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

Published version of a preprint

Open this paper in CoChat — free account

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

Integrity signals

Registry

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

Cites

23 of 23 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer
Kwak, E. L., Bang, Y., Camidge, D. R., Shaw, A. T., Solomon, B., Maki, R. G., Ou, S. I., Dezube, B. J., Janne, P. A., Costa, D. B., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1006448 · Cited by 4,477
Self-citation
Efficacy of Larotrectinib in TRK Fusion–Positive Cancers in Adults and Children
Drilon, A., Laetsch, T. W., Kummar, S., DuBois, S. G., Lassen, U. N., Demetri, G. D., Nathenson, M., Doebele, R. C., Farago, A. F., Pappo, A. S., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1714448 · Cited by 2,824
Self-citation
Alectinib versus Crizotinib in Untreated ALK -Positive Non–Small-Cell Lung Cancer
Peters, S., Camidge, D. R., Shaw, A. T., Gadgeel, S., Ahn, J. S., Kim, D.-W., Ou, S.-H. I., Pérol, M., Dziadziuszko, R., Rosell, R., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1704795 · Cited by 2,527
Self-citation
Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer
Shaw, A. T., Ou, S.-H. I., Bang, Y.-J., Camidge, D. R., Solomon, B. J., Salgia, R., Riely, G. J., Varella-Garcia, M., Shapiro, G. I., Costa, D. B., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1406766 · Cited by 1,964
Self-citation
Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK -Rearranged Lung Cancer
Gainor, J. F., Dardaei, L., Yoda, S., Friboulet, L., Leshchiner, I., Katayama, R., Dagogo‐Jack, I., Gadgeel, S. M., Schultz, K. R., Singh, M., et al. (2016) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-0596 · Cited by 1,180
Self-citation
The ALK Inhibitor Ceritinib Overcomes Crizotinib Resistance in Non–Small Cell Lung Cancer
Friboulet, L., Li, N., Katayama, R., Lee, C. C., Gainor, J. F., Crystal, A., Michellys, P., Awad, M. M., Yanagitani, N., Kim, S., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0846 · Cited by 867
Self-citation
Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1)
Drilon, A. E. D. C., Siena, S., Ou, S. I., Patel, M. R., Ahn, M., Lee, J., Bauer, T. M., Farago, A. F., Wheler, J. J., Liu, S. V., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1237 · Cited by 833
Self-citation
Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial
Shaw, A. T., Felip, E., Bauer, T. M., Besse, B., Navarro, A., Postel-Vinay, S. C., Gainor, J. F., Johnson, M. L., Dietrich, J., James, L. P., et al. (2017) · The Lancet Oncology · doi:10.1016/s1470-2045(17)30680-0 · Cited by 673
Self-citation
Targeting ALK: Precision Medicine Takes on Drug Resistance
Lin, J. J., Riely, G. J., & Shaw, A. T. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1123 · Cited by 532
Self-citation
A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion–Positive Solid Tumors
Drilon, A. E. D. C., Nagasubramanian, R., Blake, J. F., Ku, N. C., Tuch, B. B., Ebata, K. T., Smith, S., Lauriault, V., Kolakowski, G. R., Brandhuber, B. J., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-0507 · Cited by 460
Self-citation

