NTRK fusions in lung cancer: From biology to therapy

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• TRK (tropomyosin receptor kinase) fusions are oncogenic drivers in various cancers, including non-small cell lung cancer (NSCLC).
• Their diagnosis can be challenging due to complex genetic alterations like NTRK intron length variations.
• Next-generation sequencing (NGS) methods, particularly RNA-based NGS, enhance the detection of these fusions.

Purpose of the Study:

• To review NTRK fusions and TRK-directed targeted therapy in lung cancer.
• To discuss the efficacy and tolerability of first-generation TRK inhibitors.
• To highlight emerging next-generation TRK inhibitors and resistance mechanisms.

Main Methods:

• Literature review focusing on NTRK fusions and TRK inhibitors in lung cancer.
• Analysis of clinical trial data for TRK-targeted therapies.
• Discussion of diagnostic advancements using NGS.

Main Results:

• First-generation TRK inhibitors (larotrectinib, entrectinib) demonstrate significant antitumor activity in TRK fusion-positive cancers, including lung cancer.
• These inhibitors are generally well-tolerated but require monitoring for on-target adverse events.
• Resistance mechanisms to TRK inhibitors are being identified, prompting the development of next-generation agents.

Conclusions:

• TRK fusion-positive lung cancers can be effectively treated with TRK inhibitors, representing a tumor-agnostic therapeutic approach.
• First-generation TRK inhibitors are recommended as first-line options for TRK fusion-positive lung cancer.
• Ongoing clinical trials are evaluating next-generation TRK inhibitors to overcome resistance and improve patient outcomes.