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

Cited 72 time in Web of Science Cited 78 time in Scopus
Authors
Drilon, Alexander; Ou, Sai-Hong Ignatius; Cho, Byoung Chul; Kim, Dong-Wan; Lees, Jeeyun; Lin, Jessica J.; Zhu, Viola W.; Ahns, 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.
Issue Date
2018-10
Citation
Cancer Discovery, Vol.8 No.10, pp.1227-1236
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, 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.
ISSN
2159-8274
URI
http://hdl.handle.net/10371/165233
DOI
https://doi.org/10.1158/2159-8290.CD-18-0484
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College of Medicine/School of Medicine (의과대학/대학원)Cancer Research Institute (암연구소)Journal Papers (저널논문_암연구소)
College of Medicine/School of Medicine (의과대학/대학원)Internal Medicine (내과학전공)Journal Papers (저널논문_내과학전공)
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