Entrectinib
Overview
Entrectinib is an oral small-molecule tyrosine kinase inhibitor developed to treat cancers driven by ROS1 rearrangements or NTRK gene fusions. Its mechanism targets abnormal kinase activity of ROS1 and TRKA/B/C proteins, thereby disrupting proliferative signals in tumour cells harbouring those alterations. It is taken once daily and offers a targeted therapy approach in selected patient populations rather than a broad cytotoxic regimen. Entrectinib helps fulfil the paradigm of precision oncology by offering therapeutic benefit in defined genetic subsets of non-small cell lung cancer and advanced solid tumours.
Background and Date of Approval
Entrectinib, marketed as Rozlytrek, was first approved by the U.S. FDA in 2019 for ROS1-positive metastatic non-small cell lung cancer and solid tumours with NTRK gene fusions. Subsequent approval was granted in the European Union for adult and adolescent patients with NTRK-fusion positive tumours and adult patients with ROS1-positive NSCLC. The drug emerged from clinical trials that demonstrated measurable tumour responses and durability of response in patients with these genetic drivers, shifting treatment focus from histology to molecular profile in oncology.
Uses
Entrectinib is indicated in adult patients with metastatic non-small cell lung cancer whose tumours harbour ROS1 rearrangements as detected by a validated test. It is also indicated in adult and paediatric patients with solid tumours that carry an NTRK gene fusion, are metastatic or unresectable, or where surgical removal is likely to cause severe morbidity, and have progressed after prior treatment or lack alternative satisfactory therapy. The treatment strategy requires molecular testing before initiation of therapy, making it a precision-based approach rather than empirical.
Administration
Entrectinib is administered orally once daily, typically at a dose of 600 mg for adult patients with ROS1-positive NSCLC or NTRK-fusion positive solid tumours. Paediatric dosing is determined based on body surface area in children and adolescents. The capsules should be taken with or without food, and treatment continues until disease progression or unacceptable toxicity. Dose modifications may be required in the event of adverse effects, hepatic or renal impairment, or drug-drug interactions. Prior to and during therapy, assessments of left ventricular ejection fraction, serum uric acid, QT interval and electrolytes are recommended.
Side Effects
Among the most frequently observed side effects of entrectinib are fatigue, dizziness, cognitive impairment, taste changes, constipation, diarrhea, edema, weight gain, anemia, increased creatinine and uric acid, and visual disturbances. These side effects are generally manageable with monitoring and symptomatic care, although they may impact quality of life if unaddressed.
Warnings
Entrectinib carries warnings for more severe adverse events such as congestive heart failure, mood disorders, cognitive dysfunction, QT interval prolongation, fractures, embryo-fetal toxicity, and hepatotoxicity. Liver enzyme elevations are common, and though clinically apparent liver injury is rare, careful monitoring is essential. The drug must be used cautiously in patients with pre-existing cardiac conditions or those taking concomitant QT-prolonging medications; in such cases discontinuation may be required if severe toxicity arises.
Precautions
Entrectinib is metabolised primarily via the CYP3A4 enzyme system, and strong inhibitors or inducers of CYP3A4 can significantly affect its plasma concentrations. Patients should be reviewed for concomitant use of such agents and electrolyte disturbances that can predispose to QT prolongation. Pregnancy and breastfeeding are contraindicated due to potential for embryo-fetal harm. Additionally, this therapy should only be initiated after confirmation of the relevant molecular alteration (ROS1 or NTRK) and appropriate baseline assessments. Regular monitoring for cardiac, hepatic and neurological adverse effects is advised.
Expert Tips
Ensure molecular testing is completed and documented before selecting entrectinib. Counsel patients about the importance of adherence to once-daily dosing and prompt reporting of symptoms such as shortness of breath, new cognitive changes, mood disturbances, or visual problems. Prior to therapy initiation assess baseline ECG, hepatic and renal function, serum uric acid and left ventricular ejection fraction, and monitor these periodically. Store capsules at room temperature in a dry place, advise on medication reconciliation regarding CYP3A modifiers, and ensure patients understand the therapy continues until progression or unacceptable toxicity.