Entrectinib (Monograph)

Brand name: Rozlytrek
Drug class: Antineoplastic Agents

Medically reviewed by Drugs.com on Aug 28, 2023. Written by ASHP.

Introduction

Antineoplastic agent; potent inhibitor of multiple receptor tyrosine kinases including tropomyosin receptor kinases (Trk) A, TrkB, TrkC, c-ros oncogene-1 (ROS-1), and anaplastic lymphoma kinase (ALK).

Uses for Entrectinib

Non-small Cell Lung Cancer (NSCLC)

Treatment of ROS-1-positive metastatic NSCLC (based on an objective response rate of 78% in a cohort of patients with ROS-1-positive locally advanced or metastatic NSCLC).

Designated an orphan drug by FDA for treatment of TrkA-positive, TrkB-positive, TrkC-positive, ROS-1-positive, and ALK-positive NSCLC.

Confirmation of ROS-1 fusion by an FDA-approved test is necessary prior to initiation of therapy. In clinical studies, presence of ROS-1 fusion was determined by fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS).

Solid Tumors with Neurotrophic Receptor Tyrosine Kinase (NTRK) Gene Fusion

Treatment of solid tumors harboring an NTRK gene fusion (without a known acquired mutation for resistance) in patients who have metastatic disease or who may experience severe morbidity following surgical resection and whose disease progressed following prior therapy or those who are not candidates for other treatment options.

Accelerated approval based on objective response rate and duration of response. Continued approval may be contingent on verification and description of clinical benefit in confirmatory studies.

Designated an orphan drug by FDA for treatment of solid tumors harboring NTRK gene fusion.

Confirmation of NTRK fusion with an FDA-approved test is necessary prior to initiation of therapy. In clinical studies, presence of NTRK fusion status was determined by NGS or other nucleic acid-based tests.

Related/similar drugs

Rybrevant, methotrexate, Keytruda, pembrolizumab, Avastin, cisplatin, Tagrisso

Entrectinib Dosage and Administration

General

Pretreatment Screening

• Confirm presence of ROS-1 fusion with an FDA-approved test in patients with metastatic NSCLC prior to initiation of therapy.

• Confirm presence of NTRK fusion with an FDA-approved test prior to initiation of therapy for the treatment of locally advanced or metastatic solid tumors.

• LVEF in patients with symptoms or known risk factors for heart failure.

• Serum uric acid levels.

• QT interval and serum electrolyte concentrations.

• Verify pregnancy status in females of reproductive potential.

Patient Monitoring

• Monitor for signs and symptoms of heart failure (e.g., dyspnea, edema).

• Monitor liver function tests (e.g., ALT, AST) every 2 weeks during the first month of therapy, monthly thereafter, and as clinically indicated.

• Assess serum uric acid levels periodically during therapy.

• Monitor for signs and symptoms of hyperuricemia.

• Monitor QT interval and serum electrolyte concentrations periodically during therapy. More frequent monitoring may be necessary in patients with preexisting QT_c-interval prolongation or risk factors for developing QT_c-interval prolongation (e.g., long QT syndrome, clinically important bradyarrhythmia, severe or uncontrolled heart failure, electrolyte abnormalities, concomitant use of drugs known to prolong QT interval).

Dispensing and Administration Precautions

• Based on the Institute for Safe Medication Practices (ISMP), entrectinib is a high-alert medication that has a heightened risk of causing significant patient harm when used in error.

Administration

Oral Administration

Administer orally once daily without regard to food.

Swallow capsules whole; do not open, crush, chew, or dissolve.

Dosage

Pediatric Patients

Solid Tumors with NTRK Fusion

Oral

Adolescents ≥12 years of age with body surface area (BSA) >1.5 m²: 600 mg once daily. If concomitant use with moderate or potent CYP3A inhibitors cannot be avoided, adjust dosage of entrectinib.

Adolescents ≥12 years of age with BSA of 1.11–1.5 m²: 500 mg once daily.

Adolescents ≥12 years of age with BSA of 0.91–1.1 m²: 400 mg once daily.

Continue therapy until disease progression or unacceptable toxicity occurs.

Dosage Modification for Toxicity

Oral

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of drug may be necessary (see Table 2). When dosage modification is required in pediatric patients, reduce dosage of entrectinib as described .

If an adverse reaction occurs, modify treatment accordingly (see Table 2).

Adults

NSCLC

Oral

600 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

If concomitant use with moderate or potent CYP3A inhibitors cannot be avoided, adjust dosage of entrectinib.

