Phase 1 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).

The impact of metformin use on the outcomes of locally advanced breast cancer patients receiving neoadjuvant chemotherapy: an open-labelled randomized controlled trial

“…On the other side, the most common adverse events in both groups were blood disorders, GIT side effects, neuropathic events, fatigue, and hair loss. It is worth mentioning that the metformin group experienced worse GIT symptoms in agreement with the literature 7 , 12 , 16 , 59 , 71 . Besides, it was observed a lower incidence of adverse events; arthralgia, myalgia, and bone pain in the metformin group in comparison to the control arm.…”

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…A phase 1 study of the erlotinib and metformin combination was conducted in 8 patients with TNBC [ 649 ]. with a fixed dose of erlotinib of 150 mg daily, a 3 + 3 design of metformin dose escalation was evaluated to determine the dose-limiting toxicities (DLTs).…”

Rewired Cellular Metabolic Profiles in Response to Metformin under Different Oxygen and Nutrient Conditions

“…Findings showing the possible contribution of metformin to reducing the risk of cancer in diabetes patients in 2005 was a prelude to the study of metformin in cancer prevention and treatment [23,27]. A group of clinical trials suggested that metformin showed well-tolerated safe profiles combined with or without traditional or targeted therapies in various cancers [28][29][30][31][32][33][34][35][36]. Clinical applications of metformin in cancer prevention and treatment recently indicated its promising therapeutic effects in colorectal cancer, breast cancer, non-small cell lung cancer, head and neck cancer, and other cancer types, whereas other studies found no beneficial effects in many cancers in non-diabetic patients [37][38][39].…”