Rozlytrek

Entrectinib is an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) TRKA, TRKB and TRKC (encoded by the neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2 and NTRK3, respectively), receptor tyrosine kinase c-ros oncogene 1 (ROS1; encoded by the gene ROS1), and anaplastic lymphoma kinase (ALK; encoded by the gene ALK) with half-maximal inhibitory concentration (IC50) values of 0.1 to 2 nM. Entrectinib also inhibits Janus kinase 2 (JAK2) and tyrosine kinase non receptor 2 (TNK2) with IC50 values > 5 nM. The major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1 and ALK.Fusion proteins that include TRK, ROS1 or ALK kinase domains can drive tumourigenic potential through hyperactivation of downstream signalling pathways leading to unconstrained cell proliferation. Entrectinib inhibits the TRK kinases, ROS1 and ALK, leading to inhibition of downstream signalling pathways, cell proliferation and induction of tumour cell apoptosis. Entrectinib demonstrated in vitro and in vivo inhibition of cancer cell lines derived from multiple tumour types harbouring NTRK, ROS1 and ALK fusion genes. Entrectinib demonstrated steady-state brain-to-plasma concentration ratios of 0.4 to 2.2 in multiple animal species (mice, rats and dogs) and demonstrated in vivo anti-tumour activity in mice with intracranial implantation of TRKA- and ALK-driven tumour cell lines.