Entrectinib

Indications

Entrectinib is used for: Non-small Cell Lung Cancer, Neurotrophic Tyrosine Receptor Kinase Gene Fusion Solid Tumors

Adult Dose

Non-small Cell Lung Cancer Indicated for metastatic non-small cell lung cancer (NSCLC) in adults whose tumors are ROS1-positive 600 mg PO qDay Continue until disease progression or unacceptable toxicity Neurotrophic Tyrosine Receptor Kinase Gene Fusion Solid Tumors Indicated for patients with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and progressed following treatment or have no satisfactory alternative therapy 600 mg PO qDay Continue until disease progression or unacceptable toxicity Hepatic impairment Mild (total bilirubin ?1.5x ULN): No dosage adjustment necessary Moderate-to-severe (total bilirubin >1.5x ULN): Not studied

Child Dose

Neurotrophic Tyrosine Receptor Kinase Gene Fusion Solid Tumors Indicated for adult and pediatric patients (?12 years) with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and progressed following treatment or have no satisfactory alternative therapy <12 years: Safety and efficacy not established >12 years Recommended dosage is based on body surface area (BSA) 0.91-1.1 m2: 400 mg PO qDay 1.11-1.5 m2: 500 mg PO qDay >1.5 m2: 600 mg PO qDay Continue until disease progression or unacceptable toxicity

Renal Dose

Renal impairment Mild-to-moderate (CrCl 30 to <90 mL/min): No dosage adjustment necessary Severe (CrCl <30 mL/min): Not studied

Administration

Oral Administration Take orally with or without food Swallow capsules whole; do not open, crush, chew, or dissolve contents of capsule

Contra Indications

Hypersensitivity

Precautions

Increase of fractures reported; promptly evaluate patients with signs or symptoms (eg, pain, changes in mobility, deformity) of fractures Increased liver transaminase reported; monitor liver tests every 2 weeks during the first month of treatment, then monthly thereafter, and as clinically indicated Hyperuricemia reported, as well as elevated uric acid levels; assess serum uric acid levels prior to initiation and periodically during treatment Vision disorders have occurred, including blurred vision, photophobia, diplopia, visual impairment, photopsia, cataract, and vitreous floaters Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, fetal harm may occur when administered to a pregnant woman

Pregnancy-Lactation

Pregnancy Based on literature reports in humans with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, fetal harm may occur when administered to a pregnant woman No data available on use in pregnant women Verify pregnancy status of females of reproductive potential before initiating treatment Animal data Administration of entrectinib to pregnant rats during organogenesis resulted in malformations at maternal exposures ~2.7 times the human exposure at the 600-mg dose Advise pregnant women of the potential risk to a fetus Contraception Females of reproductive potential: Use effective contraception during treatment and for at least 5 weeks following the final dose Males with female partners of reproductive potential: Use effective contraception during treatment and for 3 months following the final dose Lactation There are no data on the presence of entrectinib or its metabolites in human milk or their effects on either the breastfed child or on milk production Owing to the potential adverse reactions in breastfed children from entrectinib, advise a lactating woman to discontinue breastfeeding during treatment and for 7 days after the final dose

Interactions

Adverse Effects

Side effects of Entrectinib : >10% All grades Increased creatinine (73%) Anemia (67%) Hyperuricemia (52%) Fatigue (48%) Constipation (46%) Dysgeusia (44%) Increased AST (44%) Edema (40%) Lymphopenia (40%) Increased ALT (38%) Hyponatremia (35%) Diarrhea (35%) Dysesthesia (34%) Nausea (34%) Hypocalcemia (34%) Hypophosphatemia (30%) Dyspnea (30%) Increased lipase (28%) Hypoalbuminemia (28%) Dizziness (28%) Neutropenia (28%) Myalgia (28%) Cognitive impairment (27%) Increased amylase (26%) Hyperkalemia (25%) Increased weight (25%) Increased alkaline phosphatase (25%) Cough (24%) Vomiting (24%) Pyrexia (21%) Arthralgia (21%) Vision disorders (21%) Peripheral sensory neuropathy (18%) Headache (18%) Hypotension (18%) Ataxia (17%) Abdominal pain (16%) Sleep (14%) Urinary tract infection (13%) Decreased appetite (13%) Muscular weakness (12%) Back pain (12%) Extremity pain (11%) Rash (11%) Grade 3 or 4 Lymphopenia (12%)

Mechanism of Action

An inhibitor of tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes NTRK1, NTRK2, and NTRK3, respectively), proto-oncogene tyrosine-protein kinase ROS1 (ROS1), and anaplastic lymphoma kinase (ALK); also, inhibits JAK2 and TNK2 Major active metabolite of entrectinib, M5, showed similar in vitro activity against TRK, ROS1, and ALK Fusion proteins that include TRK, ROS1, or ALK kinase domains can drive tumorigenic potential through hyperactivation of downstream signaling pathways, leading to unconstrained cell proliferation