Usual Adult Dose for Non-Small Cell Lung Cancer

600 mg orally once a day until disease progression or unacceptable toxicity

Use: For adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are ROS1-positive

Usual Adult Dose for Solid Tumors

600 mg orally once a day until disease progression or unacceptable toxicity

Uses: For adult 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 have progressed following treatment or have no satisfactory alternative therapy.

Usual Pediatric Dose for Solid Tumors

12 years and older:

• Body surface area (BSA) greater than 1.5 m2: 600 mg orally once a day
• BSA 1.11 to 1.5 m2: 500 mg orally once a day
• BSA 0.91 to 1.1 m2: 400 mg orally once a day

Use: For pediatric patients 12 years and older 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 have progressed following treatment or have no satisfactory alternative therapy.

Renal Dose Adjustments

• Mild or moderate renal impairment (CrCl 30 to less than 90 mL/min: No adjustment recommended.
• Severe renal impairment (CrCl greater than 30 mL/min): Data not available

Liver Dose Adjustments

• Grade 3 hepatic impairment: Withhold therapy until recovery to less than or equal to Grade 1 or baseline; resume at same dose if resolution occurs within 4 weeks; permanently discontinue if adverse reaction does not resolve within 4 weeks; resume at reduced dose for recurrent Grade 3 events that resolve within 4 weeks.
• Grade 4 hepatic impairment: Withhold therapy until recovery to less than or equal to Grade 1 or baseline; resume at reduced dose if resolution occurs within 4 weeks; permanently discontinue if adverse reaction does not resolve within 4 weeks; permanently discontinue for recurrent Grade 4 events.
• ALT or AST greater than 3 times upper limit of normal (ULN) with concurrent total bilirubin greater than 1.5 x ULN (in the absence of cholestasis or hemolysis): Permanently discontinue therapy.

Dose Adjustments

DOSE REDUCTIONS FOR ADVERSE REACTIONS:
FIRST DOSE REDUCTION:

• Adults and pediatric patients 12 years and older with BSA greater than 1.50 m2: 400 mg orally once daily
• Pediatric patients 12 years and older with BSA of 1.11 to 1.50 m2: 400 mg orally once daily
• Pediatric patients 12 years and older with BSA of 0.91 to 1.1 m2: 300 mg orally once daily

SECOND DOSE REDUCTION (if the patient cannot tolerate the second dose reduction permanently discontinue therapy):

• Adults and pediatric patients 12 years and older with BSA greater than 1.50 m2: 200 mg orally once daily
• Pediatric patients 12 years and older with BSA of 1.11 to 1.50 m2: 200 mg orally once daily
• Pediatric patients 12 years and older with BSA of 0.91 to 1.1 m2: 200 mg orally once daily

DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
CONGESTIVE HEART FAILURE:

• Grade 2 or 3: Withhold therapy until recovered to less than or equal to Grade 1; resume at reduced dose.
• Grade 4: Permanently discontinue therapy.

CENTRAL NERVOUS SYSTEM EFFECTS:

• Intolerable Grade 2: Withhold therapy until recovered to less than or equal to Grade 1 or baseline; resume at same dose or reduced dose.
• Grade 3: Withhold therapy until recovered to less than or equal to Grade 1 or baseline; resume at same dose if resolution occurs within 4 weeks; permanently discontinue if adverse reaction does not resolve within 4 weeks; resume at a reduced dose for recurrent Grade 3 events that resolve within 4 weeks.
• Grade 4: Withhold therapy until recovered to less than or equal to Grade 1 or baseline; resume at same dose or reduced dose if resolution occurs within 4 weeks; permanently discontinue if adverse reaction does not resolve within 4 weeks; permanently discontinue therapy for recurrent Grade 4 events.

HYPERURICEMIA:

• QTc greater than 500 ms: Withhold therapy until QTc interval recovers to baseline; resume at same dose if factors that cause QT prolongation are identified and corrected; resume at reduced dose if other factors that cause QT prolongation are not identified.
• Torsade de pointes; polymorphic ventricular tachycardia; signs/symptoms of serious arrhythmia: Permanently discontinue therapy.

VISION DISORDERS:

• Grade 2 or higher: Withhold therapy until improvement or stabilization; resume at same dose or reduced dose as appropriate.

ANEMIA OR NEUTROPENIA:

• Grade 3 or 4: Withhold therapy until adverse reaction resolves or improves to recovery or improvement to Grade 1 or baseline; resume at the same or reduced dose, if resolution occurs within 4 weeks; permanently discontinue if adverse reaction does not resolve within 4 weeks; permanently discontinue for recurrent Grade 4 events.

DOSAGE MODIFICATIONS FOR DRUG INTERACTIONS:
MODERATE AND STRONG CYP450 3A INHIBITORS:
Adults and pediatric patients 12 years and older with BSA Greater than 1.5 m2: Avoid coadministration of this drug with moderate or strong CYP450 3A inhibitors; if coadministration cannot be avoided, reduce the dose of this drug as follows:

• Moderate CYP450 3A Inhibitors: 200 mg orally once daily
• Strong CYP450 3A Inhibitors: 100 mg orally once daily

After discontinuation of a strong or moderate CYP450 3A inhibitor for 3 to 5 elimination half-lives, resume the dose that was taken prior to initiating the CYP450 3A inhibitor.

Precautions

CONTRAINDICATIONS:

• None

Safety and efficacy have not been established in patients younger than 12 years with solid tumors who have an NTRK gene fusion have not been established.
Safety and efficacy have not been established in patients younger than 18 years with ROS1-positive NSCLC have not been established.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• This drug may be taken with or without food.
• Swallow capsules whole do not open, crush, chew, or dissolve the contents of the capsule.
• If a dose is missed, take it as soon as it is remembered unless the next dose is due within 12 hours.
• If a patient vomits immediately after taking a dose, instruct them to repeat that dose.

Storage requirements:

• Store below 30C (86F).

General:

• Select patients for the treatment of metastatic non-small lung cancer (NSCLC) with this drug based on the presence of ROS1 rearrangement(s) in tumor specimens.
• Select patients for treatment of locally advanced or metastatic solid tumors with this drug based on the presence of a NTRK gene fusion.