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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“As we have discussed before, entrectinib is able to inhibit TRKA, TRKB y TRKC.”
BackgroundInfluential
Receptor Tyrosine Kinase Signaling and Targeting in Glioblastoma Multiforme
Tilak, M., Holborn, J., New, L. A., Lalonde, J., & Jones, N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041831 · Cited by 105
Resistance to Avapritinib in PDGFRA-Driven GIST Is Caused by Secondary Mutations in the PDGFRA Kinase Domain
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NTRK Fusion in Non-Small Cell Lung Cancer: Diagnosis, Therapy, and TRK Inhibitor Resistance
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NTRK Fusions Identified in Pediatric Tumors: The Frequency, Fusion Partners, and Clinical Outcome
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“Other NTRK inhibitors are in clinical development including selitrectinib (LOXO-195), taletrectinib (DS-6051b),(12) and repotrectinib (TPX-005).(13,14) Clinical trials are ongoing to determine the optimal use of these drugs in children (Children’s Oncology Group Trial ADVL1823, ClinicalTrials.”
Background
An overview of kinase downregulators and recent advances in discovery approaches
Wang, B., Wu, H., Hu, C., Wang, H., Liu, J., Wang, W., & Liu, Q. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00826-7 · Cited by 93
“To overcome the mutations of TRK, two macrocyclic compounds were designed using macrocycle strategy based on the structure of larotrectinib.(90,91) Both selitrectinib and recrotrectinib contain a pyrazolopyrimidine structure and entered clinical trials in 2017 for the treatment of advanced solid tumors.”
MethodSelf-citation
Molecular Characteristics of Repotrectinib That Enable Potent Inhibition of TRK Fusion Proteins and Resistant Mutations
Murray, B. W., Rogers, E., Zhai, D., Deng, W., Chen, X., Sprengeler, P. A., Zhang, X., Graber, A., Reich, S. H., Stopatschinskaja, S., et al. (2021) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-21-0632 · Cited by 89
“Repotrectinib dosed at 3 mg/kg treatment resulted in incomplete suppression of TRKA autophosphorylation (85%and56% inhibition at 3 hours and 12hours, respectively) relative to 15 mg/kg repotrectinib (96% and 74% inhibition at 3 hours and 12 hours, respectively) and the degree of TRKA autophosphorylation suppression co…”
BackgroundMethodInfluentialSelf-citation
EML4‑ALK fusion gene in non‑small cell lung cancer (Review)
Lei, Y., Yan, L., Shi, X., & Wang, J. (2022) · Oncology Letters · doi:10.3892/ol.2022.13397 · Cited by 86
“…EML4‑ALK‑targeted drugs, such as ceritinib (72), brigatinib (73) and alectinib (74), as well as the third‑generation targeted drug lorlatinib, have been developed (75), and the fourth‑generation targeted drug repot‑ rectinib (TPX‑0005) has been undergoing phase I/II clinical trials (76,77).”
Clinicopathologic Features and Response to Therapy of NRG1 Fusion–Driven Lung Cancers: The eNRGy1 Global Multicenter Registry
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Self-citation
Evidence of NTRK1 Fusion as Resistance Mechanism to EGFR TKI in EGFR+ NSCLC: Results From a Large-Scale Survey of NTRK1 Fusions in Chinese Patients With Lung Cancer
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Self-citation
TRK xDFG Mutations Trigger a Sensitivity Switch from Type I to II Kinase Inhibitors
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Self-citation
Larotrectinib, a highly selective tropomyosin receptor kinase (TRK) inhibitor for the treatment of TRK fusion cancer
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Entrectinib, a new multi-target inhibitor for cancer therapy
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SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy
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“The inhibitor-bound SHP2 protein complex was prepared by mixing purified SHP2(1-525) with a 5-fold molar excess of PF-07282892 (in DMSO) and incubated on ice for at least 30 minutes.”
