Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations
2018
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,
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 ,
ROS1G2032R or
ROS1D2033N , 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 ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with
ROS1or NTRK3 fusion–positive cancers who had relapsed on earlier-generation TKIs due to
ROS1or 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-, NTRK1–3-, or ALK -rearranged malignancies who have progressed on earlier-generation TKIs. Cancer Discov; 8(10); 1227–36. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195
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