entrectinib

General

Genetic Implications: Genetic Implications

Pronunciation:
en-trek-ti-nib


Trade Name(s)

  • Rozlytrek

Ther. Class.

antineoplastics

Pharm. Class.

kinase inhibitors

Indications

  • Genetic implication Metastatic non-small cell lung cancer (NSCLC) in patients whose tumors are ROS1-positive.
  • Genetic implication Solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or are likely to result in severe morbidity with surgical resection, and have either progressed following treatment or have no satisfactory alternative therapy.

Action

Acts as an inhibitor of the tropomyosin receptor tyrosine kinases (TRK) (encoded by the neurotrophic tyrosine receptor kinase [NTRK] genes), proto-oncogene tyrosine-protein kinase ROS1, and anaplastic lymphoma kinase, which ultimately inhibits grown of cancer cell lines.

Therapeutic Effect(s):

Decreased spread of NSCLC and certain solid tumors.

Pharmacokinetics

Absorption: Well absorbed following oral administration.

Distribution: Extensively distributed to tissues.

Protein Binding: >99%.

Metabolism and Excretion: Primarily metabolized in the liver by the CYP3A4 isoenzyme to an active metabolite (M5). Primarily excreted in feces (36% as unchanged drug, 22% as M5), with minimal excretion in urine (3%).

Half-life: Entrectinib– 20 hr;  M5– 40 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTEONSETPEAKDURATION
POunknown4–6 hr24 hr

Contraindication/Precautions

Contraindicated in:

  • Severe renal impairment (CCr <30 mL/min)
  • Moderate or severe hepatic impairment
  • OB:   Pregnancy (may cause fetal harm)
  •  Lactation:  Lactation.

Use Cautiously in:

  • History of HF, MI, unstable angina, or coronary artery bypass graft surgery (↑ risk of HF)
  • Long QT syndrome, bradyarrhythmias, uncontrolled HF, electrolyte abnormalities, or concurrent use of QT interval prolonging medications (↑ risk of QT interval prolongation)
  • Rep:   Women of reproductive potential and men with female partners of reproductive potential
  • Pedi:   ↑ risk of bone fractures in children
  • Pedi:   Children <18 yr (safety and efficacy not established for ROS-1 positive NSCLC); 12 yr (safety and efficacy not established in those with solid tumors that have a NTRK gene fusion) .

Adverse Reactions/Side Effects

CV: QT INTERVAL PROLONGATION, edema, hypotension, HF, myocarditis, syncope

Derm: rash

EENT: blurred vision, cataracts, diplopia, photophobia, visual impairment

Endo: hyperuricemia

F and E: hyperkalemia, hypernatremia, hypocalcemia, hypophosphatemia

GI: HEPATOTOXICITY, abdominal pain, constipation, diarrhea, dysgeusia, dysphagia, hypoalbuminemia, ↑ amylase, ↑ lipase, ↑ liver enzymes, nausea, vomiting

GU: dehydration, ↑ serum creatinine

Hemat: NEUTROPENIA, anemia, lymphopenia

Metabolic: ↓ appetite, ↑ weight

MS: arthralgia, bone fractures, muscle weakness, myalgia

Neuro: balance disorder, paresthesia, peripheral neuropathy, ataxia, confusion, dizziness, fatigue, headache, agitation, amnesia, anxiety, aphasia, attention disturbances, cognitive disorders, depression, delirium, hallucinations, insomnia, memory impairment, mental status changes, sedation

Resp: PULMONARY EMBOLISM, cough, dyspnea, pleural effusion

Misc: fever

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Moderate or strong CYP3A4 inhibitors, including  itraconazole , may ↑ levels and risk of toxicity; avoid concurrent use. If must use moderate or strong CYP3A4 inhibitor, ↓ entrectinib dose.
  •  Moderate or strong CYP3A4 inducers, including  rifampin , may ↓ levels and effectiveness; avoid concurrent use.
  •  QT interval prolonging medications  may ↑ risk of QT interval prolongation; avoid concurrent use.

Drug-Food:

Grapefruit juice may ↑ levels and risk of toxicity; avoid concurrent use.

Route/Dosage

ROS1-Positive Non-Small Cell Lung Cancer

PO (Adults): 600 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of moderate CYP3A4 inhibitor– 200 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor– 100 mg once daily until disease progression or unacceptable toxicity.

NTRK Gene Fusion-Positive Solid Tumors

PO (Adults): 600 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of moderate CYP3A4 inhibitor– 200 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor– 100 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥12 yr and BSA >1.5 m2): 600 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of moderate CYP3A4 inhibitor– 200 mg once daily until disease progression or unacceptable toxicity.  Concurrent use of strong CYP3A4 inhibitor– 100 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥12 yr and BSA 1.11–1.5 m2): 500 mg once daily until disease progression or unacceptable toxicity.

PO (Children ≥12 yr and BSA 0.91–1.10 m2): 400 mg once daily until disease progression or unacceptable toxicity.

