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.

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<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)

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