Solid Tumors with NTRK Fusion

Oral

600 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.

If concomitant use with moderate or potent CYP3A inhibitors cannot be avoided, adjust dosage of entrectinib.

Dosage Modification for Toxicity

Oral

Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of drug may be necessary. Recommendations for dosage modification for toxicity in pediatric patients also apply to adults (see Table 2). When dosage modification is required in adults, reduce dosage of entrectinib as described in Table 3.

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration ≤1.5 times the ULN): No dosage adjustment required.

Renal Impairment

Mild or moderate renal impairment (Cl_cr 30 to <90 mL/minute): No dosage adjustment required.

Geriatric Patients

No specific dosage recommendations.

Cautions for Entrectinib

Contraindications

• Manufacturer states none known.

Warnings/Precautions

Heart Failure

Heart failure reported; median time to onset is 2 months. Resolves in 75% of patients following initiation of appropriate treatment for heart failure and interruption or discontinuance of drug.

Assess LVEF prior to initiation of therapy in patients with symptoms or known risk factors for heart failure. Monitor for signs and symptoms of heart failure (e.g., dyspnea, edema). For patients with myocarditis with or without a decreased ejection fraction, diagnosis may require magnetic resonance imaging (MRI) or cardiac biopsy. If new onset or worsening heart failure occurs, interrupt therapy, initiate appropriate therapy for heart failure, and reassess LVEF; dosage reduction or permanent discontinuance of therapy may be necessary. and

CNS Effects

Entrectinib can cause a variety of adverse CNS effects including cognitive impairment, mood disorder, dizziness, and sleep disturbance.

Inform patients and their caregivers of the risk of adverse CNS effects. Advise patients not to drive or operate hazardous machinery if they are experiencing adverse CNS effects. If adverse CNS effects occur, interruption of therapy, dosage reduction, or permanent discontinuance of therapy may be necessary.

Fractures

Fractures, mostly involving the lower extremity (e.g., hip, femoral or tibial shaft) reported. Sometimes associated with trauma (e.g., fall) in adults and with minimal or no trauma in pediatric patients. Radiographic abnormalities potentially indicating bone metastases reported in some patients.

Promptly evaluate patients with signs or symptoms of fracture (e.g., pain, changes in mobility, deformity). Effect on healing of known fractures or long-term fracture risk is unknown.

Hepatotoxicity

Hepatotoxicity reported; median time to onset of elevated AST or ALT concentrations is 2 weeks.

Monitor liver function tests (e.g., ALT, AST), every 2 weeks during the first month of therapy, monthly thereafter, and as clinically indicated. If hepatotoxicity occurs, interruption of therapy, dosage reduction, or permanent discontinuance of therapy may be necessary.

Hyperuricemia

Hyperuricemia, sometimes symptomatic, reported. Grade 4 hyperuricemia (associated with tumor lysis syndrome) resulted in death in one patient.

Assess serum uric acid levels prior to initiating entrectinib and then periodically during therapy. Monitor patients for signs and symptoms of hyperuricemia. In patients experiencing signs or symptoms of hyperuricemia, initiate urate-lowering therapy as clinically indicated and interrupt entrectinib therapy; dosage reduction may be necessary.

Prolongation of the QT Interval

Prolongation of QT_c interval reported.

Monitor QT interval and electrolyte concentrations at baseline and periodically during therapy. More frequent monitoring may be necessary in patients with preexisting QT_c-interval prolongation or risk factors for developing QT_c-interval prolongation (e.g., long QT syndrome, clinically important bradyarrhythmia, severe or uncontrolled heart failure, electrolyte abnormalities, concomitant use of drugs known to prolong QT interval). If QT_c-interval prolongation occurs, temporary interruption of entrectinib therapy, dosage reduction, or permanent discontinuance of therapy may be necessary.

Visual Disturbances

Visual disturbances (i.e., blurred vision, photophobia, diplopia, visual impairment, photopsia, cataract, vitreous floaters) reported.

In patients who report new visual symptoms, including changes that interfere with activities of daily living, temporarily interrupt entrectinib therapy and perform an ophthalmologic evaluation as clinically appropriate; dosage reduction may be necessary.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm. Teratogenicity and embryofetal toxicity (i.e., reduced fetal weight, reduced skeletal ossification) demonstrated in animals.

Literature reports in individuals with congenital mutations in the tropomyosin receptor kinase (Trk) pathway suggest decreased Trk-mediated signaling may be associated with obesity, developmental delays, cognitive impairment, insensitivity to pain, and anhidrosis.