Flagged first, then by citations

Show all 23 references

Research works printed but not linked: 2

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

Sorted by citations

Items 301–400 of 523

Synthesis and clinical application of small-molecule inhibitors and PROTACs of anaplastic lymphoma kinase
Gao, H., Zhang, J., Zhao, L.-J., & Guo, Y. (2023) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2023.106807 · Cited by 7
Current treatment and novel insights regarding ROS1 ‐targeted therapy in malignant tumors
Li, S., Zhang, H., Chen, T., Zhang, X., & Shang, G. (2024) · Cancer Medicine · doi:10.1002/cam4.7201 · Cited by 8
“83 Furthermore, studies by Davare and Facchinetti have shown slight differences in the inhibitory effects of TKIs on different ROS1 fusion phenotypes.”
Background
BPI-28592 as a novel second generation inhibitor for NTRK fusion tumors
Sheng, J., Chen, H., Fu, B., Pan, H., Wang, J., & Han, W. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00686-8 · Cited by 7
“Repotrectinib is a multitarget inhibitor of TRK, ALK, ROS1 and Src 29 , and has been approved by the U.S. FDA for the treatment of ROS1 -positive non-small cell lung cancer 25,30 .”
Influential
Resistance mutations and the blood–brain barrier: Key challenges in targeted treatment of brain metastatic non-small cell lung cancer
Rijmers, J., Lebre, M. C., Beijnen, J. H., & Schinkel, A. H. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.06.002 · Cited by 9
“It was developed to be active against ROS1-, ALK-and TRK-activating gene rearrangements 79 .”
ALK inhibitors against resistance in non-small cell lung cancer: an 18 year medical arms race
Ashton, J. C. (2025) · Biochemical Pharmacology · doi:10.1016/j.bcp.2025.117214 · Cited by 7
Intratumoral Nerve Phased Development: A Promising Therapeutic Target
Che, X., Wang, H., Wang, H., & Jiang, Y. (2025) · Medicine Bulletin · doi:10.1002/mdb2.70009 · Cited by 10
Design, synthesis and biological evaluation of novel 1H-indole-3-carbonitrile derivatives as potent TRK Inhibitors
Xu, S., Jiang, X.-S., Xu, M., Ai, C., Zhao, G., Jiang, T., Liu, Y., Tian, Z., Zhang, M., & Jin-hua, D. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.117231 · Cited by 7
RASAL1 and ROS1 Gene Variants in Hereditary Breast Cancer
Isidori, F., Bozzarelli, I., Ferrari, S., Godino, L., Innella, G., Turchetti, D., & Bonora, E. (2020) · Cancers · doi:10.3390/cancers12092539 · Cited by 7
How selecting best upfront therapy for metastatic disease?—Focus on ROS1-rearranged disease
Landi, L. M., & Cappuzzo, F. (2020) · Translational Lung Cancer Research · doi:10.21037/tlcr-20-1109 · Cited by 7
“Secondary ROS1 mutations were identified in five specimens collected at baseline, including 3 G2032R and 2 novel mutations, S1861I and V2054A, each occurring in 1 case.”
BackgroundInfluential
High‐throughput sequencing detection and ensartinib treatment of lung cancer harboring NTRK1 fusion
Song, Z., Xu, C., Pu, X., Zhu, Y., Wang, W., Li, X., Gao, Y., Zhu, W., He, Y., Wu, L., et al. (2021) · 癌症：英文版 · doi:10.1002/cac2.12133 · Cited by 7
NTRK2 gene fusion and resistance mutation: Seventeen‐year course of a paediatric glioma
Barritault, M., Poncet, D., Meyronet, D., Vasiljevic, A., Lopez, J., Descôtes, F., Mottolèse, C., Basle, A., Benoit‐Janin, M., Pissaloux, D., et al. (2021) · Pediatric Blood & Cancer · doi:10.1002/pbc.29114 · Cited by 7
Neurotrophic receptor tyrosine kinase family members in secretory and non-secretory breast carcinomas
Stravodimou, A., & Voutsadakis, I. A. (2022) · World Journal of Clinical Oncology · doi:10.5306/wjco.v13.i2.135 · Cited by 7
Diagnosis and management of TRK fusion cancer
Kummar, S. (2022) · The American Journal of Managed Care · doi:10.37765/ajmc.2022.88834 · Cited by 6
Anaplastic lymphoma kinase inhibitors: an updated patent review (2014–2018)
Liu, Y.-M., Kuo, C.-N., & Liou, J. (2020) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2020.1738389 · Cited by 8
Prediction of Resistance Mutations Against Upcoming Anaplastic Lymphoma Kinase Inhibitors
Doi, Y., Tagaya, H., Noge, A., & Semba, K. (2022) · Targeted Oncology · doi:10.1007/s11523-022-00919-5 · Cited by 7
“1c, d; Table 1), which is consistent with previous reports [23, 24].”