Self-citation
Tropomyosin Receptor Kinase Inhibitors for the Treatment of TRK Fusion Cancer
Laetsch, T. W., & Hong, D. S. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-0465 · Cited by 71
Molecular diagnosis and targeted treatment of advanced follicular cell-derived thyroid cancer in the precision medicine era
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FYN: emerging biological roles and potential therapeutic targets in cancer
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“Repotrectinib Locally Advanced Solid Tumors/Metastatic Solid Tumors I, II NCT03093116 [153]”
Background
Advances and challenges in precision medicine in salivary gland cancer
Lassche, G., van Boxtel, W., Ligtenberg, M. J. L., Grunsven, A. C. H. V. E., & van Herpen, C. M. L. (2019) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2019.101906 · Cited by 68
Targeting ALK Rearrangements in NSCLC: Current State of the Art
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Targeting Gatekeeper Mutations for Kinase Drug Discovery
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NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability
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Medicinal Chemistry Strategies for the Development of Kinase Inhibitors Targeting Point Mutations
Lu, X., Smaill, J. B., & Ding, K. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c00507 · Cited by 67
NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors
Somwar, R., Hofmann, N. E., Smith, B. D., Odintsov, I., Vojnic, M., Linkov, I., Tam, A., Khodos, I., Mattar, M. S., de Stanchina, E., et al. (2020) · Communications Biology · doi:10.1038/s42003-020-01508-w · Cited by 65
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NTRK Fusion-positive Non–small-cell Lung Cancer: The Diagnosis and Targeted Therapy
Haratake, N., & Seto, T. (2020) · Clinical Lung Cancer · doi:10.1016/j.cllc.2020.10.013 · Cited by 65
Taletrectinib in ROS1 + Non–Small Cell Lung Cancer: TRUST
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“16,17 While active against G2032R and brain metastases, a high incidence and wide spectrum of neurologic adverse events (AEs) were observed in most patients receiving repotrectinib.”
Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK‐rearranged lung cancer
Yun, M. R., Choi, H. M., Lee, Y. W., Joo, H. S., Park, C. W., Choi, J. W., Kim, D. H., Kang, H. N., Pyo, K., Shin, E. J., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201910581 · Cited by 63
“TGI was calculated using the method of Drilon et al (2018): 100% × [1 (TVt TV0)/(CVt CV0)] where V0 was the tumor volume at the beginning of the study, Vt was the tumor volume at the end of the study, TV0 was the V0 in the treatment group, TVt was the Vt in the treatment, CV0 was the V0 in the…”
Self-citation
NTRK fusions in lung cancer: From biology to therapy
Harada, G., Santini, F. C., Wilhelm, C., & Drilon, A. E. D. C. (2021) · Lung Cancer · doi:10.1016/j.lungcan.2021.09.005 · Cited by 64
Self-citation
PGR Gene Fusions Identify a Molecular Subset of Uterine Epithelioid Leiomyosarcoma With Rhabdoid Features
Chiang, S., Samore, W. R., Zhang, L., Sung, Y., Turashvili, G., Murali, R., Soslow, R. A., Hensley, M. L., Swanson, D. M., Dickson, B. C., et al. (2019) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000001239 · Cited by 59
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Translocation-Related Sarcomas
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Background
Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer
Wang, Z., Xing, Y., Li, B., Li, X., Liu, B., & Wang, Y. (2022) · Molecular Biomedicine · doi:10.1186/s43556-022-00107-x · Cited by 62
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Self-citation
Targeting non-small cell lung cancer: driver mutation beyond epidermal growth factor mutation and anaplastic lymphoma kinase fusion
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NTRK Fusions in Sarcomas: Diagnostic Challenges and Clinical Aspects
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Targeting ROS1 Rearrangements in Non-small Cell Lung Cancer: Crizotinib and Newer Generation Tyrosine Kinase Inhibitors
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Targeting the NTRK Fusion Gene in Pancreatic Acinar Cell Carcinoma: A Case Report and Review of the Literature
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Preclinical Study of a Biparatopic METxMET Antibody–Drug Conjugate, REGN5093-M114, Overcomes MET-driven Acquired Resistance to EGFR TKIs in EGFR-mutant NSCLC
Oh, S. Y., Lee, Y. W., Lee, E. J., Kim, J. H., Park, Y., Heo, S. G., Yu, M. R., Hong, M. H., DaSilva, J. O., Daly, C., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-2180 · Cited by 51
Self-citation
Entrectinib for the treatment of metastatic NSCLC: safety and efficacy
Bianchi, A. S., Pizzutilo, E. G., Marrapese, G., Tosi, F., Cerea, G., & Siena, S. (2020) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2020.1747439 · Cited by 52
“Two main agents specifically designed to best accommodate the Trk binding pocket in the presence of these clinically observed resistance mutations are currently in development: selitrectinib (LOXO-195) and repotrectinib (TPX-0005) [39,51].”
Background
Clinical Relevance of an Amplicon-Based Liquid Biopsy for DetectingALKandROS1Fusion and Resistance Mutations in Patients With Non–Small-Cell Lung Cancer
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“Mutations in this region, particularly G2032R, have been hypothesized to cause a steric clash between protein and inhibitor, reducing TKI affinity and conferring TKI resistance (32, 35).”
BackgroundInfluentialSelf-citation
Discovery of the Next-Generation Pan-TRK Kinase Inhibitors for the Treatment of Cancer
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Discovery of the First Highly Selective and Broadly Effective Macrocycle-Based Type II TRK Inhibitors that Overcome Clinically Acquired Resistance
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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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