Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (28578312)
Authors Drilon A, Nagasubramanian R, Blake JF, Ku N, Tuch BB, Ebata K, Smith S, Lauriault V, Kolakowski GR, Brandhuber BJ, Larsen PD, Bouhana KS, Winski SL, Hamor R, Wu WI, Parker A, Morales TH, Sullivan FX, DeWolf WE, Wollenberg LA, Gordon PR, Douglas-Lindsay DN, Scaltriti M, Benayed R, Raj S, Hanusch B, Schram AM, Jonsson P, Berger MF, Hechtman JF, Taylor BS, Andrews S, Rothenberg SM, Hyman DM
Title A Next-Generation TRK Kinase Inhibitor Overcomes Acquired Resistance to Prior TRK Kinase Inhibition in Patients with TRK Fusion-Positive Solid Tumors.
Journal Cancer discovery
Vol 7
Issue 9
Date 2017 09
URL
Abstract Text 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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Selitrectinib Selitrectinib 7 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
Selitrectinib LOXO-195|BAY 2731954 Trk Receptor Inhibitor (Pan) 29 Selitrectinib (LOXO-195) is an inhibitor of NTRK1, NTRK2, and NTRK3, which may result in inhibition of tumor growth and tumor regression (PMID: 28578312).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
NTRK1 G595R NTRK1 act mut Advanced Solid Tumor decreased response Larotrectinib Preclinical Actionable In a preclinical study, a cell line oncogenic mouse model expressing an NTRK1 activating mutation and a secondary resistance mutation, NTRK1 G595R, demonstrated a decreased response when treated with Vitrakvi (larotrectinib) (PMID: 28578312). 28578312
NTRK1 G667C NTRK1 act mut Advanced Solid Tumor decreased response Larotrectinib Preclinical Actionable In a preclinical study, a cell line oncogenic mouse model expressing an NTRK1 activating mutation and a secondary resistance mutation, NTRK1 G667C, demonstrated a decrease response when treated with Vitrakvi (larotrectinib) (PMID: 28578312). 28578312
NTRK1 act mut Advanced Solid Tumor predicted - sensitive Selitrectinib Preclinical Actionable In a preclinical study, a cell line oncogenic mouse model expressing a constitutively active NTRK1 mutation demonstrated decreased phosphorylation of Ntrk1 and inhibition of tumor growth when treated with Selitrectinib (LOXO-195) (PMID: 28578312). 28578312
NTRK1 G667C NTRK1 act mut Advanced Solid Tumor sensitive Selitrectinib Preclinical Actionable In a preclinical study, a cell line oncogenic mouse model expressing an NTRK1 activating mutation and a secondary resistance mutation, NTRK1 G667C, was sensitive to treatment with Selitrectinib (LOXO-195), demonstrating inhibition of tumor growth (PMID: 28578312). 28578312
NTRK1 act mut Advanced Solid Tumor predicted - sensitive Larotrectinib Preclinical Actionable In a preclinical study, a cell line oncogenic mouse model expressing a constitutively active NTRK1 mutation demonstrated decreased phosphorylation of Ntrk1 and inhibition of tumor growth when treated with Vitrakvi (larotrectinib) (PMID: 28578312). 28578312
NTRK1 G595R NTRK1 act mut Advanced Solid Tumor sensitive Selitrectinib Preclinical Actionable In a preclinical study, a cell line oncogenic mouse model expressing an NTRK1 activating mutation and a secondary resistance mutation, NTRK1 G595R, demonstrated sensitivity to Selitrectinib (LOXO-195) (PMID: 28578312). 28578312