Vitrakvi

Larotrectinib is an orally-bioavailable, adenosine triphosphate (ATP)-competitive, potent and highly selective tyrosine receptor kinase (TRK) inhibitor that was rationally designed to avoid activity with off-target kinases. The target for larotrectinib is the TRK family of proteins inclusive of TRKA, TRKB, and TRKC that are encoded by neurotrophic tyrosine receptor kinase 1 (NTRK1), NTRK2 and NTRK3 genes, respectively.In-frame gene fusion events resulting from chromosomal rearrangements of the human genes NTRK1, NTRK2, and NTRK3 lead to the formation of oncogenic TRK fusion proteins. These resultant novel chimeric oncogenic proteins are aberrantly expressed driving constitutive kinase activity subsequently activating downstream cell signalling pathways involved in cell proliferation and survival leading to TRK fusion cancer.Larotrectinib demonstrated potent inhibition of TRK proteins and inhibition of proliferation of tumour cells in a concentration-dependent manner. In TRK fusion-driven mouse xenograft models larotrectinib treatment induced a significant reduction of tumour growth.Acquired resistance mutations after progression on TRK inhibitors have been observed. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutation in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.