TABLE 4.

Clinical experience with select MET- and HGF-directed targeted therapies

Agent	Target(s)	Patients	Phase	Results
Multikinase MET TKIs
Crizotinib	MET, ALK, ROS1	Crizotinib monotherapy Patients with MET exon 14-altered and MET-amplified NSCLC	I/II	MET exon 14-altered NSCLC: responses observed in 8/18 (44%) patients; MET-Amplified NSCLC: At data cut-off, partial responses were observed in 1/6 (16.7%) patients with a MET/CEP7 ratio >2.2–<5 and in 3/6 (50%) patients with a MET/CEP7 ratio ≥554
Cabozantinib	MET, RET, ROS1, VEGFR2	Erlotinib +/− cabozantinib Patients with non-squamous NSCLC and no EGFR mutation. MET expression assessed by IHC	II	Overall improvement in PFS with cabozantinib but MET IHC score was not predictive.74
MET-Selective TKIs
Tivantinib	MET	Erlotinib +/− tivantinib MARQUEE: Western cohort of patients with non-squamous NSCLC. Not selected based on MET analysis	III	Tivantinib was not associated with any improvement in OS, although PFS was increased in the tivantinib group compared with erlotinib alone.65
		Erlotinib +/− tivantinib ATTENTION: East Asian cohort of patients with non-squamous NSCLC. Not selected based on MET analysis	III	Tivantinib was not associated with any improvement in OS, although PFS was increased in the tivantinib group compared with erlotinib alone. Trial terminated early due to an increase of interstitial lung disease in the tivantinib group.17
Capmatinib	MET	Gefitinib + capmatinib Patients with EGFR-mutated NSCLC, refractory to EGFR-TKIs, and MET amplification or MET overexpression	Ib/II	Partial responses in 15% [6/41] of patients, all with either high MET amplification or MET overexpression15
Anti-MET Monoclonal Antibody
Onartuzumab	MET	Erlotinib +/− onartuzumab Patients with stage IIIB or IV NSCLC. MET expression evaluated at baseline	II	Onartuzumab plus erlotinib did not show an OS advantage, but the MET-positive subgroup did.20
		Erlotinib +/− onartuzumab Patients with previously treated MET-positive stage IIIB or IV NSCLC	III	Stopped for futility as there was no improvement in OS, PFS or ORR.19
Emibetuzumab (LY2875358)	MET	Emibetuzumab monotherapy Patients with locally advanced or metastatic CRPC with bone metastasis, RCC, NSCLC, and HCC. Patients with RCC, NSCLC, and HCC were required to have ≥50% of tumor cells to be ≥2+ for MET expression by IHC	I	In patients with NSCLC, the disease control rate (PR + SD) was 26% (5/19), and the median duration of disease stabilization was 3.9 months (range 2.5–6.4) in NSCLC.18
Anti-HGF Monoclonal Antibody
Ficlatuzumab	HGF	Gefitinib +/− ficlatuzumab Asian patients with stage IIIB or IV pulmonary adenocarcinoma. Patients were not selected based on MET analysis	II	Failed to demonstrate significant improvement in PFS and overall response.21
Rilotumumab	HGF	Erlotinib + rilotumumab Patients with recurrent or progressive NSCLC. Not selected based on MET analysis	II	Ongoing (NCT01233687).

+/−, with or without; ALK, anaplastic lymphoma kinase; ATP, adenosine triphosphate; CEP7, centromeric portion of chromosome 7; CRPC, castration-resistant prostate cancer; EGFR, epidermal growth factor receptor; FLT3, Fms-related tyrosine kinase 3; HCC, hepatocellular carcinoma; HGF, hepatocyte growth factor; IHC, immunohistochemistry; MET, mesenchymal epithelial transition receptor; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma; RET, ret proto-oncogene; RON, Recepteur d’Origine Nantais; SD, stable disease; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor