Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ros1/trk/alk solvent-front mutations

Alexander Drilon, Sai Hong Ignatius Ou, ByoungChul Cho, Dong Wan Kim, Jeeyun Lee, Jessica J. Lin, Viola W. Zhu, Myung Ju Ahn, D. Ross Camidge, Judy Nguyen, Dayong Zhai, Wei Deng, Zhongdong Huang, Evan Rogers, Juliet Liu, Jeff Whitten, John K. Lim, Shanna Stopatschinskaja, David M. Hyman, Robert C. Doebele & 2 others J. Jean Cui, Alice T. Shaw

Research output: Contribution to journalComment/debate

23 Citations (Scopus)

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.

Original languageEnglish
JournalCancer Discovery
Volume8
Issue number10
DOIs
Publication statusPublished - 2018 Oct 1

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Protein-Tyrosine Kinases
Mutation
Neoplasms
Phosphotransferases
Molecular Weight
Therapeutics
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Drilon, Alexander ; Ou, Sai Hong Ignatius ; Cho, ByoungChul ; 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. / Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ros1/trk/alk solvent-front mutations. In: Cancer Discovery. 2018 ; Vol. 8, No. 10.
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title = "Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ros1/trk/alk solvent-front mutations",
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.",
author = "Alexander Drilon and Ou, {Sai Hong Ignatius} and ByoungChul Cho and Kim, {Dong Wan} and Jeeyun Lee and Lin, {Jessica J.} and Zhu, {Viola W.} and Ahn, {Myung Ju} and Camidge, {D. Ross} and Judy Nguyen and Dayong Zhai and Wei Deng and Zhongdong Huang and Evan Rogers and Juliet Liu and Jeff Whitten and Lim, {John K.} and Shanna Stopatschinskaja and Hyman, {David M.} and Doebele, {Robert C.} and Cui, {J. Jean} and Shaw, {Alice T.}",
year = "2018",
month = "10",
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doi = "10.1158/2159-8290.CD-18-0484",
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Drilon, A, Ou, SHI, Cho, B, 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 2018, 'Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ros1/trk/alk solvent-front mutations', Cancer Discovery, vol. 8, no. 10. https://doi.org/10.1158/2159-8290.CD-18-0484

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, ByoungChul; 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.

In: Cancer Discovery, Vol. 8, No. 10, 01.10.2018.

Research output: Contribution to journalComment/debate

TY - JOUR

T1 - Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ros1/trk/alk solvent-front mutations

AU - Drilon, Alexander

AU - Ou, Sai Hong Ignatius

AU - Cho, ByoungChul

AU - Kim, Dong Wan

AU - Lee, Jeeyun

AU - Lin, Jessica J.

AU - Zhu, Viola W.

AU - Ahn, Myung Ju

AU - Camidge, D. Ross

AU - Nguyen, Judy

AU - Zhai, Dayong

AU - Deng, Wei

AU - Huang, Zhongdong

AU - Rogers, Evan

AU - Liu, Juliet

AU - Whitten, Jeff

AU - Lim, John K.

AU - Stopatschinskaja, Shanna

AU - Hyman, David M.

AU - Doebele, Robert C.

AU - Cui, J. Jean

AU - Shaw, Alice T.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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.

AB - 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.

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U2 - 10.1158/2159-8290.CD-18-0484

DO - 10.1158/2159-8290.CD-18-0484

M3 - Comment/debate

VL - 8

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

IS - 10

ER -