This study demonstrates a good correlation between the degree of inhibition of EGFR in skin and in breast tumors. The lack of significant clinical activity of gefitinib in our study population is not due to lack of receptor inhibition in these tumors but rather to lack of EGFR dependence in the tested population.

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BMS-214662 can be safely delivered in both the 1-hour and 24-hour infusions at biologically active doses, with the preclinical, PK, and pharmacodynamic profiles favoring the 24-hour schedule.

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Purpose: To determine the recommended dose (RD) of EKB-569, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with FOLFIRI chemotherapy in patients with metastatic colorectal cancer (mCRC). Methods: Patients with previously untreated mCRC received FOLFIRI and EKB-569 at doses of 10, 25, 50, and 75 mg/day (EKB started on day 3).Three sequential skin biopsies were obtained in selected patients to assess the pharmacodynamic effects on EGFR signaling of FOLFIRI alone and with EKB-569. Complete pharmacokinetic sampling and tumor biopsies, when feasible, were conducted. Results: Forty-seven patients were enrolled. Dose-limiting toxicities (grade 3 diarrhea or asthenia) were observed in 1/7 patients at 50 mg EKB-569 and in 2/3 at 75 mg. Two additional dose levels (35 mg EKB-569/day and 50 mg EKB-569/day plus modified FOLFIRI) were evaluated. The RD was 25 mg EKB-569/full dose FOLFIRI. Grades 3 to 4 toxicities in >10% of patients were diarrhea (30%), neutropenia (21%), and asthenia (17%). Twenty-one patients had an objective response [48%; 95% confidence interval (95% CI), 32-65%]. The median time to tumor progression was 7.7 months. At the RD, EKB-569 resulted in complete inhibition of phosphorylated EGFR (pEGFR) and downstream receptor signaling in skin and tumor samples. FOLFIRI alone did not affect pEGFR, but inhibited epidermal proliferation and activated mitogenactivated protein kinase (MAPK) and induced p27 expression in the skin. Conclusion: The RD of EKB-569 is 25 mg/day when combined with FOLFIRI and results in complete EGFR inhibition. Chemotherapy alone interferes with pharmacodynamic markers, an observation to be taken into account in future studies of targeted agents with chemotherapy.Colorectal cancer is the second most frequent cause of cancerrelated death worldwide, and patients with metastatic colorectal cancer (mCRC) have a median survival of 8.5 months without chemotherapy (1). Current standard chemotherapy regimens such as FOLFIRI [irinotecan/5-fluorouracil (5-FU)/ leucovorin (LV)] or FOLFOX (oxaliplatin/5-FU/LV) induce response rates of about 50%, prolong progression-free survival to about 8 months, and increase the median overall survival to 20 months (2 -5). Despite these advances, the long-term prognosis of patients with mCRC remains poor, with <5% surviving 5 years. Therefore, new treatment strategies have to be explored to improve the prognosis of this disease.The epidermal growth factor receptor (EGFR) has emerged as an important therapeutic target in a variety of cancers including mCRC. Two different approaches have been clinically developed to target the EGFR: monoclonal antibodies (i.e., cetuximab and panitumumab) directed to the ectodomain of the receptor that have shown meaningful clinical activity in patients with mCRC refractory to standard chemotherapy (6); and small-molecule tyrosine kinase inhibitors (TKI).