Avoid pregnancy during therapy. Perform pregnancy test prior to initiation of entrectinib in women of reproductive potential. Women of reproductive potential should use effective contraceptive methods while receiving the drug and for ≥5 weeks after the last dose. Men who are partners of such women should use effective methods of contraception while receiving the drug and for 3 months after the last dose. If used during pregnancy or if patient becomes pregnant, apprise patient of potential fetal hazard.

Specific Populations

Pregnancy

May cause fetal harm.

Lactation

Not known whether entrectinib or its metabolites distribute into human milk or affect milk production or nursing infants.

Discontinue nursing during therapy and for 1 week after the last dose.

Pediatric Use

Safety and efficacy not established in pediatric patients with NSCLC.

Safety and efficacy in pediatric patients ≥12 years of age with solid tumors harboring NTRK gene fusion are supported by extrapolation of data from 3 noncomparative studies in adults and limited safety data in 30 pediatric patients. Grade 3 or 4 neutropenia, fractures, weight gain, thrombocytopenia, lymphopenia, elevations in γ-glutamyltransferase (GGT, γ-glutamyltranspeptidase, GGTP) concentrations, and device-related infection occurred more frequently in pediatric patients compared with adults.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether efficacy and safety are similar to those in younger adults.

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration ≤1.5 times the ULN): No clinically important effect on pharmacokinetics.

Effect of moderate hepatic impairment (total bilirubin > 1.5 – 3 times ULN with any aspartateaminotransferase) or severe hepatic impairment (total bilirubin >3 times ULN with any aspartate aminotransferase) on pharmacokinetics not established.

Consider the risk/benefit profile in patients with moderate to severe hepatic impairment. Monitor more frequenty for adverse reactions in these patients as they may be at increased risk for adverse reactions.

Renal Impairment

Mild to moderate renal impairment (Cl_cr 30 to <90 mL/minute): No clinically important effect on pharmacokinetics.

Effect of severe renal impairment (Cl_cr <30 mL/minute) on pharmacokinetics not established.

Common Adverse Effects

Adverse effects (≥20%): fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, increased weight, cough, vomiting, pyrexia, arthralgia, and vision disorders.

Drug Interactions

Metabolized principally by CYP3A4 to form M5 (major active metabolite), and to a lesser extent by CYP isoenzymes 2C9 and 1C19.

Entrectinib is not a substrate of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP), but M5 is a substrate of both P-gp and BCRP.

Neither entrectinib nor M5 is a substrate of organic anion transport protein (OATP) 1B1 or 1B3.

Drugs and Foods Affecting Hepatic Microsomal Enzymes

Potent inhibitors of CYP3A: Possible increased systemic exposure to, and increased toxicity of, entrectinib. Avoid concomitant use. If concomitant use cannot be avoided in adults and pediatric patients ≥12 years of age with BSA >1.5 m², reduce entrectinib dosage to 100 mg once daily. When concomitant use of the potent CYP3A inhibitor is discontinued, return entrectinib dosage (after 3–5 elimination half-lives of the CYP3A inhibitor) to dosage used prior to initiation of the potent CYP3A inhibitor.

Moderate inhibitors of CYP3A: Possible increased systemic exposure to, and increased toxicity of, entrectinib. Avoid concomitant use. If concomitant use cannot be avoided in adults and pediatric patients ≥12 years of age with BSA >1.5 m², reduce entrectinib dosage to 200 mg once daily. When concomitant use of the moderate CYP3A inhibitor is discontinued, return entrectinib dosage (after 3–5 elimination half-lives of the CYP3A inhibitor) to dosage used prior to initiation of the moderate CYP3A inhibitor.

Inducers of CYP3A: Possible decreased systemic exposure to, and decreased therapeutic efficacy of, entrectinib. Avoid concomitant use.

Drugs that Prolong the QT Interval

Because entrectinib has been associated with QT-interval prolongation, avoid concomitant use with other drugs with known potential to prolong the QT interval.

Specific Drugs and Foods

Entrectinib Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics of entrectinib and its active metabolite are linear and time-independent over a dosage range of 100–400 mg/m² when coadministered with food.

Peak plasma concentrations achieved in 4–6 hours following oral administration.

Steady-state concentrations of entrectinib and its active metabolite achieved within 1–2 weeks; systemic accumulation is approximately 2-fold.

Food

Administration with a high-fat, high-calorie meal has no clinically important effect on systemic exposure.

