Entrectinib (Rozlytrek) is a targeted kinase inhibitor indicated for the treatment of ROS1‑positive non‑small cell lung cancer and NTRK gene fusion‑positive solid tumors.
1. Overview of Entrectinib (Rozlytrek)
1.1 Drug Class and Indications
1.1.1 Drug Class: Kinase inhibitor that targets kinases including TRK, ROS1, and ALK.
1.1.2 Indication 1: Metastatic ROS1‑positive non‑small cell lung cancer in adults (confirmed by an FDA‑approved test).
1.1.3 Indication 2: NTRK gene fusion‑positive solid tumors in adults and pediatric patients aged >1 month, who meet all of the following criteria:
(1) Have NTRK gene fusion (confirmed by an FDA‑approved test).
(2) Have no known acquired resistance mutations.
(3) Have metastatic disease, or surgical resection is likely to result in severe complications.
(4) Have progressed following prior therapy, or have no satisfactory alternative treatment options.
1.2 Pretreatment Evaluation
(1) Left ventricular ejection fraction: Evaluation is required in patients with symptoms or risk factors for heart failure.
(2) Serum uric acid level.
(3) QT interval and electrolytes.
2. Mechanism of Action and Drug Interactions
2.1 Mechanism of Action
(1) Target inhibition: Entrectinib inhibits TRKA, TRKB, TRKC (encoded by NTRK1, NTRK2, NTRK3), ROS1, and ALK kinases, with IC₅₀ values of 0.1–2 nM.
(2) Antitumor activity: Blocks tumor cell proliferation by inhibiting downstream signaling pathways driven by fusion proteins.
(3) Blood‑brain barrier penetration: In animal studies, the brain‑to‑plasma concentration ratio is 0.4–2.2, showing inhibitory activity against intracranial tumors.
(4) Active metabolite: The major metabolite M5 demonstrates in vitro activity similar to the parent drug.
2.2 Drug Interaction: CYP3A Inhibitors
Strong or moderate CYP3A inhibitors (e.g., itraconazole):
(1) May increase entrectinib AUC by 6‑fold and Cmax by 1.7‑fold.
(2) Adults and pediatric patients ≥2 years: If co‑administration cannot be avoided, reduce the dose and limit the duration to no more than 14 days (see Dose Modification Table 5 for details).
(3) Pediatric patients <2 years: Avoid co‑administration.
(4) Grapefruit products: Avoid consumption during treatment, as they contain CYP3A inhibitors.
2.3 Drug Interaction: CYP3A Inducers
Strong or moderate CYP3A inducers (e.g., rifampicin):
(1) May decrease entrectinib AUC by 77% and Cmax by 56%.
(2) Recommendation: Avoid co‑administration to prevent reduced efficacy.
2.4 Drug Interaction: QT‑Prolonging Drugs
(1) Risk: Entrectinib can prolong the QT interval; co‑administration with other QT‑prolonging drugs may increase the risk of arrhythmias.
(2) Recommendation: Avoid co‑administration. If unavoidable, closely monitor ECG and electrolytes.
2.5 Drug Interaction: Gastric Acid Suppressants
Proton pump inhibitors (e.g., lansoprazole):
(1) With capsules: Entrectinib AUC decreased by 25%, Cmax decreased by 23%.
(2) With oral suspension: AUC increased by 25%, Cmax increased by 17%.
(3) Clinical significance: Changes are not clinically meaningful; no dose adjustment is needed.
2.6 Drug Interaction: Transporter Substrates
(1) Digoxin (P‑gp substrate): Co‑administration may increase digoxin Cmax by 28% and AUC by 18%.
(2) Recommendation: Monitor digoxin plasma concentrations during co‑administration.
3. Management of Missed Doses and Overdose
3.1 Missed Dose
(1) Principle: If a dose is missed and the next scheduled dose is >12 hours away, take the missed dose immediately; otherwise, skip the missed dose and resume the regular dosing schedule.
(2) Note: Do not take a double dose to compensate for the missed dose.
3.2 Management of Vomiting
(1) Immediate vomiting: If vomiting occurs immediately after dosing, repeat the same dose.
(2) Delayed vomiting: If vomiting occurs a considerable time after dosing, do not re‑dose; take the next scheduled dose.
3.3 Management of Overdose
(1) Seek medical attention immediately if overdose is suspected.
(2) Symptom monitoring: Closely monitor ECG, liver function, uric acid, neurological symptoms, etc.
(3) Supportive care: Administer appropriate supportive treatment based on clinical manifestations.
(4) Treatment interruption: Depending on the severity of adverse reactions, interrupt dosing, reduce the dose, or discontinue permanently.
