Activation of the MET/HGF pathway has been linked to tumour initiation, metastasis, angiogenesis and resistance to therapeutic agents. Here we present pharmacological characterization of OMO-1 (formerly JNJ-38877618), a potent, highly selective, orally bioavailable MET kinase inhibitor with nM binding affinity on wild-type (wt), M1250T and, Y1235D mutants MET (1.2, 2.1 and, 21 nM Kd). OMO-1 potently inhibited MET receptor phosphorylation and downstream pathway modulation in the nanomolar range and induced anti-proliferative and anti-migratory activity in models with MET gene amplification, mutant or ligand-mediated pathway activation. In vivo, OMO-1 treatment led to complete inhibition of tumour growth in 3 models: the SNU5 MET amplified gastric, U87-MG HGF autocrine glioblastoma and, Hs746T MET exon 14 skipping mutant gastric cancer. OMO-1 induced regression of large MET amplified EBC-1 SqNSCLC due to the inhibition of MET kinase activation, with the duration of target shut down considerably exceeding plasma exposure times. Combination treatments are well tolerated and improve EGFR targeted therapy. Although single agent OMO-1 had no effect on NSCLC HCC827 EGFR, combination with Erlotinib delayed tumour recurrence. The acquired EGFR inhibitor resistant model HCC827-ER1 was determined to be MET amplified. OMO-1 and erlotinib both inhibited tumour growth of this model whilst combination induced tumour regression. In an EGFR inhibitor resistant PDX having MET amplification, single agent OMO-1 caused tumour stasis whereas MetMab/erlotinib only led to tumour growth delay. The potent preclinical activity we have observed, supports ongoing clinical development of OMO-1 in patients with MET pathway-driven tumours.