Phase I study of erlotinib and metformin in metastatic triple negative breast cancer

Abstract Purpose Epidermal growth factor receptor (EGFR) is frequently overexpressed in metastatic triple negative breast cancer (mTNBC). One strategy for overcoming resistance to EGFR inhibition is concomitant inhibition of downstream signaling. The antidiabetic drug metformin inhibits both MAPK and PI3K/mTOR pathway signaling. We evaluated the combination of erlotinib and metformin in a phase 1 study of patients with mTNBC. Patients and Methods Patients with mTNBC who had received at least one prior line of therapy for metastatic disease were eligible. Erlotinib dose was fixed at 150 mg daily. Metformin dose escalation was planned according to a 3+3 design. Dose-limiting toxicities (DLT) were assessed during the first five weeks of therapy. The primary objective was to determine the maximum tolerated dose (MTD) of metformin with fixed dose erlotinib. Secondary endpoints were response rate, stable disease rate, and progression free survival (PFS). Results Eight patients were enrolled. Median number of prior therapies for metastatic disease was 2.5 (range 1-6). No DLT events were reported during the DLT assessment period. A majority of adverse events were grade 1/2. Grade 3 diarrhea despite maximum supportive care required dose reduction of metformin in one patient. Grade 3 rash led to study withdrawal in one patient. No grade 4 AEs were reported. The best observed response was stable disease in two patients (25%). Median PFS was 60 days (range 36-61). Conclusion Erlotinib and metformin were well tolerated in a population of pre-treated mTNBC patients but did not demonstrate efficacy in this population.