Encorafenib Prescribing Information

Encorafenib is mainly indicated for the treatment of metastatic melanoma harboring BRAF V600E or V600K mutations, metastatic colorectal cancer, and metastatic non-small cell lung cancer harboring BRAF V600E mutation.

FDA-Approved Indications

1. Melanoma: In combination with binimetinib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutation.

2. Metastatic colorectal cancer: In combination with cetuximab and fluoropyrimidine-based chemotherapy (mFOLFOX6 or FOLFIRI) for adult patients; or in combination with cetuximab for adult patients who have received prior therapy. Both require BRAF V600E mutation.

3. Non-small cell lung cancer: In combination with binimetinib for adult patients with metastatic non-small cell lung cancer with BRAF V600E mutation.

Limitations of Use: Not indicated for wild-type BRAF melanoma, colorectal cancer, or non-small cell lung cancer.

Dosage and Administration

Recommended Dosage

1. Recommended dosage for melanoma and non-small cell lung cancer: 450 mg orally once daily in combination with binimetinib until disease progression or unacceptable toxicity.

2. Recommended dosage for colorectal cancer: 300 mg (four 75 mg capsules) orally once daily until disease progression or unacceptable toxicity.

Administration

May be taken with or without food.

Missed Dose

If the next scheduled dose is within 12 hours, do not take the missed dose.

Vomiting After Taking a Dose

Do not take an additional dose; take the next dose as scheduled.

Dosage Adjustments for Adverse Reactions

1. Melanoma and lung cancer: Two dose reductions of 450 mg → 300 mg → 225 mg; if 225 mg is still not tolerated, permanently discontinue.

2. Colorectal cancer: Two dose reductions of 300 mg → 225 mg → 150 mg; if 150 mg is still not tolerated, permanently discontinue. If binimetinib is withheld, cap encorafenib at 300 mg daily.

3. Adjustment with concomitant strong or moderate CYP3A4 inhibitors: Reduce by one dose level based on the current daily dose; for example, when the current dose is 450 mg, reduce to 225 mg with a moderate inhibitor and to 150 mg with a strong inhibitor; after the inhibitor is discontinued for 3 to 5 half-lives, resume the original dose.

Warnings and Precautions

1. New primary malignancies: New primary cutaneous and non-cutaneous malignancies may occur. Perform dermatologic examinations as necessary; suspicious skin lesions should be excised and sent for dermatopathologic evaluation. Permanently discontinue for non-cutaneous RAS mutation-positive malignancies.

2. Tumor promotion in wild-type BRAF tumors: In vitro studies show paradoxical activation of the MAPK pathway and increased proliferation in wild-type BRAF cells.

3. Cardiomyopathy: Manifested as symptomatic or asymptomatic decreases in ejection fraction. Assess ejection fraction before treatment, after 1 month of treatment, and every 2 to 3 months thereafter.

4. Hepatotoxicity: Monitor liver function before treatment and monthly during treatment.

5. Hemorrhage: Major hemorrhagic events may occur, including fatal intracranial hemorrhage and gastrointestinal bleeding.

6. Uveitis: Including iritis and iridocyclitis. Assess visual symptoms at each visit and perform periodic ophthalmologic examinations.

7. QT prolongation: Dose-dependent. Monitor electrolytes before and during treatment; correct hypokalemia and hypomagnesemia. Withhold treatment when QTc is 500 ms or greater.

8. Embryo-fetal toxicity: May cause fetal harm. Women of reproductive potential should use effective non-hormonal contraception.

9. Risk with single-agent use: At the same dose, the risk of certain adverse reactions with encorafenib alone is higher than with the combination with binimetinib. See the specific numbers in Section 9 below.

10. Risks associated with combination therapy: Refer also to the prescribing information for binimetinib, cetuximab, and the individual components of mFOLFOX6 and FOLFIRI.

Adverse Reactions

1. Melanoma

Most common (≥25%) adverse reactions: fatigue, nausea, vomiting, abdominal pain, arthralgia.

2. Colorectal Cancer

In combination with mFOLFOX6 most common adverse reactions: peripheral neuropathy, nausea, fatigue, diarrhea, decreased appetite, rash, vomiting, hemorrhage, abdominal pain, arthralgia, pyrexia, constipation.

Most common adverse reactions in combination with cetuximab: fatigue, nausea, diarrhea, acneiform dermatitis, abdominal pain, decreased appetite, arthralgia, rash.

3. Non-Small Cell Lung Cancer

Most common adverse reactions when used in combination with binimetinib: fatigue, nausea, diarrhea, musculoskeletal pain, vomiting, abdominal pain, visual impairment, constipation, dyspnea, rash, cough.

Drug Interactions

1. Strong or moderate CYP3A4 inhibitors: Avoid concomitant use; if unavoidable, reduce the dose.

2. Strong CYP3A4 inducers: Avoid concomitant use.

3. Sensitive CYP3A4 substrates: Avoid concomitant use; hormonal contraceptives are included in this category.

4. Substrates of OATP1B1, OATP1B3, or BCRP: Concomitant use may require reducing the dose of these substrates.

5. Drugs that may prolong the QT interval: Avoid concomitant use.

6. Grapefruit and grapefruit juice: Avoid.

Use in Specific Populations

Pregnancy: May cause fetal harm; human data in pregnancy are lacking.

Lactation: Breastfeeding is not recommended; breastfeeding should not occur during treatment or for 2 weeks after the last dose.

Contraception: Women should use effective non-hormonal contraception during treatment and for 2 weeks after the last dose.

Fertility: May impair male fertility.

Pediatric: Safety and efficacy have not been established.

Geriatric: No overall differences have been observed in patients aged 65 years and older; no dosage adjustment is required per the prescribing information.

Hepatic impairment: No adjustment is needed for mild impairment; the recommended dose has not been established for moderate or severe impairment.

Renal impairment: No adjustment is needed for mild to moderate impairment; the recommended dose has not been established for severe impairment.

Storage

Store at 20°C to 25°C; keep in the original bottle, tightly closed; do not remove the desiccant from the bottle; protect from moisture.