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


Authors: Drilon, A.; Ou, S. H. I.; Cho, B. C.; Kim, D. W.; Lee, J.; Lin, J. J.; Zhu, V. W.; Ahn, M. J.; Camidge, D. R.; Nguyen, J.; Zhai, D.; Deng, W.; Huang, Z.; Rogers, E.; Liu, J.; Whitten, J.; Lim, J. K.; Stopatschinskaja, S.; Hyman, D. M.; Doebele, R. C.; Cui, J. J.; Shaw, A. T.
Article Title: 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 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. ©2018 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 8
Issue: 10
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2018-10-01
Start Page: 1227
End Page: 1236
Language: English
DOI: 10.1158/2159-8290.cd-18-0484
PUBMED: 30093503
PROVIDER: scopus
DOI/URL:
Notes: Note -- Export Date: 1 November 2018 -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. David Hyman
    354 Hyman
  2. Alexander Edward Drilon
    633 Drilon
  3. James Huy Nguyen
    8 Nguyen