Encorafenib (Braftovi) is a targeted therapy for the treatment of patients with metastatic or unresectable melanoma. It targets cells with BRAF mutations and inhibits protein kinase B-RAF (BRAF). (see details in the section: Mechanism of action)

Encorafenib Uses:

• Unresectable or metastatic melanoma:

  • It is indicated in patients metastatic or unresectable  melanoma with a BRAF V600E or V600K mutation (in combination with binimetinib)
  • Limitations of use: Not used for wild-type BRAF melanoma.

Encorafenib (Braftovi) Dose in Adults

Note:  Confirm BRAF V600 mutation status before starting therapy

Encorafenib (Braftovi) Dose in the treatment of unresectable or metastatic melanoma (with BRAF V600E or BRAF V600K mutation):

• Oral: 450 mg once a day (along with binimetinib).

• Dosage adjustment for concomitant moderate or strong CYP3A4 inhibitors:

  • Avoids its use with moderate or strong CYP3A4 inhibitors
  • If it needs to be given reduce the dose as follows:
    • Encorafenib plus strong CYP3A4 inhibitor:
      • reduce the dose to one-third of the dose before concurrent use with a CYP3A4 inhibitor.
    • Encorafenib plus moderate CYP3A4 inhibitor:
      • reduce the dose to one-half of the dose before the concurrent use of a moderate CYP3A4 inhibitor.
  • After discontinuation of inhibitor for 3 - 5 half-lives, resume the encorafenib dose at normal dosage

• Missed doses:

  • Do not take a missed dose if <12 hours until the next dose.
  • If the patient has an episode of vomiting after encorafenib administration, do not take an extra dose, take the next scheduled dose.

Dose in Children:

Not indicated.

Encorafenib Pregnancy Category: X

• Studies on animal reproduction show that the drug can cause fetal harm, so it is not recommended for use during pregnancy.
• Before you start the therapy, do a pregnancy test.
• Use a highly effective contraceptive during therapy, and at least two weeks thereafter
• It is not recommended to use hormonal contraceptives.
• It can cause male infertility.

Use Encorafenib while you are breastfeeding

• It is not known if it is present in breast milk.
• Breastfeeding infants may be at risk. Therapy is not recommended for them during or after 2 weeks.

Encorafenib (Braftovi) Dose in Kidney disease:

• CrCl ≥30 mL/minute:

  • No dosage adjustment required.

• CrCl <30 mL/minute:

  • No dose adjustments listed in the manufacturer's labeling.

• Hemodialysis:

  • It has extensive protein binding, and probably not dialyzable

Encorafenib (Braftovi) Dose in Liver disease:

• Preexisting hepatic impairment:

  • Mild impairment (Child-Pugh class A):
    • No dosage adjustment required.
  • Moderate to severe impairment (Child-Pugh class B or C):
    • No dose adjustments listed in the manufacturer's labeling

• Hepatotoxicity during treatment:

  • Grade 2 AST or ALT elevations:
    • Continue encorafenib dose while monitoring
    • If no improvement in 4 weeks, withhold encorafenib until improvement to mild elevation (≤ grade 1) or to pretreatment or baseline levels and then resume at the same dose.
  • Grade 3 AST or ALT elevation:
    • First time of grade 3 AST or ALT elevations, withhold encorafenib for 4 weeks while monitoring, if improves to mild elevations (≤ grade 1) or to pretreatment/baseline level, resume at a reduced dose. If no improvement, discontinue it permanently
    • Recurrent grade 3 toxicity, permanently discontinuing encorafenib.
  • Grade 4 AST or ALT elevation:
    • The first occurrence of grade 4 AST or ALT elevations:
      • Permanently discontinue or withhold for 4 weeks; if improves to mild elevations (≤ grade 1) or to pretreatment/baseline level, resume at a reduced dose. If no improvement, permanently discontinue it permanently.
    • Recurrent grade 4 toxicity:
      • permanently discontinue.

Incidences of adverse effects include those defined during combination therapy with binimetinib.

Common Side Effects of Encorafenib (Braftovi):

• Central Nervous System:

  • Fatigue
  • Headache
  • Dizziness
  • Peripheral Neuropathy

• Dermatologic:

  • Hyperkeratosis
  • Alopecia
  • Palmar-Plantar Erythrodysesthesia
  • Skin Rash
  • Xeroderma
  • Pruritus
  • Dermatological Reaction
  • Erythema

• Endocrine & Metabolic:

  • Increased Gamma-Glutamyl Transferase
  • Hyperglycemia
  • Hyponatremia

• Gastrointestinal:

  • Nausea
  • Vomiting
  • Abdominal Pain
  • Constipation
  • Dysgeusia

• Hematologic & Oncologic:

  • Anemia
  • Hemorrhage
  • Leukopenia
  • Lymphocytopenia
  • Neutropenia

• Hepatic:

