Tropomyosin receptor kinases in sarcomas - of joy and despair

The relatively recent discovery of neurotrophic tropomyosin receptor kinase (NTRK) gene arrangements as pan-tumor predictive biomarkers has led to impressive novel treatments for patients with TRK fusions. Although the number of patients who qualify for treatment is vanishingly small for cancer patients in general, a few histological subsets of sarcomas exhibit NTRK fusions more commonly leading to large expectations within the sarcoma community.

Larotrectenib and entrectenib have recently been approved based on durable responses in TRK positive cancers with nonresectable or metastatic disease, including many sarcomas. Identification of resistance mutations to TRKi has led to the development of novel salvage therapies which may soon further expand the armamentarium of treatments. The greatest barrier and frustration to date is the actual identification of patients who harbor the fusion. The dimension of rarity in sarcomas remains difficult to comprehend for both patients and caregivers. Diagnosis of NTRK fusions is complex, particularly in the context of sarcomas and can involve immunohistochemistry as a screening tool but frequently requires fluorescence-in-situ hybridization or next-generation sequencing (NGS) to confirm the diagnosis.

The growing evidence on subtype-specific incidence of NTRK fusions will help to improve strategic prioritization or exclusion of subtypes to reduce the burden of negative testing. Next-generation inhibitors provide potential salvage treatment options for patients failing first-line therapy.