Abstract P6-18-35: A phase 1 study of erlotinib and metformin in advanced triple negative breast cancer
Authors: Fenn KM , Maurer MA , Lee SM , Crew KD , Trivedi MS , Accordino MK , Hershman DL , Kalinsky K 
Published: May 2019

Abstract
Background: The epidermal growth factor receptor (EGFR) is frequently overexpressed in triple negative breast cancer (TNBC). However, EGFR inhibitors have not shown efficacy as monotherapy in TNBC. One strategy for overcoming resistance to EGFR inhibition is concomitant inhibition of downstream signaling. Metformin is a LKB1-dependent AMPK activator that inhibits both MAPK and AKT signaling. The combination of the EGFR inhibitor erlotinib and metformin synergistically induces apoptosis in TNBC cell lines and decreases tumor burden in PTEN-null EGFR-amplified mouse xenograft models. We evaluated the combination of erlotinib and metformin in a phase 1 study of patients with advanced TNBC.
Methods: Patients with advanced TNBC who had received at least one prior line of therapy for metastatic disease were eligible. Erlotinib dose was fixed at 150mg daily. Metformin dose escalation was planned according to a 3+3 design, beginning at 850mg BID and escalating to 850mg TID. One de-escalation to 500mg BID was allowed. Dose-limiting toxicities (DLT) were assessed during the first five weeks of therapy. The primary objectives were to determine the maximum tolerated dose (MTD) of metformin with fixed dose erlotinib and to determine the potential for clinical benefit. Secondary endpoints were response rate, stable disease rate, and progression free survival. Pre- and on-treatment skin biopsies were collected to determine the effect of the study drugs on their respective cell signaling targets, particularly EGFR, AMPK, and mTOR.
Results: Between March 2013 and May 2015, nine patients were screened and eight were enrolled. Median age was 48 years (range 37-79). Median number of prior therapies for metastatic disease was 2.5 (range 1-6). No DLT events were reported in either of the dose escalation cohorts during the DLT assessment period. AEs occurring in three or more patients and all grade III AEs are reported in Table 1. Grade III diarrhea despite maximum supportive care required dose reduction of metformin from 850mg TID to 850mg BID in one patient. Grade III rash led to study withdrawal in one patient. No grade IV AEs were reported. Per RECIST v1.1, the best observed response was stable disease in two patients (25%). Median time on study was 2.0 months (range 1.2-3.0). Skin biopsy marker assessment is ongoing and will be reported.
Conclusion: The combination of erlotinib and metformin was generally well tolerated in a population of pre-treated metastatic TNBC patients. No unexpected toxicities occurred. While no responses were achieved, stable disease was observed in patients who received this non-chemotherapy combination.
Adverse EventsEventMetformin 850mg BID n=3Metformin 850mg TID n=5All patients n=8 Number of patients (percent) All gradesGrade IIIAll gradesGrade IIIAll gradesGrade IIIRash3 (100)1 (33.3)5 (100)08 (100)1 (12.5)Diarrhea3 (100)05 (100)2 (40.0)8 (100)2 (25.0)Weight loss1 (33.3)05 (100)06 (75.0)0Dry skin1 (33.3)05 (100)06 (75.0)0Nausea2 (66.7)03 (60.0)05 (62.5)0Vomiting1 (33.3)03 (60.0)04 (50.0)0Dry mouth1 (33.3)03 (60.0)04 (50.0)0Dysgeusia1 (33.3)02 (40.0)03 (37.5)0Increased creatinine2 (66.7)01 (20.0)03 (37.5)0Fatigue1 (33.3)02 (40.0)03 (37.5)0Anorexia1 (33.3)02 (40.0)03 (37.5)0Hyponatremia1 (33.3)1 (33.3)001 (12.5)1 (12.5)
Citation Format: Fenn KM, Maurer MA, Lee SM, Crew KD, Trivedi MS, Accordino MK, Hershman DL, Kalinsky K. A phase 1 study of erlotinib and metformin in advanced triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-35.