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

The use of tyrosine kinase inhibitors (TKI) with activity against ALK, ROS1, or TRKA-C can result in significant clinical benefit in patients with diverse tumors harboring ALK, ROSI, 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 ROS1(D2033N), TRKA(G595R), and TRKCG623R 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 solventfront substitutions in vitro and in vivo. As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with ROS1 or NTRK3 fusionpositive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance. SIGNIFICANCE: Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1-3, and ALK. Repotrectinib may represent an effective therapeutic option for patients with ROS1-, NTRKI-3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. (C) 2018 AACR.