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 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).
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Acknowledgements
Canadian Cancer Trials Group was supported by the Canadian Cancer Society Research Institute to the Canadian Cancer Trials Group (grant #021039).
Funding
PB was funded by a Cancer Care Ontario Research Chair in Experimental Therapeutics. Fellow (PB) was funded by AstraZeneca—CCTG Drug Development Fellowship and the Terry Fox Foundation Training Program in Transdisciplinary Cancer Research in partnership with CIHR, Canadian Cancer Trials Group Development Fellowship
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Dr. Rayson has received honoraria from Ipsen, Amgen, and Novartis and has served as a consultant for Ipsen and Novartis. Dr Lupichuk has served as a consultant for Genomic Health. Dr Potvin has received honoraria from Novartis, Pfizer, and Janssen and has been on a speakers’ bureau for Novartis and Pfizer. Dr Dent has received honoraria from Roche, Amgen, and Astra Zeneca and has served as a consultant for Novartis. Dr Shenkier has received honoraria from Novartis and Roche and has served as a consultant for Novartis, Roche, and Janssen. Dr Ellard owns stock in Pfizer, Abbvie, and GSK and has served as a consultant for GSK. Dr Prady has served as a consultant for AstraZeneca. Dr Allo reports spousal employment with GSK. Dr Goodwin has served as a consultant for Celgene, Novartis, BMS, Amgen, and Ipsen. Drs Dhesy-Thind, Salim, Farmer, Tsao, Allan, Ludkovski, Bonomi, Tu, Eisenhauer, and Bradbury report no potential conflicts of interest as does Ms. Hagerman. GSK provided foretinib and supplied funding to the Canadian Cancer Trials Group to support IND 197 but was not involved with the trial design, data analysis, or reporting of results.
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Rayson, D., Lupichuk, S., Potvin, K. et al. 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. Breast Cancer Res Treat 157, 109–116 (2016). https://doi.org/10.1007/s10549-016-3812-1
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DOI: https://doi.org/10.1007/s10549-016-3812-1