Cited by 523Lung Cancer Treatments and MutationsCancer Mechanisms and TherapyCancer Genomics and Diagnostics

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

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.·2018·Cancer Discovery

DOI 10.1158/2159-8290.cd-18-0484

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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. Cancer Discov; 8(10); 1227–36. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 1195

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Ahn, 15–18, 2017, Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non–small cell lung cancer (NSCLC) rearrangements
Solomon, 15–18, Phase 2 Study of lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer

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BindingDB Entry 50011293: Medicinal Chemistry Strategies for the Development of Kinase Inhibitors Targeting Point Mutations.
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BindingDB Entry 50023496: Discovery of Oral Degraders of the ROS1 Fusion Protein with Potent Activity against Secondary Resistance Mutations.
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BindingDB Entry 50021320: Synthesis and clinical application of new drugs approved by FDA in 2023.
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BindingDB Entry 50018558: Targeting Gatekeeper Mutations for Kinase Drug Discovery.
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BindingDB Entry 50023827: Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the Treatment of Solid Tumors.
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BindingDB Entry 50022746: Macrocyclic-based strategy in drug design: From lab to the clinic.
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BindingDB Entry 50023401: Design, synthesis and biological evaluation of novel 1H-indole-3-carbonitrile derivatives as potent TRK Inhibitors.
BindingDB (2026) · UC San Diego · doi:10.7270/q2rn3drz
BindingDB Entry 50008470: Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK).
BindingDB (2021) · UC San Diego · doi:10.7270/q2s185wv
BindingDB Entry 50020119: Design, synthesis and anti-tumor efficacy of novel phenyl thiazole/triazole derivatives as selective TrkA inhibitors.
BindingDB (2024) · UC San Diego · doi:10.7270/q2tq6602

Authors: 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., Doebele, R. C., Cui, J. J., & Shaw, A. T.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
University of California, Irvine (US)
Yonsei University (KR)
Seoul National University Hospital (KR)
Samsung Medical Center (KR)
Harvard University (US)
University of Colorado Anschutz (US)
8TP Therapeutics Inc., San Diego, California.
Corresponding author: Cui, J. Jean
Shaw, Alice T.
ORCID: 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
Rogers, Evan
Hyman, David M.
Doebele, Robert C.
Cui, J. Jean
Shaw, Alice T.
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2018-10-01
Volume: 8
Issue: 10
Pages: 1227-1236
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-18-0484
OpenAlex: W2885875860
Cited by: 504
References: 23
Citations by year: 2026: 48 · 2025: 64 · 2024: 71 · 2023: 66 · 2022: 69 · 2021: 83 · 2020: 62 · 2019: 37 · 2018: 4
FWCI: 35.60
Type: journal article
Language: en
Open access: closed
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
Seoul National University Open Repository (Seoul National University) (submittedVersion)
Topics: Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
Keywords: repotrectinib, ROS1, TRK, anaplastic lymphoma kinase, tyrosine kinase inhibitors, solvent-front mutations, acquired drug resistance, NTRK3 fusion, kinase domain mutations
MeSH terms: Humans, Mutation, Protein-Tyrosine Kinases, Proto-Oncogene Proteins, Protein Kinase Inhibitors

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

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