A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors. Academic Article uri icon

Overview

abstract

  • Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. Although responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a selective TRK TKI designed to overcome acquired resistance mediated by recurrent kinase domain (solvent front and xDFG) mutations identified in multiple patients who have developed resistance to TRK TKIs. Activity against these acquired mutations was confirmed in enzyme and cell-based assays and in vivo tumor models. As clinical proof of concept, the first 2 patients with TRK fusion-positive cancers who developed acquired resistance mutations on larotrectinib were treated with LOXO-195 on a first-in-human basis, utilizing rapid dose titration guided by pharmacokinetic assessments. This approach led to rapid tumor responses and extended the overall duration of disease control achieved with TRK inhibition in both patients.Significance: LOXO-195 abrogated resistance in TRK fusion-positive cancers that acquired kinase domain mutations, a shared liability with all existing TRK TKIs. This establishes a role for sequential treatment by demonstrating continued TRK dependence and validates a paradigm for the accelerated development of next-generation inhibitors against validated oncogenic targets. Cancer Discov; 7(9); 963-72. ©2017 AACR.See related commentary by Parikh and Corcoran, p. 934This article is highlighted in the In This Issue feature, p. 920.

authors

  • Drilon, Alexander
  • Nagasubramanian, Ramamoorthy
  • Blake, James F
  • Ku, Nora
  • Tuch, Brian B
  • Ebata, Kevin
  • Smith, Steve
  • Lauriault, Veronique
  • Kolakowski, Gabrielle R
  • Brandhuber, Barbara J
  • Larsen, Paul D
  • Bouhana, Karyn S
  • Winski, Shannon L
  • Hamor, Robyn
  • Wu, Wen-I
  • Parker, Andrew
  • Morales, Tony H
  • Sullivan, Francis X
  • DeWolf, Walter E
  • Wollenberg, Lance A
  • Gordon, Paul R
  • Douglas-Lindsay, Dorothea N
  • Scaltriti, Maurizio
  • Benayed, Ryma
  • Raj, Sandeep
  • Hanusch, Bethany
  • Schram, Alison
  • Jonsson, Philip
  • Berger, Michael
  • Hechtman, Jaclyn F
  • Taylor, Barry S
  • Andrews, Steve
  • Rothenberg, S Michael
  • Hyman, David M

publication date

  • June 3, 2017

Research

keywords

  • Antineoplastic Agents
  • Drug Resistance, Neoplasm
  • Neoplasms
  • Protein Kinase Inhibitors
  • Receptor, trkA

Identity

PubMed Central ID

  • PMC5581710

Scopus Document Identifier

  • 85028777325

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-17-0507

PubMed ID

  • 28578312

Additional Document Info

volume

  • 7

issue

  • 9