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

The DOI matches its Crossref record; 23 of the 23 references it cites were found in a registry or an index.

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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Crossref · 10.1158/2159-8290.cd-18-0484

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Research works printed but not linked: 2

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

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Metadata

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
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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