Abstract Background: The EGFR and the PI3K pathways have been implicated in breast cancer's prognosis and mechanisms of resistance to conventional therapies. Preclinical data have shown synergy between EGFR and PI3K/Akt pathway blockade. Therefore, we conducted a phase Ib trial to determine the maximum tolerated dose (MTD) and antitumor activity of Erlotinib, an oral EGFR tyrosine kinase inhibitor, and Everolimus (RAD001), an oral mTOR inhibitor, given daily to patients with metastatic breast cancer.Materials and Methods: This was an open-label, phase I dose-escalation study. Everolimus was started at 2.5 mg/d and Erlotinib was started at 100 mg/d on a 28-day treatment cycle. Doses were escalated over 6 levels (Everolimus 2.5, 5 or 10 mg daily with Erlotinib 100 or 150 mg daily). Treatment was continued until consistent dose-limiting toxicity (DLT) was observed or until progression of disease. All toxicities were documented using the NCI CTC v.3. Disease assessment was done every 2 months after initiation of therapy.Results: A total of 14 patients were enrolled on the first 2 dose levels (Erlotinib 100 mg with Everolimus 2.5 mg [level I] and 5 mg [level II] daily). Eight patients were enrolled on level I and 6 patients were enrolled on level II. The median age of all patients enrolled was 55 years of age, and 92% of them had visceral disease. Half of the patients had ER+ disease, 35% had HER2 + disease, and 15% had triple-negative disease. The median number of previous chemotherapy regimens in the metastatic setting was 4. Two patients on the level II cohort discontinued trial due to grade 3 stomatitis prior to their first disease assessment. Of the remaining 13 patients, 11 progressed at the time of their first disease assessment, and 1 patient on the dose level I cohort had a partial response that lasted for 7 months. The most common toxicities were rash (16%), transaminase elevation (15%), stomatitis (13%), fatigue (7%) and diarrhea (5%). Grade 3 and 4 toxicities were overall uncommon (3.5%), and mostly consisted of stomatitis, transaminase elevation and rash. Stomatitis was the only DLT, and was seen at dose level II. The MTD was determined to be Erlotinib 100 mg and Everolimus 2.5 mg daily.Discussion: In patients with metastatic HER2-negative breast cancer the combination of Erlotinib and Everolimus was overall well tolerated, but clinically ineffective from a tumor activity point of view in this heavily pre-treated patient population. Stomatitis was one of the most common toxicities and also the DLT in the cohort treated with dose level II. In view of the plethora of novel active agents currently in clinical trials in breast cancer, we do not believe the above combination warrants further testing in this disease. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3094.