Foretinib (GSK1363089)

Foretinib (GSK1363089) is a novel, potent, small-molecule inhibitor of member of the vascular endothelial growth factor (VEGF)and hepatocyte growth factor (HGF) receptor tyrosine kinase families [1].

Foretinib inhibits Met, Ron, KDR, Flt-1, Flt-4, KIT, Flt-3, Platelet-derived growth factor receptor α, Platelet-derived growth factor receptor β and Tie-2 with IC50 values of 0.4, 3, 0.86, 6.8, 2.8, 6.7, 3.6, 3.6, 9.6 and 1.1 nmol/L, respectively. Foretinib has shown to inhibit cellular MET in murine B16F10 melanoma cells and PC-3 prostate cells with IC50 values of 21 and 23 nmol/L [1].

Foretinib revealed to inhibit the migration and invasion induced by HGF in?murine B16F10 melanoma cells. Additionally, Foretinib suppressed the B16F10,?A549 and HT29 tumor cells growth with IC50 values of 40, 29 and 165 nmol/L [1].

References:
[1] Qian F1,?Engst S,?Yamaguchi K,?Yu P,?Won KA,?Mock L,?Lou T,?Tan J,?Li C,?Tam D,?Lougheed J,?Yakes FM,?Bentzien F,?Xu W,?Zaks T,?Wooster R,Greshock J,?Joly AH. Inhibition of tumor cell growth, invasion, and metastasis by EXEL-2880 (XL880, GSK1363089), a novel inhibitor of HGF and VEGF receptor tyrosine kinases. Cancer Res.?2009 Oct 15;69(20):8009-16. doi: 10.1158/0008-5472.CAN-08-4889.

Foretinib (GSK1363089), a multi-kinase inhibitor of MET and VEGFRs, inhibits growth of gastric cancer cell lines by blocking inter-receptor tyrosine kinase networks.[Pubmed:21655918]

Invest New Drugs. 2012 Aug;30(4):1352-60.

To explore the mechanism of action of Foretinib (GSK1363089), an oral multi-kinase inhibitor known to target MET, RON, AXL, and vascular endothelial growth factor receptors (VEGFRs), in gastric cancer, we evaluated the effects of the agent on cell growth and cell signaling in the following panel of gastric cancer cell lines: KATO-III, MKN-1, MKN-7, MKN-45, and MKN-74. Of these, only MKN-45 and KATO-III, which harbor MET and fibroblast growth factor receptor 2 (FGFR2) amplification, respectively, were highly sensitive to foretinib. In MKN-45, 1 muM of foretinib or PHA665752, another MET kinase inhibitor, inhibited phosphorylation of MET and downstream signaling molecules as expected. In KATO-III, however, PHA665752 inhibited phosphorylation of MET independently of downstream molecules. Further, 1 muM of foretinib or PD173074, a selective FGFR kinase inhibitor, inhibited phosphorylation of FGFR2 and downstream molecules, suggesting that foretinib targets FGFR2 in KATO-III. We confirmed this novel activity of foretinib against FGFR2 in OCUM-2M, another FGFR2-amplified gastric cancer cell line. Using a phospho-receptor tyrosine kinase array, we found that foretinib inhibits phosphorylation of epidermal growth factor receptor (EGFR), HER3 and FGFR3 via MET inhibition in MKN-45, and EGFR, HER3 and MET via FGFR2 inhibition in KATO-III. Knockdown of HER3 and FGFR3 in MKN-45 with siRNA resulted in the partial inhibition of cell signaling and cell growth. In conclusion, foretinib appears effective against gastric cancer cells harboring not only MET but also FGFR2 amplification, and exerts its inhibitory effects by blocking inter-RTK signaling networks with MET or FGFR2 at their core.

Phase II trial of single-agent foretinib (GSK1363089) in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.[Pubmed:22918720]

Invest New Drugs. 2013 Apr;31(2):417-24.

BACKGROUND: Foretinib is a small-molecule, oral multikinase inhibitor primarily targeting the mesenchymal epithelial transition (MET) factor receptor, and the vascular endothelial growth factor receptor 2. We conducted a phase II study to evaluate the single-agent activity and tolerability of foretinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). METHODS: An open-label, single-arm, multicenter trial employing a Simon 2-stage design was conducted with a total of 41 patients planned for the study. One or more responses in the first 14 patients were required in order to progress to the second stage. Foretinib was administered as 240 mg orally for 5 consecutive days of a 14-day treatment cycle (5/9 schedule) to patients with recurrent and/or metastatic SCCHN. RESULTS: Fourteen patients were enrolled. The study did not meet criteria for continuing to the second stage. A maximum of 30 cycles were administered (median = 4.0). Fifty percent of patients (7/14) showed stable disease (SD), 43% of patients (6/14) experienced tumor shrinkage and two patients had prolonged disease stabilization for >/=13 months. The most common adverse events were fatigue, constipation and hypertension, which were manageable with additional medication or adjustments to the dosing schedule. CONCLUSION: Foretinib 240 mg on a 5/9 schedule was generally well tolerated. SD was the best-observed outcome, with minor tumor shrinkage detected in nearly half of all patients. The efficacy results, prolonged disease stabilization and tolerable side-effect profile, support further investigation, possibly in combination with other targeted agents or cytotoxic chemotherapy for SCCHN.

Foretinib (GSK1363089), an orally available multikinase inhibitor of c-Met and VEGFR-2, blocks proliferation, induces anoikis, and impairs ovarian cancer metastasis.[Pubmed:21551255]

Clin Cancer Res. 2011 Jun 15;17(12):4042-51.

PURPOSE: Currently, there are no approved targeted therapies for the treatment of ovarian cancer, despite the fact that it is the most lethal gynecological malignancy. One proposed target is c-Met, which has been shown to be an important prognostic indicator in a number of malignancies, including ovarian cancer. The objective of this study was to determine whether an orally available multikinase inhibitor of c-Met and vascular endothelial growth factor receptor-2 (foretinib, GSK1363089) blocks ovarian cancer growth. EXPERIMENTAL DESIGN: The effect of foretinib was tested in a genetic mouse model of endometrioid ovarian cancer, several ovarian cancer cell lines, and an organotypic 3D model of the human omentum. RESULTS: In the genetic mouse model, treatment with foretinib prevented the progression of primary tumors to invasive adenocarcinoma. Invasion through the basement membrane was completely blocked in treated mice, whereas in control mice, invasive tumors entirely replaced the normal ovary. In 2 xenograft mouse models using human ovarian cancer cell lines, the inhibitor reduced overall tumor burden (86% inhibition, P < 0.0001) and metastasis (67% inhibition, P < 0.0001). The mechanism of inhibition by foretinib involved (a) inhibition of c-Met activation and downstream signaling, (b) reduction of ovarian cancer cell adhesion, (c) a block in migration and invasion, (d) reduced proliferation mediated by a G(2)-M cell-cycle arrest, and (e) induction of anoikis. CONCLUSIONS: This study shows that foretinib blocks tumorigenesis and reduces invasive tumor growth in different models of ovarian cancer by affecting several critical tumor functions. We believe that it provides a rationale for the further clinical development of foretinib for the treatment of ovarian cancer.

Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer.[Pubmed:23516391]

PLoS One. 2013;8(3):e54014.

PURPOSE: The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma. PATIENTS AND METHODS: Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha = 0.10 and beta = 0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of >/= 25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity. RESULTS: From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25-88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9-7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET:total MET protein ratio decreased with foretinib treatment. CONCLUSION: These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in unselected patients with metastatic gastric cancer.