Dosage of Encorafenib

Melanoma

Administration Route: Oral

Dose: 450 mg once daily, in combination with binimetinib.

Treatment Duration: Continue until disease progression or unacceptable toxicities occur.

Colorectal Cancer

Administration Route: Oral

In combination with cetuximab: 300 mg once daily. Continue until disease progression or unacceptable toxicities occur.

In combination with cetuximab plus modified FOLFOX6 regimen: 300 mg once daily. Continue until disease progression or unacceptable toxicities occur.

Non-Small Cell Lung Cancer (NSCLC)

Administration Route: Oral

Dose: 450 mg once daily, in combination with binimetinib.

Treatment Duration: Continue until disease progression or unacceptable toxicities occur.

Dose Modifications for Toxicities

Temporary treatment interruption, dose reduction, and/or permanent discontinuation may be required for certain adverse reactions. When encorafenib is administered with binimetinib or cetuximab, no dose adjustment of encorafenib is needed in the event of interstitial lung disease, pneumonitis, cardiac dysfunction, elevated serum creatine kinase, rhabdomyolysis, or venous thromboembolism.

Dose Modifications for Melanoma and NSCLC

If dose reduction from 450 mg once daily is necessary, first adjust to 300 mg once daily; if further reduction is required, adjust to 225 mg once daily.

Doses below 225 mg once daily are not recommended; permanent discontinuation is required if the 225 mg once daily dose is not tolerable.

If binimetinib treatment is interrupted, reduce encorafenib dose to 300 mg once daily (maximum dose) until binimetinib treatment is resumed.

Dose Modifications for Colorectal Cancer

If dose reduction from 300 mg once daily is necessary, first adjust to 225 mg once daily; if further reduction is required, adjust to 150 mg once daily.

Doses below 150 mg once daily are not recommended; permanent discontinuation is required if the 150 mg once daily dose is not tolerable.

If cetuximab combination therapy is discontinued, discontinue encorafenib concurrently.

Management of New Primary Malignancies

During encorafenib plus binimetinib treatment, no dose adjustment is needed for the development of new primary cutaneous malignant neoplasms.

Permanent discontinuation of encorafenib is required for the development of new primary non-cutaneous malignant neoplasms with RAS mutation positivity.

Management of Cardiomyopathy

If symptomatic congestive heart failure occurs, or the absolute decrease in left ventricular ejection fraction (LVEF) from baseline is >20% and LVEF falls below the institutional lower limit of normal, reduce encorafenib dose by one level.

Encorafenib may be continued at the reduced dose if LVEF recovers to at least the institutional lower limit of normal and the absolute decrease from baseline is ≤10%.

If LVEF does not recover, interrupt encorafenib treatment until the above criteria are met, then resume at the reduced dose or reduce the dose by an additional level.

Management of Uveitis

Grade 1 or 2 uveitis unresponsive to ocular symptomatic treatment: Interrupt encorafenib for up to 6 weeks until toxicity resolves, then resume at the original or reduced dose. Permanent discontinuation is required if toxicity does not resolve after 6 weeks of interruption.

Grade 3 uveitis: Interrupt encorafenib for up to 6 weeks until toxicity resolves, then resume at the original or reduced dose. Permanent discontinuation is required if toxicity does not resolve after 6 weeks of interruption.

Grade 4 uveitis: Permanent discontinuation of encorafenib is required.

During encorafenib plus binimetinib treatment, no dose adjustment of encorafenib is needed for ocular adverse reactions other than uveitis, iritis, and iridocyclitis.

Management of QT Interval Prolongation

If Fridericia-corrected QT interval (QTcF) >500 msec with an absolute increase from baseline ≤60 msec: Interrupt encorafenib treatment until QTcF recovers to ≤500 msec, then resume at a reduced dose. Permanent discontinuation is required if this condition recurs more than once.

If QTcF >500 msec with an absolute increase from baseline >60 msec: Permanent discontinuation of encorafenib is required.

Management of Hepatotoxicity

Grade 2 elevation of serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST): Continue treatment at the original dose for up to 4 weeks. If toxicity persists, interrupt encorafenib until recovery to Grade 1 or lower or baseline, then resume at the original dose.

First occurrence of Grade 3 ALT/AST elevation: Interrupt encorafenib for up to 4 weeks until recovery to Grade 1 or lower or baseline, then resume at a reduced dose. Permanent discontinuation is required if toxicity does not resolve after 4 weeks of interruption. Consider permanent discontinuation for recurrent Grade 3 ALT/AST elevation.

First occurrence of Grade 4 ALT/AST elevation: Permanent discontinuation or temporary interruption may be considered. If temporary interruption is chosen, discontinue treatment for up to 4 weeks until recovery to Grade 1 or lower or baseline, then resume at a reduced dose. Permanent discontinuation is required if toxicity does not resolve after 4 weeks of interruption. Permanent discontinuation is required for recurrent Grade 4 ALT/AST elevation.

Management of Cutaneous Toxicities

For cutaneous toxicities excluding hand-foot skin reaction:

Grade 2 reaction: Continue treatment at the original dose for up to 2 weeks. If toxicity persists, interrupt encorafenib until recovery to Grade 1 or lower, then resume at the original dose.

First occurrence of Grade 3 reaction: Interrupt encorafenib until recovery to Grade 1 or lower, then resume at the original dose. For recurrent Grade 3 reaction, interrupt treatment until symptoms resolve, then resume at a reduced dose.

Grade 4 reaction: Permanent discontinuation of encorafenib is required.

Management of Other Toxicities (Including Bleeding and Hand-Foot Skin Reaction)

Recurrent Grade 2 adverse reaction: Interrupt encorafenib for up to 4 weeks until toxicity recovers to Grade 1 or lower or baseline, then resume at a reduced dose. Permanent discontinuation is required if toxicity does not resolve after 4 weeks of interruption.

First occurrence of any Grade 3 adverse reaction: Interrupt encorafenib for up to 4 weeks until toxicity recovers to Grade 1 or lower or baseline, then resume at a reduced dose. Permanent discontinuation is required if toxicity does not resolve after 4 weeks of interruption. Consider permanent discontinuation for recurrent Grade 3 adverse reaction of any type.

First occurrence of any Grade 4 adverse reaction: Permanent discontinuation or temporary interruption may be considered. If temporary interruption is chosen, discontinue treatment for up to 4 weeks until toxicity recovers to Grade 1 or lower or baseline, then resume at a reduced dose. Permanent discontinuation is required if toxicity does not resolve after 4 weeks of interruption. Permanent discontinuation is required for recurrent Grade 4 adverse reaction of any type.

Concomitant Use with Drugs and Foods Affecting Hepatic Microsomal Enzymes

Avoid concomitant use with moderate or strong CYP3A4 inhibitors. If concomitant use is unavoidable, reduce the dose of encorafenib.

If the concomitant strong/moderate CYP3A4 inhibitor is discontinued, resume the original encorafenib dose after 3 to 5 elimination half-lives of the inhibitor.

FDA，2025.03