach) and for all four tumor types together. RESULTS: The in vitro cell line model was predictive for non-small cell lung cancer under the disease-oriented approach, for breast and ovarian cancers under the compound-oriented approach, and for all four tumor types together. The mouse allograft model was not predictive. The human xenograft model was not predictive for breast or colon cancers, but was predictive for non-small cell lung and ovarian cancers when panels of xenografts were used. CONCLUSIONS: These results suggest that under the right framework and when panels are used, the in vitro cell line and human xenograft models may be useful in predicting the Phase II clinical trial performance of cancer drugs. Murine allograft models, as used in this analysis, appear of limited utility.

Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: Patients with advanced pancreatic cancer have a poor prognosis and there have been no improvements in survival since the introduction of gemcitabine in 1996. Pancreatic tumors often overexpress human epidermal growth factor receptor type 1 (HER1/EGFR) and this is associated with a worse prognosis. We studied the effects of adding the HER1/EGFR-targeted agent erlotinib to gemcitabine in patients with unresectable, locally advanced, or metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomly assigned 1:1 to receive standard gemcitabine plus erlotinib (100 or 150 mg/d orally) or gemcitabine plus placebo in a double-blind, international phase III trial. The primary end point was overall survival. RESULTS: A total of 569 patients were randomly assigned. Overall survival based on an intent-to-treat analysis was significantly prolonged on the erlotinib/gemcitabine arm with a hazard ratio (HR) of 0.82 (95% CI, 0.69 to 0.99; P = .038, adjusted for stratification factors; median 6.24 months v 5.91 months). One-year survival was also greater with erlotinib plus gemcitabine (23% v 17%; P = .023). Progression-free survival was significantly longer with erlotinib plus gemcitabine with an estimated HR of 0.77 (95% CI, 0.64 to 0.92; P = .004). Objective response rates were not significantly different between the arms, although more patients on erlotinib had disease stabilization. There was a higher incidence of some adverse events with erlotinib plus gemcitabine, but most were grade 1 or 2. CONCLUSION: To our knowledge, this randomized phase III trial is the first to demonstrate statistically significantly improved survival in advanced pancreatic cancer by adding any agent to gemcitabine. The recommended dose of erlotinib with gemcitabine for this indication is 100 mg/d.