Neurotrophic tyrosine kinase inhibitors: A review of implications for patients, clinicians and healthcare services

Abstract

Neurotrophic tyrosine receptor kinase (NTRK) inhibitors represent the latest advancement as a treatment option in targeted therapies for malignant disease. NTRK gene fusions involving NTRK1, 2 or 3 are implicated as genetics drivers for a number of tumour types which arise within adult and paedatric patients. NTRK inhibitors (Larotrectinib and Entrectinib) are effective agents which have demonstrated clinical benefit in the treatment of NTRK fusion positive solid tumours. Larotrectinib represents the first targeted agent to receive approval from international authorisation and commissioning bodies for the treatment of a specific genetic expression indiscriminate of the site from which the tumour has arisen. As such NTRK inhibitors could pave the way for international healthcare bodies to adopt a similar approach for future targeted therapies thereby altering the manner in which healthcare providers and patients are able to access and utilise innovative, targeted treatment options in future. The potential implications of this new approach are likely to impact upon several aspects of the traditional authorisation and commissioning pathways with potential changes to the design of clinical trials, the review and approval process by regulatory bodies and immunohistopathology services.

Prognostic Value of Neurotrophic Tyrosine Receptor Kinase Gene Fusions in Solid Tumors for Overall Survival: A Systematic Review and Meta-Analysis

“… 2 Laboratory evidence and clinical evidence suggest that they are oncogenic drivers of various adult and pediatric tumor types and predictive biomarkers for targeted inhibition. 3 …”

“… 4 , 6 Larotrectinib and entrectinib represent the first innovative precision therapies to receive approval from international authorization and commissioning bodies for the treatment of a specific genetic expression, regardless of the site from which the tumor originated. 3 The development of second-generation TRK inhibitors is currently underway. Such targeted therapies have clear advantages over conventional cytotoxic treatments and the systemic side effects they induce.…”

Interstitial Deletions Generating Fusion Genes

“…The LMNA-NTRK1 codes for a chimeric tyrosine kinase. Patients with this fusion can be treated with kinase inhibitors such as crizotinib, entrectinib, and larotrectinib with significant clinical response (71,72,79,(81)(82)(83)(84)(85).…”

“…The mice developed high-grade gliomas which responded to the Ntrk1 inhibitor entrectinib. In general, patients whose cancers carry NTRK1 fusion genes have responded satisfactorily to treatment with tyrosine kinase inhibitors (85,(91)(92)(93)(94)(95).…”

A novel agnostic tumor: NTRKoma

“…This term will enable clinicians to consider NTRK inhibitors (eg, entrectinib, larotrectinib) against cancers harboring NTRK gene rearrangements regardless of the histology, age, and fusion type. 15,16…”