Related Experiment Video

Updated: Feb 6, 2026

A Blood-based Test for the Detection of ROS1 and RET Fusion Transcripts from Circulating Ribonucleic Acid Using Digital Polymerase Chain Reaction
10:35

A Blood-based Test for the Detection of ROS1 and RET Fusion Transcripts from Circulating Ribonucleic Acid Using Digital Polymerase Chain Reaction

Published on: April 5, 2018

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

Alexander Drilon1, Sai-Hong Ignatius Ou2, Byoung Chul Cho3

  • 1Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, New York.

Cancer Discovery
|August 11, 2018
PubMed

Insights

Repotrectinib is a novel tyrosine kinase inhibitor (TKI) that overcomes resistance mutations in ALK, ROS1, and NTRK cancers. This next-generation TKI shows promise for patients with advanced, rearranged solid tumors who have relapsed on prior therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Tyrosine kinase inhibitors (TKIs) targeting ALK, ROS1, or TRK rearrangements offer clinical benefits in various cancers.
  • Acquired resistance to TKIs, often due to solvent-front mutations in kinase domains, limits treatment efficacy.
  • Specific mutations like ALKG1202R and ROS1G2032R are particularly challenging to overcome with existing therapies.

Purpose of the Study:

  • To evaluate repotrectinib (TPX-0005), a next-generation TKI, for its efficacy against ALK, ROS1, and TRK fusions.
  • To assess repotrectinib's activity against resistant solvent-front mutations.
  • To establish clinical proof of concept for repotrectinib in patients with TKI-resistant fusions.

Main Methods:

  • Preclinical in vitro and in vivo studies of repotrectinib's potency and selectivity.
  • First-in-human Phase I/II clinical trial enrollment.
  • Assessment of confirmed responses in patients with ROS1 or NTRK3 fusion-positive cancers.

Main Results:

  • Repotrectinib demonstrated potent activity against ROS1, TRKA-C, and ALK targets.
  • The drug showed efficacy against various solvent-front substitutions in vitro and in vivo.
  • Clinical trials confirmed responses in patients with ROS1 or NTRK3 fusions resistant to prior TKIs due to solvent-front mutations.

Conclusions:

  • Repotrectinib effectively overcomes acquired resistance mediated by solvent-front mutations in ROS1, NTRK1-3, and ALK.
  • Repotrectinib represents a potential therapeutic option for patients with ROS1-, NTRK1-3-, or ALK-rearranged tumors who have progressed on earlier TKIs.

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