entrectinib (Rx)

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

Dosage Modifications

Dosage modifications for adverse reactions

• First dose reduction: 400 mg qDay
• Second dose reduction: 200 mg qDay
• Permanently discontinue if toxicities persist or recur following 2 dose reductions

Congestive heart failure

• Grade 2 or 3: Withhold until recovered to Grade ≤1; resume at reduced dose
• Grade 4: Permanently discontinue

Central nervous system effects

• Intolerable Grade 2: Withhold until recovered to Grade ≤1; resume at reduced dose, as clinically appropriate
• Grade 3: Withhold until recovered to Grade ≤1; resume at reduced dose
• Grade 4: Permanently discontinue

Hepatoxicity

• Grade 3
  • Withhold until recovered to Grade ≤1; resume at reduced dose;
  • If resolution occurs within 4 weeks, resume at same dose
  • If adverse reaction persists after 4 weeks, permanently discontinue
  • For recurrent Grade 3 events that resolve within 4 weeks, resume at a reduced dose

• Grade 4

  • Withhold until recovered to Grade ≤1; resume at reduce dose;
  • If adverse reaction does not resolve within 4 weeks or Grade 4 events recurs, permanently discontinue

• Elevated ALT or AST

  • ALT or AST >3x ULN with concurrent total bilirubin >1.5x ULN (in the absence of cholestasis or hemolysis): Permanently discontinue

Hyperuricemia

• Symptomatic or Grade 4: Initiate urate-lowering therapy; withhold until improvement of signs or symptoms; resume at same or reduced dose

QTc prolongation

• QTc >500 ms

  • Withhold until QTc interval recovers to baseline
  • Resume at same dose if causes of QT prolongation are identified and corrected
  • Resume at reduced dose if other causes of QT prolongation are not identified

• Life-threatening arrhythmia

  • Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia: Permanently discontinue

Vision disorders

• Grade ≥2: Withhold until improvement or stabilization; resume at same dose or reduced dose, as clinically appropriate

Anemia or neutropenia

• Grade 3 or 4: Withhold until recovery to Grade≤2; resume at same or reduced dose, as clinically appropriate

Other clinically relevant adverse reactions

• Grade 3 or 4

  • Withhold until adverse reaction resolves to Grade 1 or baseline
  • Resume at same or reduced dose if resolved within 4 weeks
  • Permanently discontinue if adverse reaction does not resolve within 4 weeks or Grade 4 events recurs

Coadministration of moderate and strong CYP3A inhibitors

• Avoid coadministration

• If coadministration is unavoidable, reduce entrectinib dose as follows:

  • Moderate CYP3A Inhibitors: 200 mg PO qDay
  • Strong CYP3A Inhibitors: 100 mg PO qDay
  • After discontinuation of strong or moderate CYP3A inhibitor for 3-5 elimination half-lives, resume entrectinib dose taken prior to initiating the CYP3A inhibitor

Renal impairment

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

Hepatic impairment

• Mild (total bilirubin ≤1.5x ULN): No dosage adjustment necessary
• Moderate-to-severe (total bilirubin >1.5x ULN): Not studied

Dosing Considerations

Patient selection

• Select patients for treatment based on the following:

  • NSCLC: Presence of ROS1 rearrangement
  • Locally advanced or metastatic solid tumors: Presence of a NTRK gene fusion
  • FDA-approved tests for detecting ROS1 rearrangement for NSCLC and NTRK gene fusion in solid tumors are not available

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

Dosage Modifications

Dosage modifications of adverse reactions

• BSA 0.91-1.1 m2

  • First dose reduction: 300 mg qDay
  • Second dose reduction: 200 mg qDay

• BSA >1.11 m2

  • First dose reduction: 400 mg qDay
  • Second dose reduction: 200 mg qDay
• If toxicities persist or recur following 2 dose reductions, permanently discontinue

Congestive heart failure

• Grade 2 or 3: Withhold until recovered to Grade ≤1; resume at reduced dose
• Grade 4: Permanently discontinue

Central nervous system effects

• Intolerable Grade 2: Withhold until recovered to Grade ≤1; resume at reduced dose, as clinically appropriate
• Grade 3: Withhold until recovered to Grade ≤1; resume at reduced dose
• Grade 4: Permanently discontinue

Hepatoxicity

• Grade 3

  • Withhold until recovered to Grade ≤1
  • If resolution occurs within 4 weeks, resume at same dose
  • If adverse reaction persists after 4 weeks, permanently discontinue
  • For recurrent Grade 3 events that resolve within 4 weeks, resume at reduced dose

• Grade 4

  • Withhold until recovered to Grade ≤1If resolution occurs within 4 weeks, resume at reduced dose
  • If adverse reaction does not resolve within 4 weeks or Grade 4 events recurs, permanently discontinue

• Elevated ALT or AST

  • ALT or AST >3x ULN with concurrent total bilirubin >1.5x ULN (in the absence of cholestasis or hemolysis): Permanently discontinue

Hyperuricemia

• Symptomatic or Grade 4: Initiate urate-lowering therapy; withhold until improvement of signs or symptoms; resume at same or reduced dose

QTc prolongation

• QTc >500 ms

  • Withhold until QTc interval recovers to baseline
  • Resume at same dose if causes of QT prolongation are identified and corrected
  • Resume at reduced dose if other causes of QT prolongation are not identified

• Life-threatening arrhythmia

  • Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia: Permanently discontinue

Vision disorders

• Grade ≥2: Withhold until improvement or stabilization; resume at same dose or reduced dose, as clinically appropriate

Anemia or neutropenia

• Grade 3 or 4: Withhold until recovery to Grade ≤2; resume at same or reduced dose, as clinically appropriate

Other clinically relevant adverse reactions

• Grade 3 or 4

  • Withhold until adverse reaction resolves to Grade 1 or baseline
  • Resume at same or reduced dose if resolved within 4 weeks
  • Permanently discontinue if adverse reaction does not resolve within 4 weeks or Grade 4 events recurs

Coadministration of moderate and strong CYP3A inhibitors

• Avoid coadministration

• If coadministration is unavoidable, reduce entrectinib dose as follows:

  • Moderate CYP3A Inhibitors: 200 mg PO qDay
  • Strong CYP3A Inhibitors: 100 mg PO qDay
  • After discontinuation of strong or moderate CYP3A inhibitor for 3-5 elimination half-lives, resume entrectinib dose taken prior to initiating the CYP3A inhibitor

Renal impairment

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

Hepatic impairment

• Mild (total bilirubin ≤1.5x ULN): No dosage adjustment necessary
• Moderate-to-severe (total bilirubin >1.5x ULN): Not studied

Dosing Considerations

Patient selection

• Select patients for treatment based on the following:

  • NSCLC: Presence of ROS1 rearrangement
  • Locally advanced or metastatic solid tumors: Presence of a NTRK gene fusion
  • FDA-approved tests for detecting ROS1 rearrangement for NSCLC and NTRK gene fusion in solid tumors are not available