BackgroundResult
Application of a macrocyclization strategy in kinase inhibitor development
Xing, K., Li, S., Li, J., Liu, D., Huang, M., & Zhao, L. (2025) · Acta Materia Medica · doi:10.15212/amm-2024-0070 · Cited by 6
“To address acquired resistance, second-generation macrocyclic inhibitors (TPX-0005 [100] and LOXO-195 in the hinge area and the fluorophenyl occupied the hydrophobic cavity consisting of Phe521, Leu657, Gly667, and Asp668.”
New drugs approved by the NMPA in 2024: Synthesis and clinical applications
Zhao, X., Lin, Y., Gong, Z., Li, M., Yuan, Y., & Geng, J. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117643 · Cited by 6
Evolving Therapeutic Landscape of ROS1-Positive Non-Small Cell Lung Cancer: An Updated Review
Bischoff, H., Gendarme, S., Somme, L., CHOUAID, C., & Schött, R. (2025) · Current Oncology · doi:10.3390/curroncol32110626 · Cited by 7
“Preclinical data had already demonstrated the potent inhibitory activity of repotrectinib against ROS1ˆG2032R and D2033N mutations, outperforming lorlatinib and entrectinib in vitro [45].”
Nociceptive sensory neuron-derived NGF orchestrates a fibrotic mesenchymal stromal cell neurogenic niche to drive tendon pathological fibrosis
Li, Y., Pang, S., Zhang, X., Lu, M., Zhao, J., Wu, R., Hu, J., Jiang, J., Chen, H., Ling, Z., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-67396-y · Cited by 6
“Myo ﬁ broblast generation and activation are central events in ﬁ bro-genesis following peripheral trauma 42 – 45 .”
Acquired NF2 mutation confers resistance to TRK inhibition in an ex vivo LMNA :: NTRK1‐ rearranged soft‐tissue sarcoma cell model
Chen, Y., Steiner, S., Hagedorn, C., Kollar, S., Pliego‐Mendieta, A., Haberecker, M., Plock, J. A., Britschgi, C., Planas‐Paz, L., & Pauli, C. (2024) · The Journal of Pathology · doi:10.1002/path.6282 · Cited by 5
“To overcome these resistance mechanisms, second-generation TRK inhibitors, selitrectinib and repotrectinib, that target different sites within the kinase domain have been developed [11,12].”
Background
Induction of resistance to neurotrophic tropomyosin‐receptor kinase inhibitors by HMGCS2 via a mevalonate pathway
Kato, Y. X., Matsumoto, M., Takano, N., Hirao, M., Matsuda, K., Tozuka, T., Onda, N., Nakamichi, S., Takeuchi, S., Miyanaga, A., et al. (2024) · Cancer Medicine · doi:10.1002/cam4.7393 · Cited by 6
“13,14 However, almost all NTRK fusion gene–positive tumors eventually acquire resistance to molecular-targeted therapies.”
Background
ROS1-rearranged non-small cell lung cancer: Understanding biology and optimizing management in the era of new approvals
Myall, N. J., & Das, M. S. (2024) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2024.101133 · Cited by 6
TRK inhibitors: managing on-target toxicities
Lim, J. S. J., & Tan, D. S. P. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.06.010 · Cited by 6
Self-citation
JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo
Wang, J., Zhou, Y., Tang, X., Yu, X., Wang, Y., Chan, S., Song, X., Tu, Z., Zhang, Z., Lu, X., et al. (2022) · Molecules · doi:10.3390/molecules27196500 · Cited by 6
“To overcome the acquired resistance to the first-generation TRK inhibitors, several second-generation TRK inhibitors such as Selitrectinib (LOXO-195, Bayer/Loxo Oncology) [10] and Repotrectinib (TPX-0005, Turning Point Therapeutics) [15] have been developed and progressed into different stages of clinical trials.”
Background
ROS1 in non-small-cell lung carcinoma: A narrative review
Nathany, S., Batra, U., Sachdeva, R., Sharma, M., Amrith, B. P., & Vaidya, S. (2022) · Cancer Research Statistics and Treatment · doi:10.4103/crst.crst_322_22 · Cited by 6
ETV6::NTRK3 gene fusion in a patient with metastatic lung atypical carcinoid successfully treated with repotrectinib: A case report
Gao, L., Ai, X., & Lü, S. (2023) · Lung Cancer · doi:10.1016/j.lungcan.2023.107443 · Cited by 6
Lead identification and characterization of hTrkA type 2 inhibitors
Subramanian, G., Zhu, Y., Bowen, S. J., Roush, N. S., White, J. A., Huczek, D., Zachary, T., Javens, C., Williams, T., Janssen, A., et al. (2019) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126680 · Cited by 6
