Antitumor activity of larotrectinib in tumors harboring NTRK gene fusions: a short review on the current evidence

Biagio Ricciuti,1 Carlo Genova,2 Lucio Crinò,3 Massimo Libra,4 Giulia Costanza Leonardi4,51Department of Medical Oncology, Thoracic Oncology Unit, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy; 2Lung Cancer Unit, Ospedale Policlinico San Martino, Genova 16132, Italy; 3Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, Italy; 4Department of Biomedical and Biotechnological Sciences, Pathology and Oncology Section, University of Catania, Catania, Italy; 5Department of Pathology, Children’s Hospital, Boston, MA, USAAbstract: The development of deep-sequencing methods is now unveiling a new landscape of previously undetected gene fusion across different tumor types. Chromosomal translocation involving the NTRK gene family occur across a wide range of cancers in both children and adults. Preclinical studies have demonstrated that chimeric proteins encoded by NTRK rearrangements have oncogenic properties and drive constitutive expression and ligand-independent activation. Larotrectinib (ARRY470, LOXO101, Vitrakvi) is a highly and potent inhibitor of TRKA, TRKB, and TRKC, and has demonstrated rema rkable antitumor activity against TRK-fusion-positive cancers with a favorable side-effect profile in phase I/II clinical trials. In November 2018, the US Food and Drug Administration granted accelerated approval to larotrectinib for adult and pediatric patients with solid tumors harboring NTRK gene fusions without known acquired resistance mutation. In this review, we discuss the clinical activity and safety profile of larotrectinib, focusing on the clinical trials that led to its first global approval.Keywords: NTRK, chromosomal rearrangements, larotrectinib, resistanc