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

• Published in: Cancer discovery 2018-10, Vol.8 (10), p.1227-1236
• Main 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
• Format: Article
• Language: English
• ISSN: 2159-8274; 2159-8290
• DOI: 10.1158/2159-8290.CD-18-0484

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 , or 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 , ROS1 or ROS1 , TRKA , and TRKC 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 and As clinical proof of concept, in an ongoing first-in-human phase I/II trial, repotrectinib achieved confirmed responses in patients with or fusion-positive cancers who had relapsed on earlier-generation TKIs due to ROS1 or TRKC solvent-front substitution-mediated resistance. Repotrectinib (TPX-0005), a next-generation ROS1, pan-TRK, and ALK TKI, overcomes resistance due to acquired solvent-front mutations involving , and Repotrectinib may represent an effective therapeutic option for patients with -rearranged malignancies who have progressed on earlier-generation TKIs. .