CLINICAL TRIAL Canadian Cancer Trials Group IND197: a phase II study of foretinib in patients with estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2-negative recurrent or metastatic breast cancer Daniel Rayson 1 • Sasha Lupichuk 2 • Kylea Potvin 3 • Susan Dent 4 • Tamara Shenkier 5 • Sukhbinder Dhesy-Thind 6 • Susan L. Ellard 7 • Catherine Prady 8 • Muhammad Salim 9 • Patricia Farmer 10 • Ghasson Allo 11 • Ming-Sound Tsao 12 • Alison Allan 3 • Olga Ludkovski 12 • Maria Bonomi 13 • Dongsheng Tu 13 • Linda Hagerman 13 • Rachel Goodwin 4 • Elizabeth Eisenhauer 13 • Penelope Bradbury 12 Received: 15 April 2016 / Accepted: 19 April 2016 Ó Springer Science+Business Media New York 2016 Abstract In murine models, overexpression of the MET receptor transgene induces tumors with human basal gene expression characteristics supporting MET inhibition as a treatment strategy for triple-negative breast cancer (TNBC). Foretinib is an oral multi-kinase inhibitor of MET, RON, AXL, TIE-2, and VEGF receptors with anti- tumor activity in advanced HCC and papillary renal cell cancer. Patients with centrally reviewed primary TNBC and 0–1 prior regimens for metastatic disease received daily foretinib 60 mg po in a 2-stage single-arm trial. Primary endpoints were objective response and early pro- gression rates per RECIST 1.1. In stage 2, correlative studies of MET, PTEN, EGFR, and p53 on archival and fresh tumor specimens were performed along with enu- meration of CTCs. 45 patients were enrolled with 37 patients having response evaluable and centrally confirmed primary TNBC (cTNBC). There were 2 partial responses (ITT 4.7 % response evaluable cTNBC 5.4 %) with a median duration of 4.4 months (range 3.7–5 m) and 15 patients had stable disease (ITT 33 %, response evaluable cTNBC 40.5 %) with a median duration of 5.4 months (range 2.3–9.7 m). The most common toxicities (all gra- des/grade 3) were nausea (64/4 %), fatigue (60/4 %), hypertension (58/49 %), and diarrhea (40/7 %). Six serious adverse events were considered possibly related to fore- tinib and 4 patients went off study due to adverse events. There was no correlation between MET positivity and response nor between response and PTEN, EGFR, p53, or MET expression in CTCs. Although CCTG IND 197 did not meet its primary endpoint, the observation of a clinical benefit rate of 46 % in this cTNBC population suggests that foretinib may have clinical activity as a single, non- cytotoxic agent in TNBC (ClinicalTrials.gov number, NCT01147484). Keywords Triple-negative breast cancer Á Foretinib Á MET targeting Á Clinical activity & Daniel Rayson daniel.rayson@nshealth.ca 1 Division of Medical Oncology, Queen Elizabeth II Health Sciences Centre, Room 457A, 1276 South Park Street, Bethune Building, Halifax, NS B3H 2Y9, Canada 2 Tom Baker Cancer Centre, Calgary, AB, Canada 3 London Regional Cancer Program, London, ON, UK 4 Ottawa Hospital Research Institute, Ottawa, ON, Canada 5 BCCA-Vancouver Cancer Centre, Vancouver, BC, Canada 6 Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada 7 BCCA-Cancer Centre for the Southern Interior, Kelowna, BC, Canada 8 Hopital Charles LeMoyne, Greenfield Park, QC, Canada 9 Allan Blair Cancer Centre, Regina, SK, Canada 10 Queen’s University, Kingston General Hospital, Kingston, ON, Canada 11 Henry Ford Health System, Detroit, MI, USA 12 University Health Network-OCI/Princess Margaret Hospital, Toronto, ON, Canada 13 Canadian Cancer Trials Group (CCTG), Queen’s University, Kingston, CA, Canada 123 Breast Cancer Res Treat DOI 10.1007/s10549-016-3812-1