Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations
-
- Alexander Drilon
- 1Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
-
- Sai-Hong Ignatius Ou
- 2Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California.
-
- Byoung Chul Cho
- 3Yonsei Cancer Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea.
-
- Dong-Wan Kim
- 4Seoul National University Hospital, Seoul, Republic of Korea.
-
- Jeeyun Lee
- 5Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
-
- Jessica J. Lin
- 6Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
-
- Viola W. Zhu
- 2Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California.
-
- Myung-Ju Ahn
- 5Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
-
- D. Ross Camidge
- 7University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
-
- Judy Nguyen
- 1Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
-
- Dayong Zhai
- 8TP Therapeutics Inc., San Diego, California.
-
- Wei Deng
- 8TP Therapeutics Inc., San Diego, California.
-
- Zhongdong Huang
- 8TP Therapeutics Inc., San Diego, California.
-
- Evan Rogers
- 8TP Therapeutics Inc., San Diego, California.
-
- Juliet Liu
- 8TP Therapeutics Inc., San Diego, California.
-
- Jeff Whitten
- 8TP Therapeutics Inc., San Diego, California.
-
- John K. Lim
- 8TP Therapeutics Inc., San Diego, California.
-
- Shanna Stopatschinskaja
- 8TP Therapeutics Inc., San Diego, California.
-
- David M. Hyman
- 1Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.
-
- Robert C. Doebele
- 7University of Colorado Denver, Anschutz Medical Campus, Aurora, Colorado.
-
- J. Jean Cui
- 8TP Therapeutics Inc., San Diego, California.
-
- Alice T. Shaw
- 6Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
この論文をさがす
説明
<jats:title>Abstract</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 1195</jats:p>
収録刊行物
-
- Cancer Discovery
-
Cancer Discovery 8 (10), 1227-1236, 2018-10-01
American Association for Cancer Research (AACR)