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Entrectinib: Uses, Mechanism & Side Effects

Entrectinib is a targeted cancer drug used to treat tumours with specific genetic alterations (NTRK, ROS1, or ALK fusions). It inhibits enzymes that drive tumour growth.

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Things worth knowing about "Entrectinib"

Entrectinib is a targeted cancer drug used to treat tumours with specific genetic alterations (NTRK, ROS1, or ALK fusions). It inhibits enzymes that drive tumour growth.

What is Entrectinib?

Entrectinib is a targeted tyrosine kinase inhibitor used to treat certain cancers in which specific genetic alterations have been identified within the tumour. Marketed under the brand name Rozlytrek, it is approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). It belongs to the class of precision oncology agents – medicines designed to act on specific molecular targets within cancer cells.

Indications – When is Entrectinib Used?

Entrectinib is approved for:

Solid tumours with NTRK gene fusions (neurotrophic tyrosine receptor kinase): Adults and children from one month of age with locally advanced or metastatic solid tumours harbouring an NTRK gene fusion, where no satisfactory alternative therapy exists.
ROS1-positive non-small cell lung cancer (NSCLC): Adults with ROS1-positive advanced non-small cell lung cancer.

Treatment requires prior molecular testing to confirm the relevant genetic alteration in the tumour.

Mechanism of Action

Entrectinib acts as an ATP-competitive inhibitor, selectively blocking the following kinases:

TRKA, TRKB, and TRKC (encoded by the NTRK1, NTRK2, and NTRK3 genes)
ROS1 (a receptor tyrosine kinase gene)
ALK (anaplastic lymphoma kinase)

In tumours carrying gene fusions of these kinases, the resulting proteins are constitutively activated, driving uncontrolled cell proliferation and survival. Entrectinib blocks these overactive kinases, disrupting the signalling pathways responsible for tumour growth. A key advantage of entrectinib over earlier agents is its CNS penetration: the drug is able to cross the blood-brain barrier, making it effective against brain metastases as well.

Dosage and Administration

Entrectinib is taken orally in capsule form. The recommended dose depends on the age and body weight of the patient:

Adults: 600 mg once daily
Children and adolescents: Dose calculated by body surface area according to the prescribing information

Capsules should be swallowed whole and not chewed or opened. Treatment is continued for as long as the patient derives clinical benefit or until unacceptable toxicity occurs.

Side Effects

Like all cancer medicines, entrectinib may cause side effects. The most commonly reported include:

Common: Fatigue, nausea, vomiting, constipation, diarrhoea, dizziness, tingling (paraesthesia), cognitive disturbances, weight gain, taste changes, elevated liver enzymes
Occasional to rare but serious: Heart problems (e.g., congestive heart failure), visual disturbances, bone fractures, interstitial lung disease/pneumonitis, QT prolongation on ECG

Patients should report any new or worsening symptoms to their treating physician so that the treatment can be adjusted if necessary.

Drug Interactions

Entrectinib is primarily metabolised by the liver enzyme CYP3A4. Therefore, interactions may occur with other medicines that inhibit or induce this enzyme:

CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): may increase entrectinib plasma levels
CYP3A4 inducers (e.g., rifampicin, carbamazepine): may decrease entrectinib levels and reduce efficacy

Grapefruit and grapefruit juice should be avoided during treatment.

Special Considerations

Pregnancy and breastfeeding: Entrectinib must not be used during pregnancy. Women of childbearing potential must use reliable contraception during treatment and for at least 5 weeks after the last dose.
Driving and operating machinery: As dizziness and cognitive disturbances may occur, patients should assess their individual ability to drive.
Testing before treatment: An approved molecular diagnostic test (e.g., next-generation sequencing) must confirm the NTRK fusion or ROS1 positivity before treatment is initiated.

References

European Medicines Agency (EMA): Rozlytrek (entrectinib) – Summary of Product Characteristics. EMA, 2020. Available at: https://www.ema.europa.eu
Demetri GD et al.: Efficacy and safety of entrectinib in patients with locally advanced or metastatic NTRK fusion-positive solid tumours. Annals of Oncology, 2020; 31(11):1506–1515.
Drilon A et al.: Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1–2 trials. The Lancet Oncology, 2020; 21(2):261–270.

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