Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	8	10	2018 Oct	1227-1236	Cancer Discov

URL

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	32	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Repotrectinib	Augtyro	TPX-0005	ALK Inhibitor 32 JAK2 Inhibitor 17 ROS1 Inhibitor 20 SRC Inhibitor 31 Trk Receptor Inhibitor (Pan) 31	Augtyro (repotrectinib) 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). Augtyro (repotrectinib) is FDA-approved for use in patients with advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (FDA.gov).

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	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Augtyro (repotrectinib) inhibited growth of transformed cells expressing EML4-ALK in culture, led to tumor growth inhibition in cell line xenograft models (PMID: 30093503).	30093503
EML4 - ALK ALK G1202R	Advanced Solid Tumor	sensitive	Repotrectinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Augtyro (repotrectinib) 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