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Ref Type Journal Article
PMID (30093503)
Authors Drilon A, Ou SI, Cho BC, Kim DW, Lee J, Lin JJ, Zhu VW, Ahn MJ, Camidge DR, Nguyen J, Zhai D, Deng W, Huang Z, Rogers E, Liu J, Whitten J, Lim JK, Stopatschinskaja S, Hyman DM, Doebele RC, Cui JJ, Shaw AT
Title Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations.
Journal Cancer discovery
Vol 8
Issue 10
Date 2018 Oct
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Repotrectinib Repotrectinib 24 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
Repotrectinib TPX-0005 ALK Inhibitor 29 JAK2 Inhibitor 16 ROS1 Inhibitor 19 SRC Inhibitor 31 Trk Receptor Inhibitor (Pan) 30 Repotrectinib (TPX-0005) is a multi-kinase inhibitor that demonstrates strong activity against Ros1, Ntrk1/2/3, and Alk, and also inhibits Jak2 and Src family kinases, resulting in tumor cell death (PMID: 30093503, PMID: 32269053).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
EML4 - ALK ALK G1202R Advanced Solid Tumor sensitive Repotrectinib Preclinical - Cell line xenograft Actionable In a preclinical study, Repotrectinib (TPX-0005) inhibited Alk activity and proliferation of transformed cells expressing ALK G1202R in the context of EML4-ALK in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 30093503). 30093503 detail...
EML4 - ALK Advanced Solid Tumor sensitive Repotrectinib Preclinical - Cell line xenograft Actionable In a preclinical study, Repotrectinib (TPX-0005) inhibited growth of transformed cells expressing EML4-ALK in culture, led to tumor growth inhibition in cell line xenograft models (PMID: 30093503). 30093503