The potential of neurotrophic tyrosine kinase (NTRK) inhibitors for treating lung cancer

ABSTRACT

Introduction: Molecular alterations in neurotrophic tyrosine kinase (NTRK) genes have been identified in several solid tumors including lung cancer. Pre-clinical and clinical evidence suggested their potential role as oncogenic drivers and predictive biomarkers for targeted inhibition, leading to the clinical development of a new class of compounds blocking the NTRK molecular pathway, which are currently undner early clinical investigation.

Area covered: This review describes the biology of the NTRK pathway and its molecular alterations in lung cancer. It focuses on the pre-clinical and clinical development of emerging NTRK inhibitors, which have shown very promising activity in early phase I studies.

Expert opinion: Among the several NTRK-inhibitors, entrectinib and LOXO-101 are those in more advanced stage of clinical development. Both agents have shown encouraging activity along with a tolerable safety profile in patients with different solid tumors harboring NTRK-fusions, emerging as new promising therapeutic options for molecularly selected patients with advanced Trk-driven lung cancers. Results from ongoing phase II basket trials are eagerly awaited.

KEYWORDS:

• NTRK1/2/3
• TrkA/B/C
• NTRK-inhibitors
• targeted therapy
• lung cancer

Article highlights.

• Neurotrophic tyrosine kinase receptors (NTRK1/2/3) molecular alterations have been identified in several solid tumors, including lung cancer.

• Several multi-kinase small molecule inhibitors with pan-Trk activity are currently under investigation.

• Preclinical studies have shown potent in vitro and in vivo antitumor effects of NTRK inhibitors in Trk A/B/C-dependent tumor models.

• Early phase I studies of pan-Trk inhibitors Entrectinib and LOXO-101 first showed promising activity and good tolerability profile in advanced solid tumors harboring NTRK oncogenic fusions, including patients with lung cancer.

• Targeting Trk-pathway could offer new therapeutic opportunities in the near future for a subgroup of lung cancer patients for whom there are not currently approved targeted therapies.

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Financial and competing interests disclosure

L Raez receives research support from 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 apart from those disclosed.