Special Populations

Age (12–86 years), sex, race, or body weight (32–130 kg) do not affect pharmacokinetics.

Distribution

Extent

Not known whether entrectinib or its metabolites are distributed into human milk.

Crosses blood-brain barrier in animals.

Plasma Protein Binding

Entrectinib and M5: >99% bound to plasma proteins.

Elimination

Metabolism

Principally metabolized by CYP3A4 to form M5.

Elimination Route

Eliminated in the feces (83% [36% as unchanged drug, 22% as M5]) and urine (3%).

Half-life

Entrectinib: 20 hours.

M5: 40 hours.

Stability

Storage

Oral

Capsules

<30°C.

Store in original container, tightly closed to protect from moisture.

Actions

• Potent inhibitor of TrkA, TrkB, TrkC, ROS-1, and ALK.

• TrkA, TrkB, and TrkC are encoded by NTRK1, NTRK2, and NTRK3 and are involved in the initiation of various cascades of intracellular signaling events (i.e., Ras/MAPK/ERK, PI3K/Akt, and PLCγ1/Pkc signal transduction pathways) that lead to cell proliferation, differentiation, apoptosis, and regulation of processes critical to neuron survival in the central and peripheral nervous systems.

• Chromosomal rearrangements of NTRK1, NTRK2, and NTRK3 genes result in formation of a constitutively active chimeric Trk oncogenic fusion protein and dysregulation of Trk signaling and subsequent tumorigenesis.

• Fusion proteins including ROS-1 or ALK kinase domains also activate tumorigenesis through hyperactivation of downstream signaling pathways.

• Inhibits cancer cell lines derived from multiple tumor types harboring NTRK, ROS-1, and ALK fusion genes.

• Major metabolite, M5, has similar inhibitory activity for TrkA, TrkB, TrkC, ROS-1, and ALK to that of entrectinib.

• In vitro, 10- to 100-fold more potent than crizotinib in activity against ROS-1, and 7- to 8-fold more potent than crizotinib in activity against ALK.

• Inhibits Janus kinase 2 (JAK2) and tyrosine kinase nonreceptor 2 (TNK2).

• Clinical resistance attributed to secondary point mutations of NTRK kinase domain (e.g., G595R and G667C point mutations in the TrkA kinase domain; G623R point mutation in the TrkC kinase domain) reported.

Advice to Patients

• Importance of advising patients to read the FDA-approved patient information.

• Importance of advising patients to swallow entrectinib capsules whole and to avoid grapefruit juice while taking entrectinib. If a dose is missed, importance of taking missed dose as soon as it is remembered unless the next dose is due within 12 hours. If a dose is vomited immediately after administration, an additional dose should be administered to make up for the vomited dose.

• Risk of heart failure. Importance of informing clinician promptly if new or worsening signs or symptoms of heart failure (e.g., dyspnea, edema) occur.

• Risk of CNS effects. Importance of informing clinician if new or worsening CNS effects (i.e., cognitive impairment, mood disorders, dizziness, sleep disturbance) occur. Necessity of advising patients to avoid driving or operating hazardous machinery if they experience CNS effects.

• Risk of hepatotoxicity and importance of monitoring liver function. Importance of informing clinician promptly if symptoms of hepatotoxicity (e.g., loss of appetite, nausea, vomiting, upper right abdominal pain) occur.

• Risk of fractures. Importance of informing clinician if symptoms such as pain, changes in mobility, or deformity occur.

• Risk of hyperuricemia. Importance of informing clinician if signs or symptoms associated with hyperuricemia occur.

• Risk of QT-interval prolongation. Importance of informing clinician promptly if abnormal heartbeat or feelings of faintness, lightheadedness, or dizziness occur.

• Risk of visual disturbances. Importance of informing clinician if visual disturbances (e.g., blurring, photophobia, diplopia, photopsia, light sensitivity, new or increased floaters) occur.

• Risk of fetal harm. Necessity of advising women of reproductive potential to use effective methods of contraception while receiving entrectinib and for ≥5 weeks after the last dose. Importance of advising men with female partners of reproductive potential to use effective methods of contraception while receiving the drug and for 3 months after the last dose. Importance of women informing clinicians if they are or plan to be pregnant. If pregnancy occurs, advise pregnant women of potential risk to the fetus.

• Importance of advising women to avoid nursing while receiving the drug and for 1 week after the last dose.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Obtain entrectinib through designated specialty pharmacies and distributors.

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