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

被引：401

作者：

Drilon, Alexander ^{[1
]}

Ou, Sai-Hong Ignatius ^{[2
]}

Cho, Byoung Chul ^{[3
]}

Kim, Dong-Wan ^{[4
]}

Lees, Jeeyun ^{[5
]}

Lin, Jessica J. ^{[6
]}

Zhu, Viola W. ^{[2
]}

Ahns, Myung-Ju ^{[5
]}

Camidge, D. Ross ^{[7
]}

Nguyen, Judy ^{[1
]}

Zhai, Dayong ^{[8
]}

Deng, Wei ^{[8
]}

Huang, Zhongdong ^{[8
]}

Rogers, Evan ^{[8
]}

Liu, Juliet ^{[8
]}

Whitten, Jeff ^{[8
]}

Lim, John K. ^{[8
]}

Stopatschinskaja, Shanna ^{[8
]}

Hyman, David M. ^{[1
]}

Doebele, Robert C. ^{[7
]}

Cui, J. Jean ^{[8
]}

Shaw, Alice T. ^{[6
]}

机构：

[1] Weill Cornell Med Coll, Mem Sloan Kettering Canc Ctr, New York, NY USA

[2] Univ Calif Irvine, Sch Med, Chao Family Comprehens Canc Ctr, Orange, CA 92668 USA

[3] Yonsei Univ, Coll Med, Yonsei Canc Ctr, Severance Hosp, Seoul, South Korea

[4] Seoul Natl Univ Hosp, Seoul, South Korea

[5] Sungkyunkwan Univ, Samsung Med Ctr, Sch Med, Seoul, South Korea

[6] Harvard Med Sch, Massachusetts Gen Hosp, Boston, MA USA

[7] Univ Colorado Denver, Anschutz Med Campus, Aurora, CO USA

[8] TP Therapeut Inc, 10628 Sci Ctr Dr,Ste 225, San Diego, CA 92121 USA

来源：

CANCER DISCOVERY | 2018年 / 8卷 / 10期

关键词：

CELL LUNG-CANCER; OVERCOMES CRIZOTINIB RESISTANCE; ACQUIRED-RESISTANCE; KINASE INHIBITION; SOLID TUMORS; ALK; ROS1; TRK; ENTRECTINIB; ALECTINIB;

D O I：

10.1158/2159-8290.CD-18-0484

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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, ROSI, 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 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 solventfront 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 fusionpositive 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-, NTRKI-3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs. (C) 2018 AACR.

引用

页码：1227 / 1236

页数：10

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