Introduction: TRK fusions occur across a wide range of cancers in children and 
adults. These fusions drive constitutive expression and ligand-independent 
activation of the TRK kinase and are oncogenic. Larotrectinib is the first 
highly potent and selective small molecule ATP competitive inhibitor of all 
three TRK kinases to enter clinical development. Areas covered: This review 
covers the current preclinical and clinical evidence for TRK inhibitors for TRK 
fusion cancers, focusing on larotrectinib. Expert commentary: Larotrectinib has 
demonstrated a remarkable 75% centrally confirmed objective response rate in 
patients with TRK fusion cancers in phase 1 and phase 2 clinical trials with 
generally mild side effects. Responses appear independent of the patient's age, 
underlying histology, and specific fusion partner and are durable in many 
patients. Larotrectinib is likely to be the first FDA-approved 
histology-agnostic molecularly targeted therapy. The evolving role of molecular 
profiling of advanced cancers is discussed.