  • Increased Serum Alanine Aminotransferase
  • Increased Serum Aspartate Aminotransferase
  • Increased Serum Alkaline Phosphatase

• Neuromuscular & Skeletal:

  • Arthralgia
  • Myopathy
  • Back Pain
  • Limb Pain

• Renal:

  • Increased Serum Creatinine

• Miscellaneous:

  • Fever

Less Common Side Effects Of Encorafenib (Braftovi):

• Central Nervous System:

  • Facial Paresis

• Dermatologic:

  • Acneiform Eruption

• Endocrine & Metabolic:

  • Hypermagnesemia

• Gastrointestinal:

  • Pancreatitis
  • Hematochezia
  • Hemorrhoidal Bleeding

• Hypersensitivity:

  • Hypersensitivity

• Hematologic & Oncologic:

  • Squamous Cell Carcinoma Of Skin
  • Malignant Melanoma
  • Rectal Hemorrhage
  • Keratoacanthoma
  • Basal Cell Carcinoma

• Neuromuscular & Skeletal:

  • Panniculitis

• Ophthalmic:

  • Uveitis

Contraindications to Encorafenib (Braftovi):

There are no contraindications in the labeling.

Warnings and precautions

• Dermatologic toxicities:

  • Encorafenib has been linked to significant dermatologic toxicity (20%) in patients who have received it as a single agent. 
  • It is possible to have a lower risk of toxicity (2%) if it is used in combination with binimetinib.

• Hemorrhage

  • Combining it with binimetinib can lead to serious hemorhagic events.
  • Hematochezia and rectal hemorhage are the most common hemorhagic manifestations.
  • A fatal intracranial hemorhage has been reported in conjunction with brain metastasis.

• Malignancy

  • BRAF inhibitors, including encorafenib, can cause new primary malignancies, both cutaneously and non-cutaneous.
  • CuSCC, also known as keratoacanthoma and basal cell carcinoma has been reported using encorafenib in combination with binimetinib or monotherapy.
  • The median time it took for cuSCC/KA to manifest was 6 months, with an interval of 1 to 9 month.
  • It is recommended that you have a dermatology evaluation done before starting treatment.
  • This can be done every two months or up to six months after stopping therapy. Monitor for any signs or symptoms of non-cutaneous malignancies.
  • For primary cutaneous malignancies, dose modification is not advised.
  • Stop using encorafenib in the case of RAS mutation-positive, non-cutaneous malignancies.

• Ocular toxicities:

  • Ocular toxicities can lead to Uveitis. This includes iritis and iridocyclitis.
  • Each visit should be monitored for ocular toxicities
  • Recommendations for severe or new visual disturbances.

• Extension of QT

  • It can prolong the QTc interval in dose-dependent ways.
  • Patients who are taking medications that have the potential to prolong QT or pose risk factors for QTc prolongation should be monitored.
  • Before starting therapy, make sure you have corrected hypokalemia and hypomagnesemia.

Encorafenib: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• BRAFV 600K or V600E mutation status before starting therapy
• Electrolytes
• Pregnancy test before starting therapy
• Dermatologic evaluations before starting therapy, every 2 months during therapy, and up to 6 months after discontinuation to assess for new cutaneous malignancies;
• Signs/symptoms of uveitis (eg, eye pain, photophobia, vision changes)
• Monitor for hemorrhage
• Monitor adherence.

How to administer Encorafenib (Braftovi)?

Oral: Once a day and can be taken with or without food.

Mechanism of action of Encorafenib (Braftovi):

• Encorafenib, an inhibitor of protein kinase BRAF (BRAF), acts as a suppressor of the MAPK pathway. 
• Encorafenib inhibits BRAF V600E and V600 D.
• This results in sustained inhibition. BRAF V600 mutations cause activation of BRAF, which stimulates tumor growth. 
• BRAF inhibition results is inhibition of tumor cell proliferation.
• Combining encorafenib with binimetinib results in greater antitumor activity for BRAF V600-mutant cell lines.
• It also delays resistance development in BRAF V600 mutant human melanoma xenografts. (Observed in mice).

Absorption:

• It has good absorption. 86% of the dose is absorbed.

Protein binding:

• Most of the drug is plasma protein bound (86%).

Metabolism:

• N-dealkylation is the primary metabolic pathway
• CYP3A4 (primary contributor), CYP2C19, and CYP2D6 (minor) contribute to total oxidative clearance in human liver microsomes

Half-life elimination:

• 3.5 hours

Time to peak:

• 2 hours

Excretion: Through both feces and urine

• Feces (47%; 5% as unchanged drug)
• Urine (47%; 2% as unchanged drug)

International Brand Names of Encorafenib:

• Braftovi

Encorafenib Brand Names in Pakistan:

No Brands Available in Pakistan.