LAUSR

NTRK gene fusions involving either NTRK1, NTRK2 or NTRK3 (encoding the neurotrophin receptors TRKA, TRKB and TRKC, respectively) are oncogenic drivers of various adult and paediatric tumour types. These fusions can be detected in the clinic using a variety of methods, including tumour DNA and RNA sequencing and plasma cell-free DNA profiling. The treatment of patients with NTRK fusion-positive cancers with a first-generation TRK inhibitor, such as larotrectinib or entrectinib, is associated with high response rates (>75%), regardless of tumour histology. First-generation TRK inhibitors are well tolerated by most patients, with toxicity profiles characterized by occasional off-tumour, on-target adverse events (attributable to TRK inhibition in non-malignant tissues). Despite durable disease control in many patients, advanced-stage NTRK fusion-positive cancers eventually become refractory to TRK inhibition; resistance can be mediated by the acquisition of NTRK kinase domain mutations. Fortunately, certain resistance mutations can be overcome by second-generation TRK inhibitors, including LOXO-195 and TPX-0005 that are being explored in clinical trials. In this Review, we discuss the biology of NTRK fusions, strategies to target these drivers in the treatment-naive and acquired-resistance disease settings, and the unique safety profile of TRK inhibitors.TRK fusion proteins are pathognomonic in certain rare tumour types and present in a small subset of diverse cancer types, including some common cancers; TRK inhibitors have promising efficacy in the treatment of these cancers, in a histology-agnostic manner. In this Review, the biology of TRK signalling and TRK fusions, strategies to target these drivers, the unique safety profile of TRK inhibitors and mechanisms of and strategies to overcome acquired resistance to these agents are discussed.Key pointsNTRK fusions, encoding TRK fusion proteins, are oncogenic drivers of a wide variety of adult and paediatric tumours, supporting a basket trial approach to drug development.These alterations are found at high frequencies (up to or greater than 90%) in rare cancer types (secretory breast carcinoma, mammary analogue secretory carcinoma, cellular or mixed congenital mesoblastic nephroma and infantile fibrosarcoma) and at lower frequencies (commonly <1%) in a range of other tumour types.NTRK fusions are clinically actionable: first-generation TRK tyrosine kinase inhibitors (larotrectinib or entrectinib) result in histology-agnostic responses in both adult and paediatric patients with NTRK fusion-positive cancers.Resistance to TRK inhibition can be mediated by the acquisition of NTRK kinase domain mutations, including solvent-front and gatekeeper mutations; second-generation TRK inhibitors have been developed to overcome these mechanisms of resistance.First-generation TRK inhibitors are generally well-tolerated and, with consideration of the biological roles of TRK receptors in normal development and adulthood, the occasional on-target adverse effects are predictable.