Safety of current treatment options for NTRK fusion-positive cancers

ABSTRACT

Introduction

Oncogenic NTRK fusions have been found in multiple cancer types affecting adults and/or children, including rare tumors with pathognomonic fusions and common cancers in which fusions are rare. The tropomyosin receptor kinase inhibitors (TRKi) larotrectinib and entrectinib are among the first agents with tissue agnostic FDA approvals for cancer treatment, and additional TRKi are undergoing development. As experience with TRKi grow, novel mechanisms of resistance and on/off target side effects have become increasingly important considerations.

Areas covered

Authors reviewed literature published through July 2023 on platforms such as PubMed, clinicaltrials.gov, and manufacturer/FDA drug labels, focusing on the development of TRKi, native functions of TRK, phenotype of congenital TRK aberrancies, efficacy, and safety profile of TRKi in clinical trials and investigator reports, and on/off target adverse effects associated with TRKi (Appendix A).

Expert Opinion

TRKi have histology-agnostic activity against tumors with NTRK gene fusions. TRKi are generally well tolerated with a side effect profile that compares favorably to cytotoxic chemotherapy. There are numerous ongoing studies investigating TRKi as frontline, adjuvant, and salvage therapy. It will be critical to continue to gather long-term safety data on the use of these agents, particularly in children.

KEYWORDS:

• Entrectinib
• larotrectinib
• neurotrophic factor
• NTRK
• repotrectinib
• TRK
• TRK inhibitor
• tropomyosin receptor kinase

Article highlights

• Tropomyosin receptor kinase inhibitors (TRKi) inhibit neurotrophin tyrosine kinase receptors TRK A, B, and C, which can be constitutively activated by oncogenic mutations in NTRK 1, 2, and 3, respectively. NTRK fusions have been found in multiple cancer types affecting adults and/or children.

• TRKi can be categorized as selective or nonselective for TRK, and first-generation versus second-generation drugs with activity against some acquired resistance mutations.

• Objective response rates (ORR) to TRKi in patients whose tumors harbor NTRK fusions have been consistently high and generally agnostic to histology, NTRK subtype, and fusion partner.

• While the first-generation TRKi larotrectinib and entrectinib have shown dramatic response in TRK fusion positive disease, durability of response can be shortened by development of mutations in TRK kinase domains in some patients.

• To address resistance mechanisms, second-generation TRK inhibitors are in early clinical development.

• Clinical trial data indicate the most common adverse effects for larotrectinib are elevations in liver function enzymes, arthralgia/myalgia, fatigue, anemia, neutropenia.

• The most common adverse effects reported for entrectinib are fatigue, peripheral edema, dizziness, weight gain, dysgeusia, nausea, constipation, diarrhea, elevations in liver enzymes, anemia, decreased in lymphocytes, decreases in neutrophils, and dyspnea.

Declaration of interest

A Yang is supported by a T32 in Clinical Pharmacology from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM008562. T Laetsch receives funding from the US Department of Defense, Grant Number W81XWH2210654, and the Alex Lemonade Stand Foundation Center of Excellence Award. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All authors were involved in the conception and design, as well as analysis and interpretation of the data; drafted the paper and revised it critically for intellectual content; and approved of the version to be published. All authors agree to be accountable for all aspects of the work.

Additional information

Funding

Adeline Yang is supported by a T32 in Clinical Pharmacology from the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM008562. Theodore Laetsch receives funding from the US Department of Defense, Grant Number W81XWH2210654, and the Alex Lemonade Stand Foundation Center of Excellence Award.