Uncommon targets in non-small cell lung cancer: Everyone wants a slice of cake
Toma, A. D., Russo, G. L., Signorelli, D., Pagani, F., Randon, G., Galli, G., Prelaj, A., Ferrara, R., Proto, C., Ganzinelli, M., et al. (2021) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2021.103299 · Cited by 6
Tropomyosin receptor kinases in sarcomas – of joy and despair
Dieckmann, N., Schildhaus, H., & Bauer, S. (2021) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000752 · Cited by 6
“2nd generation TRK-inhibitors such as selitrectinib and repotrectinib have already been shown to exhibit activity in patients that have failed 1st generation TRK-inhibitors [32,33,34].”
BackgroundInfluential
Új célzott terápiás lehetőség az onkológiában: tropomiozin receptor-tirozin-kináz gátlók
Kiss, É., & Pápai, Z. (2021) · Orvosi Hetilap · doi:10.1556/650.2021.32183 · Cited by 6
“A repotrektinib preklinikai aktivitását igazolta, hogy különböző modellekben hatékony in vitro antiproli-feratív és in vivo tumorellenes hatást mutatott [39].”
Advances in Small-Molecule C-KIT/PDGFRα Inhibitors for the Treatment of Gastrointestinal Stromal Tumors
Zheng, X., Liang, H., Zhou, Y., & Lu, X. (2024) · Pharmaceutical Fronts · doi:10.1055/s-0044-1791541 · Cited by 5
“The second-generation macrocycle-based TKIs selitrectinib 42 and repotrectinib 43 can effectively inhibit SF mutations by avoiding clashes with the mutant residues.”
Design, synthesis and evaluate of indazolylaminoquinazoline derivatives as potent Tropomyosin receptor kinase (TRK) inhibitors
Xu, Y., Zhao, W. F., Zhang, X., Yu, X., Chen, Y., Wang, Z., Zhu, X., Zhu, X., & Zhang, P. (2024) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2024.117608 · Cited by 5
A recurrent NTRK1 tyrosine kinase domain mutation pair is characteristic in a subset of dedifferentiated liposarcomas
Lippai, Z., Péterfia, B. F., Papp, G., Dezső, K., Bedics, G., Pápai, Z., Lamers, M. H., Kuin, R. C. M., Szuhai, K., & Sápi, Z. (2024) · European Journal of Cancer · doi:10.1016/j.ejca.2024.114005 · Cited by 5
Fundamentals and recent advances in the evaluation and management of medullary thyroid carcinoma
Gigliotti, B. J., Brooks, J. A., & Wirth, L. J. (2024) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2024.112295 · Cited by 5
NTRK amplification occurs frequently in pan-TRK immunopositive dedifferentiated liposarcomas
Lippai, Z., Papp, G., Szuhai, K., Sápi, J., Dezső, K., & Sápi, Z. (2025) · Pathology & Oncology Research · doi:10.3389/pore.2024.1611993 · Cited by 5
A perspective on the application of macrocyclic design strategies in antitumor drugs
Li, Y., Lin, Y., Cai, J.-F., Zou, Z.-K., & Zhao, P. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108190 · Cited by 5
Advances of dual inhibitors based on ALK for the treatment of cancer
Chen, J., Guo, S., He, B., Zheng, W., Jiang, W., Yuan, Z., Xiang, Y., Peng, C., Wei, X., & Shi, J. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108417 · Cited by 5
Research Progress on Small Molecules Inhibitors Targeting TRK Kinases
Liu, J., Zhang, Y., Zhu, Y., Tian, L., Tang, M., Shen, J., Chen, Y., & Ding, S. (2022) · Current Medicinal Chemistry · doi:10.2174/0929867329666220801145639 · Cited by 5
Self-citation
Targeted Therapy for Melanomas Without BRAF V600 Mutation
Choi, J. S., & Chandra, S. (2022) · Current Oncology Reports · doi:10.1007/s11912-022-01306-z · Cited by 5
Path Less Traveled: Targeting Rare Driver Oncogenes in Non–Small-Cell Lung Cancer
Lim, S. M., Lee, J. B., Oya, Y., Nützinger, J., & Soo, R. A. (2023) · JCO Oncology Practice · doi:10.1200/op.23.00273 · Cited by 6
Self-citation
The promising impact of Bemcentinib and Repotrectinib on sleep impairment in Alzheimer’s disease
Ariaei, A., & Ramezani, F. (2023) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2023.2276876 · Cited by 5
“Since this drug can cross the BBB, a potential CNS activity is expected (Drilon et al., 2018; Murray et al., 2021).”
Spotlight on the treatment of non‐small cell lung cancer with rare genetic alterations and brain metastasis: Current status and future perspectives
Zhang, Q., Chen, K., Yu, X., & Fan, Y. (2024) · International Journal of Cancer · doi:10.1002/ijc.35070 · Cited by 5
