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

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).

MET expression and copy number status in clear-cell renal cell carcinoma: prognostic value and potential predictive marker

“…Unfortunately, only 6.7 % of tumors were MET positive by IHC and none of the tumors harbored a MET amplification. Hence, the study was unable to confirm MET status as a predictive biomarker [37]. …”

MET exon 14 juxtamembrane splicing mutations: clinical and therapeutical perspectives for cancer therapy

“…The potential role of MET pathway in tumor progression together with the need of novel therapeutic strategy, led to investigate anti-Met drugs in BC, especially in triple-negative and basal-like subtypes. Although some encouraging results have been obtained in preclinical studies (84), to date no reliable evidence of clinical activity are available for Met inhibitors in BC (85,86).…”

A phase-I study of lapatinib in combination with foretinib, a c-MET, AXL and vascular endothelial growth factor receptor inhibitor, in human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer

“…A phase II study of single-agent foretinib in advanced-stage triple-negative breast cancer (TNBC) has been performed and recently published by our group [29]. A daily dose of foretinib of 60 mg PO was delivered in 45 patients (37 evaluable) with the most common grade-3 or greater toxicities seen as hypertension (49%), diarrhea (7%), nausea (4%) and fatigue (4%).…”