Availability

Capsules: 100 mg, 200 mg

Assessment

  • Assess left ventricular ejection fraction (LVEF) prior to starting therapy in patients with symptoms or risk factors for HF. Monitor for signs and symptoms of HF (shortness of breath, edema) periodically during therapy. MRI or cardiac biopsy may be required for diagnosis in patients with myocarditis, with or without a decreased ejection fraction. For new onset or worsening HF, hold entrectinib, manage symptoms, and reassess LVEF.  For Grade 2 or 3,  hold entrectinib until recovered to ≤Grade 1. Resume at reduced dose.  For Grade 4,  permanently discontinue entrectinib.
  • Monitor for signs and symptoms of CNS effects (cognitive impairment, mood disorders, dizziness, sleep disturbances) during therapy.  If intolerable Grade 2 effects occur,  hold entrectinib until recovery to ≤Grade 1 or baseline. Resume at same or reduced dose.  For Grade 3 effects,  hold entrectinib until recovery to ≤Grade 1 or baseline. Resume at reduced dose.  For Grade 4 effects,  discontinue entrectinib permanently.
  • Assess QT interval and electrolytes at baseline and periodically during therapy.  For QTc interval >500 ms,  hold entrectinib until QTc recovers to baseline. If factors that caused QT prolongation are identified and corrected, resume at same dose. If factors are not identified, resume at reduced dose.  If torsade de pointes; polymorphic ventricular tachycardia; or signs/symptoms of serious arrhythmia occur,  permanently discontinue entrectinib.
  • Assess for vision changes periodically during therapy.  If Grade 2 vision changes occur,  hold entrectinib until improvement or stabilization. Resume at same or reduced dose.

Lab Test Considerations:

Obtain a negative pregnancy test before starting therapy.

  • Genetic implication For metastatic NSCLC,  patient selection is based on presence of  ROS1  rearrangement in tumor specimens. No FDA approved test is available.  For other tumors,  patient selection is based on presence of  NTRK  gene fusion. No FDA approved test is available.
  • Monitor liver tests (ALT, AST) every 2 wk during 1st month of therapy, then monthly thereafter, and as clinically indicated.  For Grade 3,  hold entrectinib until recovery to ≤Grade 1 or baseline. Resume at same dose if resolution within 4 wk. Permanently discontinue entrectinib if no resolution in 4 wk. For recurrent Grade 3 events that resolve within 4 wk, resume at reduced dose.  For Grade 4,  hold entrectinib until recovery to ≤Grade 1 or baseline. If resolution within 4 wk, resume at reduced dose. Permanently discontinue if not resolved within 4 wk or for recurrent Grade 4 events. If ALT or AST >3 × ULN with concurrent total bilirubin >1.5 × ULN (in absence of cholestasis or hemolysis) occurs, permanently discontinue entrectinib.
  • Assess serum uric acid levels prior to starting therapy and periodically during therapy. Monitor for signs and symptoms of hyperuricemia (gout).  For symptomatic or Grade 4 hyperuricemia,  begin urate-lowering medications and hold entrectinib until signs and symptoms improve. Resume at same or reduced dose.
  • Monitor CBC periodically during therapy.  If Grade 3 or 4 anemia or neutropenia occur,  hold entrectinib until recovery to ≤Grade 2. Resume at same or reduced dose.

Potential Diagnoses

Implementation

  • PO Administer once daily without regard to food. Swallow capsule whole; do not open, crush or chew.

Patient/Family Teaching

  • Instruct patient to take entrectinib as directed. Take missed dose as soon as remembered unless within 12 hr of next dose. If patient vomits immediately after taking, instruct patient to repeat dose. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
  • May cause dizziness. Caution patient to avoid driving or other activities requiring alertness until response to entrectinib is known.
  • Advise patient to notify health care professional promptly if signs and symptoms if HF (persistent coughing or wheezing, increasing shortness of breath, trouble breathing when lying down, tiredness, weakness, fatigue, sudden weight gain, swelling in ankles, feet, or legs), central nervous system effects (dizziness, changes in mood, confusion, hallucinations, problems with concentration, attention, memory, and sleep), liver problems (loss of appetite, nausea or vomiting, pain on upper right side of stomach area) changes in electrical activity of the heart (feeling faint, lightheaded, dizzy, or feel heart beating irregularly or fast) or vision problems (double vision, seeing flashes of light, blurry vision, light hurting your eyes, new or increased floaters) occur.
  • Inform patient that entrectinib may increase risk of bone fractures. Advise patient to notify health care professional if fractures occur.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:  May be teratogenic. Advise females of reproductive potential to use effective contraception during and for at least 5 wk after final dose of entrectinib. Advise males with female partners of reproductive potential to use effective contraception during and for 3 mo after final dose. Advise patient to avoid breastfeeding during and for 7 days after final dose.

Evaluation/Desired Outcomes

Decrease in tumor spread.

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