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.
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 progression 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 enumeration 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 grades/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 foretinib 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).
Division of Medical Oncology, Queen Elizabeth II Health Sciences Centre, Room 457A, 1276 South Park Street, Bethune Building, Halifax, NS, B3H 2Y9, Canada. daniel.rayson@nshealth.ca.
Daniel
D
Rayson
Tom Baker Cancer Centre, Calgary, AB, Canada.
Sasha
S
Lupichuk
London Regional Cancer Program, London, ON, UK.
Kylea
K
Potvin
Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Susan
S
Dent
BCCA-Vancouver Cancer Centre, Vancouver, BC, Canada.
Tamara
T
Shenkier
Juravinski Cancer Centre at Hamilton Health Sciences, Hamilton, ON, Canada.
Sukhbinder
S
Dhesy-Thind
BCCA-Cancer Centre for the Southern Interior, Kelowna, BC, Canada.
Susan L
SL
Ellard
Hopital Charles LeMoyne, Greenfield Park, QC, Canada.
Catherine
C
Prady
Allan Blair Cancer Centre, Regina, SK, Canada.
Muhammad
M
Salim
Queen's University, Kingston General Hospital, Kingston, ON, Canada.
Patricia
P
Farmer
Henry Ford Health System, Detroit, MI, USA.
Ghasson
G
Allo
University Health Network-OCI/Princess Margaret Hospital, Toronto, ON, Canada.
Ming-Sound
MS
Tsao
London Regional Cancer Program, London, ON, UK.
Alison
A
Allan
University Health Network-OCI/Princess Margaret Hospital, Toronto, ON, Canada.
Olga
O
Ludkovski
Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, CA, Canada.
Maria
M
Bonomi
Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, CA, Canada.
Dongsheng
D
Tu
Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, CA, Canada.
Linda
L
Hagerman
Ottawa Hospital Research Institute, Ottawa, ON, Canada.
Rachel
R
Goodwin
Canadian Cancer Trials Group (CCTG), Queen's University, Kingston, CA, Canada.
Elizabeth
E
Eisenhauer
University Health Network-OCI/Princess Margaret Hospital, Toronto, ON, Canada.
Penelope
P
Bradbury
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000008:administration & dosage* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002170:Canada; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011804:Quinolines / Q000008:administration & dosage* / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics*; D011980:Receptors, Progesterone / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics
D000813:Anilides; D000970:Antineoplastic Agents; D011804:Quinolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C544831:GSK 1363089; C508053:ERBB2 protein, human
Clinical activity; Foretinib; MET targeting; Triple-negative breast cancer