Entrectinib for the treatment of metastatic NSCLC: safety and efficacy

ABSTRACT

Introduction: Gene fusions are strong driver alterations in various cancers, increasingly diagnosed with multiple testing techniques. ROS1 fusions can be found in 1-2% of non-small cell lung cancer (NSCLC) and several tyrosine kinase inhibitors (TKIs) have been tested in this oncogene-driven disease. NTRK fusions are characteristic of a few rare types of cancer, also infrequently seen in some common cancers including NSCLC. Entrectinib is a newer ROS1 and NTRK inhibitor developed across different tumor types harboring rearrangements in these genes. Entrectinib was granted FDA accelerated approval in August 2019 for the treatment of ROS1+ NSCLC and NTRK-driven solid tumors.

Areas covered: This review covers the mechanism of action, safety, and efficacy of entrectinib in patients with metastatic NSCLC.

Expert opinion: Entrectinib is an orally bioavailable TKI of TrkA, TrkB, TrkC, and ROS1, with the ability to cross the blood-brain barrier. Entrectinib was effective and well-tolerated in patients harboring ROS1- or NTRK-rearranged NSCLC treated within phase I and II studies. Entrectinib appears to be the most appropriate treatment choice for TKIs-naïve patients, especially in those presenting brain metastasis. Conversely, in case of systemic progression with the evidence of acquired resistance mutations in ROS1 or Trk proteins, a sequential therapy with entrectinib could not be successful.

KEYWORDS:

• Entrectinib
• lung cancer
• NSCLC
• NTRK
• ROS1
• Rozlytrek
• targeted therapy

Article highlights

• ROS1 fusions can be found in 1–2% of non-small-cell lung cancers (NSCLCs), but they are enriched among younger and never-smokers patients.

• NTRK fusions interest less than 0.5% of all NSCLCs, and about 3% of cases with no other driver oncogenes.

• Entrectinib is a potent orally bioavailable tyrosine kinase inhibitor of TrkA, TrkB, TrkC, and ROS1, with the ability to cross the blood-brain barrier (BBB).

• Entrectinib encompasses higher intracranial activity than crizotinib, with similar duration of response and manageable toxicity profile and can be an alternative first-line treatment for patients with ROS1-rearranged NSCLC.

• Entrectinib demonstrated high response rate and durable response in patients affected by NTRK-rearranged tumors, including NSCLC.

• Because of the capability of entrectinib to cross the BBB and the neurophysiological function of Trk receptors, peculiar side-effects mediated by Trk inhibition should be monitored (including cognitive impairment, increased appetite, or dizziness).

• Entrectinib is an appropriate treatment choice for TKIs-naïve patients with ROS1 or NTRK-positive NSCLC, while evidences of activity against the most frequent acquired mutations related to TKI-resistance are lacking.

Declaration of interest

Andrea Sartore-Bianchi has served on the advisory board for Amgen, Bayer, Sanofi and Servier. Salvatore Siena has served on the advisory board for Amgen, Bayer, BMS, Sanofi, Celgene, Incyte, Merck, Novartis, Roche and Seattle Genetics. 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 disclosures

One peer reviewer has attended editorial activities sponsored by Roche and Bristol Myers Squibb. Another reviewer has received funding for attending advisory boards by Genentech/Roche. Peer reviewers have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was partially funded by Fondazione Oncologia Niguarda Onlus.