Breakthroughs and challenges in the management of tropomyosin receptor kinase fusion-positive tumors

The past decade has witnessed a paradigm shift in the treatment of cancer, moving from ‘one size fits all’ to a more precision medicine-based approach owing to the development of molecular diagnostic technologies capable of identifying an increasing number of actionable genomic alterations in the tumor tissue and circulating tumor DNA. Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer are notable examples of successful molecularly targeted therapies in oncology (1,2). These therapies have not only proven to improve overall survival compared to standard chemotherapy, but are also remarkably well tolerated leading to an enormous impact on maintaining a good quality of life for patients with advanced or metastatic cancer. Historically, the role of oncogene rearrangements in tumorigenesis was considered negligible because of its very low prevalence compared with DNA sequencing alterations or amplifications. However, the discovery of therapeutic agents targeting gene rearrangements involving ALK, ROS1, and RET have now established gene fusion as one of the important therapeutic targets (3). One such gene fusion that has gained an increasing amount of interest in recent years is neurotrophic receptor tyrosine kinase (NTRK)