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.