CHICAGO-An open-label, phase IB study found that the combination of erlotinib (Tarceva), docetaxel(Drug information on docetaxel) (Taxotere), and capecitabine(Drug information on capecitabine) (Xeloda) is generally well tolerated and shows antitumor activity (ASCO poster 180). Data from a pharmacokinetic analysis indicate that there is no pharmacokinetic interaction between either capecitabine or docetaxel and erlotinib and its metabolite in the treatment of metastatic breast cancer. The study was based on previous work that showed the HER1 epidermal growth factor receptor (EGFR) is expressed in breast tumors, where it is thought to play a role in tumor growth and progression. "Erlotinib is an orally active, potent, selective inhibitor of the HER1/EGFR tyrosine kinase with clinical activity for the treatment of solid tumors," the investigators reported in their poster at ASCO. R. Jones, MD, of the Beatson Oncology Centre in Glasgow, UK, was the lead author. Studies Suggest Benefits Capecitabine has been approved for the treatment of patients with metastatic breast cancer, and the combination of capecitabine and docetaxel has shown significant advantages in progression-free survival and overall survival rates. Results of phase II monotherapy studies of erlotinib 150 mg/d in patients with advanced non-small-cell lung, ovarian, and head and neck cancer suggest a survival benefit compared with current treatment options. Combining erlotinib with capecitabine and docetaxel may improve survival in patients with metastatic breast cancer. According to the investigators, new therapies are urgently required to prolong progression-free and overall survival rates and to improve quality of life in patients with metastatic breast cancer. "Preclinical data suggest that the combination of capecitabine and erlotinib results in additive efficacy. Erlotinib has a favorable toxicity profile and therefore we conducted a trial to evaluate treatment with erlotinib plus capecitabine and docetaxel in patients with locally advanced or metastatic breast cancer," the investigators explained in their poster. Determining Dose Levels The primary objective of the study was to determine the maximum tolerated dose of erlotinib in combination with capecitabine and docetaxel in patients with locally advanced or metastatic breast cancer. The secondary objectives included the safety and pharmacokinetic profile of the combination regimen and evaluating its effect on response in the same patients. To be eligible for the study, patients must have had histologically confirmed, incurable disease; no prior adjuvant chemotherapy and no more than one regimen of chemotherapy for their disease; and acceptable cardiac, renal, and hepatic function. Twenty-four patients were enrolled, of which 23 were evaluable. Dose levels were selected based on previously published safety and efficacy data for each agent. Patients received medication sequentially (see Table 1), up to six cycles of therapy, with 21 days per cycle. Patients with an objective response or stable disease after six cycles were eligible to receive further treatment until disease progression or unacceptable toxicity. Patient assessments included: tumor response using the standard response evaluation criteria in solid tumors (RECIST); safety data by monitoring adverse events using the National Cancer Institute Common Toxicity Criteria (NCI-CTC version 2.0); and changes in laboratory variables, including ophthalmologic examination. Pharmacokinetic Parameters Pharmacokinetic parameters, including maximum plasma concentration (Cmax), time to reach maximum plasma concentration (Tmax), area under the plasma concentration-time curve (AUC), and apparent half-life (t 1/2), were evaluated for capecitabine and docetaxel alone (day 1), and erlotinib alone (days 21 and 36) or in combination with capecitabine and docetaxel (day 22). When one or more of three patients, or two or more of six patients, in a cohort experienced a dose-limiting toxicity (DLT), the cohort below was increased to 12 patients. The expanded cohort was used to determine the toxicity profile at the maximum tolerated dose. In cohort C, three DLTs were observed (one grade 4 febrile neutropenia, and two events of grade 3 diarrhea) out of six patients. Cohort B was then expanded to 12 patients to confirm the maximum tolerated dose. To date, patients have received up to 10 cycles of treatment. Apart from the DLTs already described above, the most frequent adverse events observed were neutropenia, rash, hyperbilirubinemia, and diarrhea. Antitumor Activity In terms of antitumor activity, four patients in cohort A had partial responses, of which three were confirmed. Two patients in cohort B had an unconfirmed complete response, and five patients had a partial response, one of which was unconfirmed. Four patients in cohort C had a partial response, of which two were confirmed. Furthermore, the analysis concluded that there is no pharmacokinetic interaction between capecitabine or docetaxel and erlotinib and its metabolite. There is no evidence of a causative relationship between erlotinib exposure (Cmax or AUC at cycle 2) and any laboratory abnormality, such as bilirubin and transaminase elevations, occurring within the first three cycles. There is no apparent causative relationship between erlotinib and the most commonly reported adverse events within the first three cycles. "The combination of erlotinib, docetaxel, and capecitabine is generally well tolerated. The recommended phase II dose of erlotinib is 100 mg/d po in combination with oral capecitabine 825 mg/m2 bid and docetaxel 75 mg/m2 IV in this patient population," the investigators concluded in their poster. Based on preliminary analyses of available data, there is no evidence of any appreciable pharmacokinetic interaction between erlotinib, capecitabine, and docetaxel or their metabolites. "Overall, the results of this study are encouraging and further trials should be considered to evaluate this combination therapy in metastatic breast cancer," the investigators stated. Final safety, efficacy, and phamacokinetic data will be presented when the study is completed.