Larotrectinib for the treatment of TRK fusion solid tumors

ABSTRACT

Introduction: TRK fusions occur across a wide range of cancers in children and adults. These fusions drive constitutive expression and ligand-independent activation of the TRK kinase and are oncogenic. Larotrectinib is the first highly potent and selective small molecule ATP competitive inhibitor of all three TRK kinases to enter clinical development.

Areas covered: This review covers the current preclinical and clinical evidence for TRK inhibitors for TRK fusion cancers, focusing on larotrectinib.

Expert commentary: Larotrectinib has demonstrated a remarkable 75% centrally confirmed objective response rate in patients with TRK fusion cancers in phase 1 and phase 2 clinical trials with generally mild side effects. Responses appear independent of the patient’s age, underlying histology, and specific fusion partner and are durable in many patients. Larotrectinib is likely to be the first FDA-approved histology-agnostic molecularly targeted therapy. The evolving role of molecular profiling of advanced cancers is discussed.

KEYWORDS:

• Larotrectinib
• TRK inhibitor
• TRK fusion
• NTRK
• neurotrophin receptor

Declaration of interest

TW Laetsch discloses consulting for Loxo Oncology, Bayer, Eli Lilly, and Novartis. TW Laetsch’s institution has received research funding from Pfizer. DS Hawkins discloses unpaid consulting for Loxo Oncology. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial relationships to disclose.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial relationships to disclose. Loxo Oncology provided a scientific accuracy review at the request of the journal editor.

Additional information

Funding

This manuscript was not funded.