NTRK fusion-positive cancers and TRK inhibitor therapy

Abstract

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.

Neurotrophic tropomyosin or tyrosine receptor kinase (NTRK) genes

“…A detailed overview of TRK in development and physiology is provided by Cocco and colleagues,6 and the reader is directed to this comprehensive publication.…”

“…The ligands bind as homodimers with NTs in the following manner: TRKA binds with nerve growth factor (NGF), TRKB with brain-derived growth factor or NT-4, and TRKC with NT3. NT3 has the potential of binding with and activating TRKA and TRKB as well but has a higher affinity for TRKC 6. None of the other ligands, other than NT3, have the potential to bind with more than one of the TRK receptors.…”

“…Numerous cancers (breast, lung and neuroblastoma) have been shown to demonstrate TRK overexpression 6. Furthermore, Nakagawara et al 11 showed that neuroblastomas that overexpressed TRKA and TRKC were associated with a better prognosis.…”

“…Cocco and colleagues grouped the frequency of occurrence of tumours containing these fusions into two categories6: (1) rare tumours with a high frequency (>90%) of NTRK fusions and (2) common tumours with a lower frequency of gene fusions (<5% and 5%–25%) as illustrated in table 1.…”

“…The two inhibitors that are available are larotrectinib and entrectinib. The former is a selective inhibitor of TRKA, TRKB and TRKC and results in dramatic clinical response 6. However, as with many inhibitors, resistance occurs and second-generation TRK inhibitors are in clinical trials.…”