Repotrectinib (TPX-0005) is a next generation ROS1/TRK/ALK inhibitor that potently inhibits ROS1/TRK/ALK solvent front mutations [Research Briefs]

The use of tyrosine kinase inhibitors (TKIs) with activity against ALK, ROS1, or TRKA-C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROS1 or NTRK1-3 rearrangements; however, resistance invariably develops. The emergence of on-target kinase domain mutations represents a major mechanism of acquired resistance. Solvent front substitutions such as ALK G1202R, ROS1 G2032R or D2033N, TRKA G595R, and TRKC G623R are among the most recalcitrant of these mechanisms. Repotrectinib (TPX-0005) is a rationally-designed, low molecular weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA-C, and ALK. Importantly, repotrectinib exhibits activity against a variety of solvent front substitutions in vitro and in vivo. As clinical proof of concept, in an on-going first-in-human phase 1/2 trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusion-positive cancers who had relapsed on earlier generation TKIs due to ROS1 or TRKC solvent front substitution-mediated resistance.

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