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; Byoung Chul 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; J. Jean Cui; Alice T. Shaw

doi: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

Alexander Drilon, Sai Hong Ignatius Ou, Byoung Chul 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. DoebeleJ. Jean Cui, Alice T. Shaw

Department of Internal Medicine

Research output: Contribution to journal › Comment/debate › peer-review

248 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 ALK^G1202R, ROS1^G2032R or ROS1^D2033N, TRKA^G595R, and TRKC^G623R 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 language	English
Journal	Cancer Discovery
Volume	8
Issue number	10
DOIs	https://doi.org/10.1158/2159-8290.CD-18-0484
Publication status	Published - 2018 Oct

Bibliographical note

Funding Information:
Funding for this study was provided by TP Therapeutics, Inc.

Funding Information:
A. Drilon has received honoraria from the speakers bureaus of TP Therapeutics, Ignyta, Loxo Oncology, and Ono. S.-H.I. Ou has received honoraria from the speakers bureaus of Roche/Genentech, AstraZeneca, and Takeda/ARIAD, has ownership interest (including stock, patents, etc.) in TP Therapeutics, is a member of the Scientific Advisory Board of TP Therapeutics, and served as a consultant for Pfizer, Roche Genen-tech, AstraZeneca, and Foundation Medicine. V.W. Zhu has received honoraria from the speakers bureaus of Roche-Foundation Medicine, Roche/Genentech, and Takeda, has ownership interest (including stock, patents, etc.) in TP Therapeutics, and is a consultant/advisory board member for TP Therapeutics. D.R. Camidge is a consultant/advisory board member for Takeda and Roche. D.M. Hyman reports receiving commercial research grants from Loxo Oncology, PUMA Biotechnology, and AstraZeneca and is a consultant/advisory board member for Pfizer, Genentech, Chugai, Atara, Boehringer Ingelheim, and CytomX. R.C. Doebele reports receiving a commercial research grant from Ignyta, has ownership interest (including stock, patents, etc.) in Rain Therapeutics, is a consultant/advisory board member for Takeda, AstraZeneca, and Ignyta, and has received other remuneration from Ignyta and Abbott Molecular. J.J. Cui has ownership interest (including stock, patents, etc.) in TP Therapeutics, Inc. A.T. Shaw is a consultant/advisory board member for member for TP Therapeutics, Pfizer, Blueprint Medicines, KSQ Therapeutics, Novartis, Roche/Genentech, LOXO, Ignyta, Takeda/Ariad, Foundation Medicine, Guardant, and Natera. No potential conflicts of interest were disclosed by the other authors.

Publisher Copyright:
©2018 American Association for Cancer Research.

All Science Journal Classification (ASJC) codes

Oncology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1158/2159-8290.CD-18-0484

Cite this

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., ... Shaw, A. T. (2018). Repotrectinib (Tpx-0005) is a next-generation ros1/trk/alk inhibitor that potently inhibits ros1/trk/alk solvent-front mutations. Cancer Discovery, 8(10). https://doi.org/10.1158/2159-8290.CD-18-0484

@article{bc3f78b0a3634354b8ae16d5b2768d5e,

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 Cho, {Byoung Chul} 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.}",

note = "Funding Information: Funding for this study was provided by TP Therapeutics, Inc. Funding Information: A. Drilon has received honoraria from the speakers bureaus of TP Therapeutics, Ignyta, Loxo Oncology, and Ono. S.-H.I. Ou has received honoraria from the speakers bureaus of Roche/Genentech, AstraZeneca, and Takeda/ARIAD, has ownership interest (including stock, patents, etc.) in TP Therapeutics, is a member of the Scientific Advisory Board of TP Therapeutics, and served as a consultant for Pfizer, Roche Genen-tech, AstraZeneca, and Foundation Medicine. V.W. Zhu has received honoraria from the speakers bureaus of Roche-Foundation Medicine, Roche/Genentech, and Takeda, has ownership interest (including stock, patents, etc.) in TP Therapeutics, and is a consultant/advisory board member for TP Therapeutics. D.R. Camidge is a consultant/advisory board member for Takeda and Roche. D.M. Hyman reports receiving commercial research grants from Loxo Oncology, PUMA Biotechnology, and AstraZeneca and is a consultant/advisory board member for Pfizer, Genentech, Chugai, Atara, Boehringer Ingelheim, and CytomX. R.C. Doebele reports receiving a commercial research grant from Ignyta, has ownership interest (including stock, patents, etc.) in Rain Therapeutics, is a consultant/advisory board member for Takeda, AstraZeneca, and Ignyta, and has received other remuneration from Ignyta and Abbott Molecular. J.J. Cui has ownership interest (including stock, patents, etc.) in TP Therapeutics, Inc. A.T. Shaw is a consultant/advisory board member for member for TP Therapeutics, Pfizer, Blueprint Medicines, KSQ Therapeutics, Novartis, Roche/Genentech, LOXO, Ignyta, Takeda/Ariad, Foundation Medicine, Guardant, and Natera. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: {\textcopyright}2018 American Association for Cancer Research.",

year = "2018",

month = oct,

doi = "10.1158/2159-8290.CD-18-0484",

language = "English",

volume = "8",

journal = "Cancer Discovery",

issn = "2159-8274",

publisher = "American Association for Cancer Research Inc.",

number = "10",

}

Drilon, A, Ou, SHI, Cho, BC, 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

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, Byoung Chul

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.

N1 - Funding Information: Funding for this study was provided by TP Therapeutics, Inc. Funding Information: A. Drilon has received honoraria from the speakers bureaus of TP Therapeutics, Ignyta, Loxo Oncology, and Ono. S.-H.I. Ou has received honoraria from the speakers bureaus of Roche/Genentech, AstraZeneca, and Takeda/ARIAD, has ownership interest (including stock, patents, etc.) in TP Therapeutics, is a member of the Scientific Advisory Board of TP Therapeutics, and served as a consultant for Pfizer, Roche Genen-tech, AstraZeneca, and Foundation Medicine. V.W. Zhu has received honoraria from the speakers bureaus of Roche-Foundation Medicine, Roche/Genentech, and Takeda, has ownership interest (including stock, patents, etc.) in TP Therapeutics, and is a consultant/advisory board member for TP Therapeutics. D.R. Camidge is a consultant/advisory board member for Takeda and Roche. D.M. Hyman reports receiving commercial research grants from Loxo Oncology, PUMA Biotechnology, and AstraZeneca and is a consultant/advisory board member for Pfizer, Genentech, Chugai, Atara, Boehringer Ingelheim, and CytomX. R.C. Doebele reports receiving a commercial research grant from Ignyta, has ownership interest (including stock, patents, etc.) in Rain Therapeutics, is a consultant/advisory board member for Takeda, AstraZeneca, and Ignyta, and has received other remuneration from Ignyta and Abbott Molecular. J.J. Cui has ownership interest (including stock, patents, etc.) in TP Therapeutics, Inc. A.T. Shaw is a consultant/advisory board member for member for TP Therapeutics, Pfizer, Blueprint Medicines, KSQ Therapeutics, Novartis, Roche/Genentech, LOXO, Ignyta, Takeda/Ariad, Foundation Medicine, Guardant, and Natera. No potential conflicts of interest were disclosed by the other authors. Publisher Copyright: ©2018 American Association for Cancer Research.

PY - 2018/10

Y1 - 2018/10

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

C2 - 30093503

AN - SCOPUS:85054377858

SN - 2159-8274

VL - 8

JO - Cancer Discovery

JF - Cancer Discovery

IS - 10

ER -

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

Abstract

Bibliographical note

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