Assessment of the toxicity and toxicokinetics of the novel potent tropomyosin receptor kinase (Trk) inhibitor LPM4870108 in rhesus monkeys
Duan, S., Dong, L., Wang, B., Wei, S., Gong, X., Yu, P., Li, C., Gao, Y., Ye, L., Wang, H., et al. (2021) · Regulatory Toxicology and Pharmacology · doi:10.1016/j.yrtph.2021.104886 · Cited by 5
Case report: Complete and durable response to larotrectinib (TRK inhibitor) in an infant diagnosed with angiosarcoma harbouring a KHDRBS1-NTRK3 fusion gene
Cervi, C., Sápi, Z., Bedics, G., Zajta, E., Hegyi, L. L., Pápay, J., Dezső, K., Varga, E., Mudra, K., Bödör, C., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.999810 · Cited by 5
An updated patent review of anaplastic lymphoma kinase inhibitors (2018–2022)
Ma, D., Guo, M., & Zhai, X. (2023) · Expert Opinion on Therapeutic Patents · doi:10.1080/13543776.2023.2216381 · Cited by 5
Advances in protein kinase drug discovery through targeting gatekeeper mutations
Guo, J., Zhou, Y., & Lu, X. (2023) · Expert Opinion on Drug Discovery · doi:10.1080/17460441.2023.2265303 · Cited by 6
“Repotrectinib is more than 10 to 100-fold more potent than selitrectinib against wild-type and various mutated TRKs in Ba/F3 cells engineered with TRK fusions [26,41].”
Background
Design, Synthesis, and Biological Evaluation of the First Novel Macrocycle-Based FGFR Inhibitors That Overcome Clinically Acquired Resistance
Xiang, S., Chen, X., Lin, J., Lin, X., Lin, Q., Song, X., Yan, L., Peng, H., Tu, Z., Patterson, A. V., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c02462 · Cited by 4
Self-citation
Oncogenic influences of neurotrophin receptors: Shedding light on Trk biology
Jagana, H., Shabar, M., Jackson, T. S., Johnson, D. E., Hemenway, J., Mukkamala, V., Lukasik, A., Hathaway, M. R., & Pattwell, S. S. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.116928 · Cited by 4
Novel drugs approved by the EMA, the FDA and the MHRA in 2025: A year in review
Papapetropoulos, A., Topouzis, S., Alexander, S. P. H., Cortese-Krott, M. M., Helyes, Z., Martemyanov, K. A., Mauro, C., Nagercoil, N., Panettieri, R., Patel, H. H., et al. (2026) · British Journal of Pharmacology · doi:10.1111/bph.70376 · Cited by 5
A review: recent developments of co-targeted TRK (tropomyosin receptor kinases) inhibitors for cancer therapy
Nasehi, P., Omidkhah, N., & Ghodsi, R. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108950 · Cited by 5
Molecular Diagnostic and Precision Medicine in Non-Small Cell Lung Cancer. An Update on the Treatment of the Most Important Actionable Oncogenic Driver Alterations
König, D., & Rothschild, S. I. (2020) · healthbook TIMES Oncology Hematology · doi:10.36000/hbt.oh.2020.05.019 · Cited by 4
Design, synthesis and anti-tumor efficacy of novel phenyl thiazole/triazole derivatives as selective TrkA inhibitors
Wang, X., Tan, Z., Wang, F., Zhang, J., Yang, J., Liu, S., Jiang, N., & Zhai, X. (2022) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2022.116995 · Cited by 4
Agnostic drug development revisited
Hernando‐Calvo, A., Rossi, A., Vieito, M., Voest, E. E., & Garralda, E. (2024) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2024.102747 · Cited by 4
Recent Advancement in Drug Designing as Small Molecules in Targeted Cancer Therapy: Challenges and Future Directions
Prakash, S., Tyagi, P., Singh, P., Rajkumar, R., & Singh, A. P. (2024) · Current Cancer Drug Targets · doi:10.2174/0115680096331827240911165227 · Cited by 8
Structural Optimization of Next-Generation TRK Inhibitors against Acquired Drug Resistance Mutations for the Treatment of Solid Tumors
Xu, Z., Liu, Y., Wang, P., Xia, P., Cheng, J., Ji, Y., Li, X., Lin, D., Zhao, J., Chen, S., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00412 · Cited by 4
Digging into lorlatinib resistance in ALK-positive lung cancer: an editorial
Facchinetti, F., & Tiseo, M. (2018) · Chinese Clinical Oncology · doi:10.21037/cco.2018.09.04 · Cited by 4
Recent Advances in the Development of RET Inhibitors
Lu, P., Qin, H., Ye, J., Chen, P., Li, J., Ren, J., Wang, Y., & Zhang, Y. (2023) · Letters in Drug Design & Discovery · doi:10.2174/1570180820666230306113551 · Cited by 4
