The promise of TRK inhibitors in pediatric cancers with NTRK fusions

Abstract

NTRK fusions are rare oncogenic drivers that occur across a range of pediatric cancers. These include infantile fibrosarcoma and secretory breast cancer in which such fusions are nearly pathognomonic, and a spectrum of more common pediatric cancers in which NTRK fusions occur at a lower frequency. Within the last 5 years, two TRK inhibitors, larotrectinib and entrectinib, have demonstrated histology-agnostic activity against NTRK fusion driven cancers and achieved FDA approval. Here the data supporting the use of these TRK inhibitors for the treatment of cancers harboring NTRK fusions is reviewed, with a particular focus on the pediatric experience. Mechanisms of acquired resistance to these first generation TRK inhibitors are discussed and investigational second generation TRK inhibitors that may overcome some of these mechanisms of resistance are highlighted.

Keywords: Entrectinib; Infantile fibrosarcoma; Larotrectinib; NTRK fusion; TRK fusion.