Tropomyosin Receptor Kinase Inhibitors for the Treatment of TRK Fusion Cancer.

Chromosomal rearrangements of resulting in gene fusions ( gene fusions) have been clinically validated as oncogenic drivers in a wide range of human cancers. Typically, gene fusions involve both inter- and intrachromosomal fusions of the 5' regions of a variety of genes with the 3' regions of genes leading to TRK fusion proteins with constitutive, ligand-independent activation of the intrinsic tyrosine kinase. The incidence of gene fusions can range from the majority of cases in certain rare cancers to lower rates in a wide range of more common cancers. Two small-molecule TRK inhibitors have recently received regulatory approval for the treatment of patients with solid tumors harboring gene fusions, including the selective TRK inhibitor larotrectinib and the TRK/ROS1/ALK multikinase inhibitor entrectinib. In this review, we consider the practicalities of detecting tumors harboring gene fusions, the pharmacologic properties of TRK inhibitors currently in clinical development, the clinical evidence for larotrectinib and entrectinib efficacy, and possible resistance mechanisms.