Research Progress on Small Molecules Targeted Therapy in Non-Small Cell Lung Cancer
申, 越. (2022) · World Journal of Cancer Research · doi:10.12677/wjcr.2022.122012 · Cited by 4
Novel insight into mechanisms of ROS1 catalytic activation via loss of the extracellular domain
Jones, K. L., Keddy, C., Jenkins, C., Nicholson, K. S., Shinde, U. P., & Davare, M. A. (2024) · Scientific Reports · doi:10.1038/s41598-024-71687-7 · Cited by 3
Revealing 5-(3,5-difluorobenzyl)-1H-indazole as the active pharmacophore of ALK/ROS1 dual inhibitors through theoretical calculations and biological activity evaluations
Huang, X., Xu, S., An, Y., Lv, X., Tian, L., Xu, S., Wang, L., & Zhu, W. (2024) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2024.108014 · Cited by 3
Pyrazolo[1,5-a]pyrimidine scaffold-based small molecules: From bench to FDA-approved TRK kinase inhibitors (Part 1)
Al-Qadhi, M. A., Yahya, T. A. A., Alqadhi, A. A., & Arafa, R. K. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.118348 · Cited by 3
Development of PROTACs for targeted degradation of oncogenic TRK fusions
Kumar, S., Jiang, J., Donald-Paladino, M. S., Chen, J., Gutierrez, A., Alexander Joel Federation, Szulzewsky, F., Holland, E. C., Ferguson, F. M., & Nabet, B. (2026) · RSC Chemical Biology · doi:10.1039/d6cb00008h · Cited by 3
Application of Bioisosteres in the Design and Discovery of FDA-Approved Drugs and Advanced Clinical Candidates
Wu, Y., Chmiel, A. F., & Bronson, J. J. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c03492 · Cited by 3
Discovery of imidazo[1,2-b]pyridazine derivatives as potent TRK inhibitors for overcoming multiple resistant mutants
Xu, Y., Zhao, W., Wang, Z., Chen, Y., Jia, Z., Chu, Y., Zhu, X., & Zhang, P. (2025) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2025.108737 · Cited by 3
NRG1 fusion glycoproteins in cancer progression – Structural mechanisms and therapeutic potential: A review
Wang, Z., Wang, H., Zhao, B., Luo, X., Yang, Y., Guo, R., Xin, D., Yue, B., & Wang, F. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.147057 · Cited by 4
Targeting Oncogenic Driver Mutations in Lung Cancer
Lee, M. H., Rous, F. A., Borczuk, A., Liu, S. V., Gadgeel, S. M., & Halmos, B. (2023) · Cambridge University Press eBooks · doi:10.1017/9781009336123 · Cited by 2
Repotrectinib’s Clinical Benefit and Its Brain Penetration in a Patient with Meningeal Carcinomatosis from G2032R-Mutated ROS-1 Positive Non-Small Cell Lung Cancer
Metro, G., Gariazzo, E., Costabile, S., Baglivo, S., Roila, F., Colamartini, F., Palumbo, B., Chiarini, P., Gori, S., Conti, A., et al. (2023) · Oncology and Therapy · doi:10.1007/s40487-023-00251-6 · Cited by 3
“By contrast, the next-generation ROS1/ALK/pan-TRK-TKI repotrectinib has recently demonstrated clinical activity against the SFM G2032R [3, 8].”
BackgroundMethod
TO MARKET, TO MARKET—2023: SMALL MOLECULES
Araujo, E., Bartels, B., Bell, I. M., Castanedo, G. M., Zeng, M., Dhar, T. G. M., Holmberg‐Douglas, N., Welin, E. R., Koester, D. C., León, B., et al. (2024) · Medicinal chemistry reviews · doi:10.1021/mc-2024-vol59.ch19 · Cited by 3
Personalized Medicine in Oncology
Vanderwalde, A. M. (2022) · MDPI eBooks · doi:10.3390/books978-3-0365-2820-5 · Cited by 4
Transcriptomic analysis of ROS1+ non-small cell lung cancer reveals an upregulation of nucleotide synthesis and cell adhesion pathways
Terrones, M., de Beeck, K. O., Camp, G. V., Vandeweyer, G., & Mateiu, L. M. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1408697 · Cited by 2
A Novel Empirical Autoinduction Model to Characterize the Population Pharmacokinetics and Recommend Dose for Repotrectinib in Adult and Adolescents With Advanced Solid Tumors Harboring ALK , ROS1 , or NTRK1 ‐3 Rearrangements
Du, S., Hu, Z., Shen, J., Hamuro, L., Lam, J. L., Lu, M., Zhu, L., Roy, A., & Kondic, A. G. (2025) · CPT Pharmacometrics & Systems Pharmacology · doi:10.1002/psp4.70036 · Cited by 3
The past, present, and future of ALK-targeted drug discovery
Qu, H., Zhang, J., Zhao, X., Ge, X., Duan, L., & Yuan, L. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.118053 · Cited by 2
5‐Amino‐7‐Oxo‐4,7‐Dihydroazolo[1,5‐a]pyrimidine‐6‐Carbonitriles: Synthesis and Study of Antitumor Effect In Vitro and In Silico
