Reference Detail

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
Date 2017 Jun 03
Abstract Text Larotrectinib, a selective TRK tyrosine kinase inhibitor (TKI), has demonstrated histology-agnostic efficacy in patients with TRK fusion-positive cancers. While responses to TRK inhibition can be dramatic and durable, duration of response may eventually be limited by acquired resistance. LOXO-195 is a novel, 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 two patients with TRK fusion-positive cancers that 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
LOXO-195 LOXO-195 0 1
Drug Name Trade Name Synonyms Drug Classes Drug Description
LOXO-195 BAY 2731954 Trk Receptor Inhibitor (Pan) 23 LOXO-195 is an inhibitor of NTRK1, NTRK2, and NTRK3, which may result in inhibition of tumor growth and tumor regression (PMID: 28578312).
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
ETV6-NTRK3 congenital fibrosarcoma sensitive Larotrectinib Case Reports/Case Series Actionable In a clinical case study, a patient with congenital fibrosarcoma harboring ETV6-NTRK3 demonstrated tumor regression by 90% when treated with Vitrakvi (larotrectinib) (PMID: 28578312). 28578312