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

Overview

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 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 ALKG1202R, ROS1G2032R or ROS1D2033N, TRKAG595R, 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 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 ROS1 or NTRK3 fusion-positive 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-, 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.

authors

  • Drilon, Alexander
  • Ou, Sai-Hong Ignatius
  • Cho, Byoung Chul
  • Kim, Dong-Wan
  • Lee, Jeeyun
  • Lin, Jessica J
  • Zhu, Viola W
  • Ahn, Myung-Ju
  • Camidge, D Ross
  • Nguyen, Judy
  • Zhai, Dayong
  • Deng, Wei
  • Huang, Zhongdong
  • Rogers, Evan
  • Liu, Juliet
  • Whitten, Jeff
  • Lim, John K
  • Stopatschinskaja, Shanna
  • Hyman, David M
  • Doebele, Robert C
  • Cui, J Jean
  • Shaw, Alice T

publication date

  • August 9, 2018

Research

keywords

  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins

Identity

Scopus Document Identifier

  • 85054377858

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-18-0484

PubMed ID

  • 30093503

Additional Document Info

volume

  • 8

issue

  • 10