Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations

Abstract

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 <i>ALK, ROS1</i>, or <i>NTRK1-3</i> 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 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 <i>in vitro</i> and <i>in vivo</i> As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with <i>ROS1</i> or <i>NTRK3</i> fusion-positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance.<b>Significance:</b> Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving <i>ROS1, NTRK1-3</i>, and <i>ALK</i> Repotrectinib may represent an effective therapeutic option for patients with <i>ROS1-, NTRK1-3-, or ALK</i>-rearranged malignancies who have progressed on earlier-generation TKIs. <i>Cancer Discov; 8(10); 1227-36. ©2018 AACR.</i> <i>This article is highlighted in the In This Issue feature, p. 1195</i>.