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A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with

Alexander Drilon1,2, Ramamoorthy Nagasubramanian3, James F Blake4

  • 1Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Cancer Discovery
|June 5, 2017
PubMed

Insights

LOXO-195, a next-generation TRK tyrosine kinase inhibitor (TKI), effectively overcomes acquired resistance mutations in TRK fusion-positive cancers. This demonstrates the potential for sequential TKI therapy to extend disease control in patients with advanced cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Larotrectinib, a TRK tyrosine kinase inhibitor (TKI), shows efficacy in TRK fusion-positive cancers.
  • Acquired resistance mutations can limit the duration of response to TRK TKIs.
  • Recurrent kinase domain mutations (solvent front and xDFG) are identified resistance mechanisms.

Purpose of the Study:

  • To evaluate LOXO-195, a selective TRK TKI, designed to overcome acquired resistance mutations.
  • To confirm activity of LOXO-195 against resistance mutations in preclinical models.
  • To establish clinical proof of concept for LOXO-195 in patients resistant to prior TRK TKIs.

Main Methods:

  • Enzyme and cell-based assays were used to confirm activity against acquired mutations.
  • In vivo tumor models were utilized to assess efficacy.
  • A first-in-human study involved rapid dose titration guided by pharmacokinetics in two patients.

Main Results:

  • LOXO-195 demonstrated activity against acquired TRK kinase domain mutations in preclinical models.
  • The first two patients treated with LOXO-195 experienced rapid tumor responses.
  • Sequential treatment with LOXO-195 extended disease control in both patients.

Conclusions:

  • LOXO-195 effectively abrogates resistance in TRK fusion-positive cancers with acquired kinase domain mutations.
  • Sequential TRK TKI therapy is a viable strategy, demonstrating continued TRK dependence.
  • This validates a paradigm for developing next-generation inhibitors against validated oncogenic targets.

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