Dolgova, V. V., Savateev, K. V., Urakov, G. V., Shabunina, E. T., Sbrodova, T. E., Lvova, E. A., Butorin, I. I., Fesenko, E. A., Melekhin, V. V., Tokhtueva, M. D., et al. (2025) · ChemMedChem · doi:10.1002/cmdc.202500535 · Cited by 2
Effectiveness and cost-effectiveness of first-line versus second-line use of repotrectinib in the treatment of ROS1 fusion-positive advanced NSCLC
Huo, G., & Chen, P. (2026) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2026.2614708 · Cited by 2
Rational design of dual ALK inhibitors: scaffolds and strategies to circumvent drug resistance
Yahya, T. A. A., & Al-Qadhi, M. A. (2026) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2026.109706 · Cited by 2
NTRK Gene Fusions: A Compendium of Fusion Partners and Tumor Types
Yang, S., Repetto, M., Rudzinski, E. R., Li, M. M., Roy, A., Gutstein, L., Huang, K., Wu, J., Bender, J. G., Brega, N. M., et al. (2026) · JCO Precision Oncology · doi:10.1200/po-25-01150 · Cited by 2
Self-citation
Advances in targeted therapies for pediatric tumors
Liu, J.-Y., Yang, D.-L., Liu, H.-Y., Xiang, S.-F., Cao, J., Yang, B., He, Q.-J., Wang, J., Shao, X., & Ying, M.-D. (2026) · Acta Pharmacologica Sinica · doi:10.1038/s41401-026-01805-w · Cited by 2
“Repotrectinib, a compact macrocyclic inhibitor, demonstrated potent activity against wild-type and mutant TRKA/B/C (including G595R/G623R) in the ongoing TRIDENT-1 trial, yielding systemic and intracranial responses in previously treated patients with NTRK fusion-positive cancers [108].”
Self-citation
Review Article: Systemic Treatments for Advanced Cholangiocarcinoma—State of the Art and Future Directions
Qi, W., Yang, X., Lv, Y., & Wu, H. (2026) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.70769 · Cited by 2
Targeted therapy in thyroid cancer: molecular alterations and clinical management
Yang, Y., Zhang, Y., Xu, Y., Gu, X., Lou, N., & Ye, G. (2026) · Frontiers in Endocrinology · doi:10.3389/fendo.2026.1810813 · Cited by 3
Paradigm shift in the management of metastatic nonsmall cell lung cancer
Gupta, R., Smalley, M., Anusim, N. I., Jindal, V., Rahi, M. S., Gupta, S., Gupta, S. K., & Jaiyesimi, I. A. (2021) · International Journal of Clinical Practice · doi:10.1111/ijcp.14533 · Cited by 3
Ensartinib (X-396), an Approved ALK Inhibitor, Falls Out as a Clinically Relevant ROS1 Inhibitor
Zhu, V. W., & Ou, S. I. (2021) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2021.07.005 · Cited by 2
Self-citation
Modern treatment of ALK-positive non-small cell lung cancer
Kharagezov, D. A., Lazutin, Y. N., Арменовна, М. Э., Milakin, A. G., Stateshny, O. N., Leyman, I. A., Gappoeva, M. A., Vitkovskaya, V. N., & Дмитриевич, И. К. (2022) · South Russian Journal of Cancer · doi:10.37748/2686-9039-2022-3-2-5 · Cited by 3
Case report: Acquired neurotrophic tyrosine receptor kinase inhibitor resistance in a patient with pancreatic neuroendocrine carcinoma receiving entrectinib
Wu, W., & Chen, M. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2022.1031396 · Cited by 2
Classification models for predicting the bioactivity of pan-TRK inhibitors and SAR analysis
Zhao, X., Kong, Y., Ji, Y., Xin, X., Chen, L., Chen, G., & Yu, C. (2023) · Molecular Diversity · doi:10.1007/s11030-023-10735-2 · Cited by 2
Repotrectinib in a Patient With NTRK Fusion-Positive Pancreatic Carcinoma and Congenital Long QT Syndrome
Yun, K. M., Narezkina, A., Redfern, C. H., Velasco, K., & Bazhenova, L. A. (2024) · JCO Precision Oncology · doi:10.1200/po.23.00265 · Cited by 2
Zirconium Hydride Catalysis Initiated by Tetrabutylammonium Fluoride
Aloiau, A. N., Bobek, B. M., Pearson, K. E., Cherry, K. E., Smith, C. R., Ketcham, J. M., Marx, M. A., & Harwood, S. J. (2024) · The Journal of Organic Chemistry · doi:10.1021/acs.joc.4c01227 · Cited by 2
Secretory Carcinoma of the Thyroid: A Case Report and Update of Literature
Chu, Y., Kobrossy, B., Schwartz, D., Bruns, A. D., & Marsh, J. (2024) · Head and Neck Pathology · doi:10.1007/s12105-024-01693-8 · Cited by 3
“Two second-generation TRK inhibitors, selitrec-tinib and repotrectinib, have shown promising preliminary results in overcoming on-target resistance [ 29 , 30 ] and are currently in clinical trials (NCT03093116, NCT04094610, NCT03215511).”
