Safety of current treatment options for NTRK fusion-positive cancers

Introduction: Oncogenic NTRK fusions have been found in multiple cancer types affecting adults and/or children, including rare tumors with pathognomonic fusions and common cancers in which fusions are rare. The tropomyosin receptor kinase inhibitors (TRKi) larotrectinib and entrectinib are among the first agents with tissue agnostic FDA approvals for cancer treatment, and additional TRKi are undergoing development. As experience with TRKi grow, novel mechanisms of resistance and on/off target side effects have become increasingly important considerations.Areas covered: Authors reviewed literature published through July 2023 on platforms such as PubMed, clinicaltrials.gov, and manufacturer/FDA drug labels, focusing on the development of TRKi, native functions of TRK, phenotype of congenital TRK aberrancies, efficacy, and safety profile of TRKi in clinical trials and investigator reports, and on/off target adverse effects associated with TRKi (Appendix A).Expert Opinion: TRKi have histology-agnostic activity against tumors with NTRK gene fusions. TRKi are generally well tolerated with a side effect profile that compares favorably to cytotoxic chemotherapy. There are numerous ongoing studies investigating TRKi as frontline, adjuvant, and salvage therapy. It will be critical to continue to gather long-term safety data on the use of these agents, particularly in children.