TRK Inhibitors: Clinical Development of Larotrectinib.

PURPOSE OF REVIEW: In this review, we highlight the pre-clinical development, recent clinical studies, and future directions of larotrectinib in patients with NTRK fusion-positive tumors.

RECENT FINDINGS: The tropomyosin receptor kinase family, TrkA, TrkB, and TrkC, transmit extracellular signals via a variety of intracellular pathways to promote normal neuronal development. TrkA, B, and C are encoded by NTRK1, 2, and 3, respectively. NTRK chromosomal alterations, most commonly gene fusions, have been identified as driver mutations in a broad range of malignancies. Small molecule tyrosine kinase inhibitors of Trk, including larotrectinib, have shown broad clinical activity across multiple tumor types with NTRK fusion events. Although the prevalence of NTRK alterations is low, the exceptional activity of larotrectinib makes NTRK alterations an important predictive biomarker to screen for in any cancer.