Designing Macrocyclic Kinase Inhibitors Using Macrocycle Scaffold Hopping with Reinforced Learning (Macro-Hop)
Liang, H., Huang, S., Xu, X., Yin, Z., Hussain, M., Song, X., Yi, J., He, Y., Guo, J., Tu, Z., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00087 · Cited by 4
NTRK expression and its clinical significance in pancreatic neuroendocrine tumors
Yan, P., Dai, X., Zhang, F., Dong, Y., Shi, H., & Han, A. (2025) · Discover Oncology · doi:10.1007/s12672-025-03506-y · Cited by 2
Hepatotoxicity of ALK/ROS1 tyrosine kinase inhibitors in non-small cell lung cancer patients: A pharmacovigilance study based on signal mining and analysis of the FDA adverse event reporting system database
Zhao, W., Jin, X., Li, Y., Peng, H., & Jiang, J. (2025) · Science Progress · doi:10.1177/00368504251387821 · Cited by 3
Current treatment approaches for brain metastases in ALK/ROS1/NTRK-positive non-small-cell lung cancer
Rossi, S., Marinello, A., Pagliaro, A., Franceschini, D., Navarria, P., Finocchiaro, G., Toschi, L., Scorsetti, M., & Santoro, A. (2022) · Expert Review of Anticancer Therapy · doi:10.1080/14737140.2023.2162044 · Cited by 3
“Similar to ALK-positive cases, patients can acquire resistance mutations in the ROS1 gene during treatment with TKIs, as the G2032R and D2033N resistance mutations, occurring, respectively, in 30% and 5% of the patients after crizotinib failure [71].”
Background
Poor outcome in congenital mesoblastic nephroma with TPM3::NTRK1 fusion: a case report from multi-disciplinary treatment to molecular tumor board
Sun, M., Chen, J., Xue, Y., Deng, Y., Mater, D. V., Hiemcke‐Jiwa, L. S., Wu, P., & Fang, Y. (2024) · Translational Pediatrics · doi:10.21037/tp-24-126 · Cited by 2
“With the development of the second-generation type I TRK inhibitor, especially the application of LOXO-195 and TPX-0005 in clinical trials (34-37), we hope to greatly reduce the drug resistance caused by site mutations of TRKA kinase.”
Novel Targets in Advanced Colorectal Cancer
Lee, J. J. X., Choo, S. P., & Chua, C. (2018) · Current Colorectal Cancer Reports · doi:10.1007/s11888-018-0422-9 · Cited by 2
Self-citation
Fusions NTRK : une nouvelle piste dans les cancers digestifs ?
Ouali, K., Pellat, A., Cohen, R., Svrcek, M., Penault-Llorca, F. M., & André, T. (2020) · Bulletin du Cancer · doi:10.1016/j.bulcan.2019.11.014 · Cited by 2
Consenso multidisciplinar para optimizar la determinación de alteraciones del gen NTRK
Rojo, F., Colomer, R., López‐Ríos, F., Bautista, F. J., Alvarez, R. M., de Álava, E., Hladun, R., & Garrido, P. (2021) · Revista Española de Patología · doi:10.1016/j.patol.2021.05.003 · Cited by 3
The Value of Population Screening in Advancing Personalized Medicine in the Field of Lung Cancer
Mogenet, A., Greillier, L., & Tomasini, P. (2021) · Pharmacogenomics and Personalized Medicine · doi:10.2147/pgpm.s267437 · Cited by 2
Therapeutic strategies to overcome ALK resistance in lung cancer
Recondo, G., & Friboulet, L. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-821774-0.00004-8 · Cited by 1
ROS1 fusions in resected stage I-III adenocarcinoma: Results from the European Thoracic Oncology Platform Lungscape project
Speel, E. M., Dafni, U. G., Thunnissen, E., Rüschoff, J. H., O’Brien, C. P., Kowalski, J., Kerr, K. M., Bubendorf, L., Sansano, I., Joseph, L., et al. (2024) · Lung Cancer · doi:10.1016/j.lungcan.2024.107860 · Cited by 1
Discovery of Oral Degraders of the ROS1 Fusion Protein with Potent Activity against Secondary Resistance Mutations
Peng, X., Guo, S., Zheng, S., Hossain, A., Zhang, C., Mottamal, M., Skripnikova, E., Ma, P., Martinez-Carter, K., Zhang, Q., et al. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01205 · Cited by 1
Pharmacological aspects of FDA-approved novel drug therapies against cancer in 2023: a comprehensive review
Sangwan, K., Goyal, P. K., & Sharma, V. (2025) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-025-03961-y · Cited by 1

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

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

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks