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
Side 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%)
Mode 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