Identifying NTRK Gene Fusions for Targeted Therapy: ‘An Ongoing Clinical Priority’
Posted: Sunday, August 1, 2021
Theodore W. Laetsch, MD, of the Children’s Hospital of Philadelphia, and David S. Hong, MD, of The University of Texas MD Anderson Cancer Center, Houston, explore in detail the “practicalities” of detecting NTRK gene fusions, pharmacologic properties of various NTRK inhibitors and their efficacy, as well as emerging strategies for overcoming acquired resistance to these targeted agents. Their review, published in Clinical Cancer Research, suggests the creation of diagnostic algorithms to identify tumors harboring such gene fusions “remains an ongoing clinical priority.”
Next-generation sequencing has been used to detect the full spectrum of NTRK fusions with great efficacy, but it is not widely available, according to the Drs. Laetsch and Hong at the time their review was published. A commercially available pan-TRK in vitro diagnostic immunohistochemistry assay has been developed to help identify these gene fusions, potentially making testing and treatment more accessible. They noted that proper detection is imperative as NTRK2 fusions seem to be associated with primary central nervous system (CNS) tumors, and NTRK1 and NTRK3 fusions are involved with other tumor types; NTRK1 notably shows the greatest range of tumor type involvement and number of fusion partners.
Larotrectinib and entrectinib are both orally available first-generation NTRK inhibitors, with known efficacy against many cancers. Phase I/II studies demonstrated objective response rates of 79% and 57%, respectively, granting them tumor-agnostic regulatory approval from the U.S. Food and Drug Administration for patients with solid tumors harboring NTRK fusions. Both agents also have been associated with CNS activity.
According to the authors, changes to bypass pathways and mutations affecting the tyrosine kinase domain of the driver have influenced resistance to NTKR inhibitors, resulting in the development of next-generation TRK inhibitors selitrectinib and repotrectinib. Selitrectinib demonstrated preclinical activity against NTRK resistance mutations linked to treatment with larotrectinib, and reprotrectinib was designed to overcome clinical resistance mutations associated with entrectinib therapy. Clinical trials for both agents are still ongoing.
Disclosure: For full disclosures of the study authors, visit clincancerres.aacrjournals.org.