Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ros1/trk/alk solvent-front mutations

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

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48 Citations (Scopus)

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.

Original languageEnglish
JournalCancer Discovery
Volume8
Issue number10
DOIs
Publication statusPublished - 2018 Oct

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All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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., ... Shaw, A. T. (2018). Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ros1/trk/alk solvent-front mutations. Cancer Discovery, 8(10). https://doi.org/10.1158/2159-8290.CD-18-0484