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

Abstract

Chromosomal rearrangements of <i>NTRK1-3</i> resulting in gene fusions (<i>NTRK</i> gene fusions) have been clinically validated as oncogenic drivers in a wide range of human cancers. Typically, <i>NTRK</i> gene fusions involve both inter- and intrachromosomal fusions of the 5' regions of a variety of genes with the 3' regions of <i>NTRK</i> genes leading to TRK fusion proteins with constitutive, ligand-independent activation of the intrinsic tyrosine kinase. The incidence of <i>NTRK</i> 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 <i>NTRK</i> 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 <i>NTRK</i> gene fusions, the pharmacologic properties of TRK inhibitors currently in clinical development, the clinical evidence for larotrectinib and entrectinib efficacy, and possible resistance mechanisms.