非小細胞肺癌、固態腫瘤
Non-small cell lung cancer, metastatic: Treatment of metastatic non-small cell lung cancer in adults whose tumors are ROS1-positive.
Solid tumors: Treatment of solid tumors in adult and pediatric patients ≥12 years of age that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation.

Antineoplastic Agent, Tropomyosin Receptor Kinase (TRK) Inhibitor:
Entrectinib inhibits tropomyosin tyrosine receptor kinases (TRKA, TRKB, TRKC). TRKA, TRKB, and TRKC are encoded by neurotrophic tyrosine receptor kinase (NTRK) genes NTRK1, NTRK2, and NTRK3, respectively. Entrectinib also inhibits proto-oncogenic tyrosine-protein kinase ROS1 and anaplastic lymphoma kinase (ALK). M5 (the major active entrectinib metabolite) demonstrated similar activity (in vitro) against TRK, ROS1, and ALK. Fusion proteins that include TRK, ROS1, or ALK kinase domains act as oncogenic drivers to promote hyperactivation of downstream signaling pathways, resulting in unchecked cell proliferation.

Distribution:
1. Vd: (Entrectinib) 551 L; (M5, active metabolite) 81.1 L
2. Protein binding: (Entrectinib) and (M5, active metabolite) >99% to plasma proteins
Metabolism:
Primarily hepatic via CYP3A4 to form the active metabolite M5
Excretion:
Feces (83%; 36% as unchanged parent drug and 22% as M5); urine (3%)
Pharmacodynamics:
1. Half-life elimination: (Entrectinib) 20 hours; (M5, active metabolite) 40 hours
2. Time to peak: 4 to 6 hours
3. Clearance: (Entrectinib) 19.6L/h; (M5, active metabolite) 52.4 L/h

Hypersensitivity to entrectinib or any component of the formulation.

Based on the mechanism of action and data from animal reproduction studies, in utero exposure to entrectinib may cause fetal harm.

Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer during therapy and for 7 days after the last entrectinib dose.

Cardiovascular: Edema, hypotension
Central nervous system: Fatigue, dizziness, dysesthesia, cognitive dysfunction, headache, peripheral sensory neuropathy, ataxia, sleep disorder, myasthenia
Dermatologic: Skin rash
Endocrine & metabolic: Hyperuricemia, hypernatremia, hypocalcemia, hypophosphatemia, hypoalbuminemia, increased amylase, hyperkalemia, weight gain
Gastrointestinal: Constipation, dysgeusia, diarrhea, nausea, increased serum lipase, vomiting, abdominal pain, decreased appetite
Genitourinary: Urinary tract infection
Hematologic & oncologic: Anemia, lymphocytopenia, neutropenia
Hepatic: Increased AST and ALT, increased serum alkaline phosphatase
Neuromuscular & skeletal: Myalgia, bone fracture, arthralgia, back pain, limb pain
Ophthalmic: Visual disturbance
Renal: Increased serum creatinine
Respiratory: Dyspnea, cough
Miscellaneous: Fever

600 mg once daily until disease progression or unacceptable toxicity.

(Children ≥12 years and Adolescents)
1. BSA 0.91-1.1 m²: 400 mg once daily until disease progression or unacceptable toxicity.
2. BSA 1.11-1.5 m²: 500 mg once daily until disease progression or unacceptable toxicity.
3. BSA >1.5 m²: 600 mg once daily until disease progression or unacceptable toxicity.

1. CrCl 30 to <90 mL/minute: No dosage adjustment is necessary.
2. CrCl <30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Impairment prior to treatment initiation:
1. Mild impairment (total bilirubin ≥1.5 times ULN): No dosage adjustment is necessary.
2. Moderate (total bilirubin >1.5 to 3 times ULN) or severe (total bilirubin >3 times ULN) impairment: There are no dosage adjustments provided in the manufacturer's labeling. Consider risks versus benefits to determine appropriateness of entrectinib therapy.
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Hepatotoxicity during treatment:
1. Grade 3&4: Withhold entrectinib until recovery to ≤grade 1 or to baseline; resume at the same dose if recovery occurs within 4 weeks. Permanently discontinue entrectinib if recovery does not occur within 4 weeks. For recurrent grade 3 toxicity, resume at a reduced dose if toxicity resolves within 4 weeks.
2. ALT or AST >3 times ULN with concurrent total bilirubin >1.5 times ULN (in the absence of cholestasis or hemolysis): Permanently discontinue entrectinib.