What Is Encorafenib (Braftovi)? FDA Approval, Licensing in Turkey, and Reimbursement

• FDA-Approved: Yes (First Approval Date: 27 June 2018)
• Brand Name: Braftovi
• Active Ingredient: Encorafenib
• Route of Administration: Oral, capsule form
• Class: Signal Transduction Inhibitor, BRAF Inhibitor (more specifically, a MAPK signaling pathway inhibitor)
• Category: Targeted Agent
• Manufacturer: Array BioPharma
• Distribution in Turkey: Pierre Fabre İlaç A.Ş.
• Approved Cancers:
  • Metastatic Melanoma: With binimetinib for unresectable or metastatic melanoma with a BRAF-V600E/K mutation (2018).
  • Metastatic Colorectal Cancer: For metastatic colorectal cancer with a BRAF-V600E mutation, with cetuximab in the second line and with cetuximab plus mFOLFOX6 in the first line (2020-2024).
  • Metastatic Non-Small Cell Lung Cancer (NSCLC): With binimetinib for metastatic NSCLC with a BRAF-V600E mutation (2023).

What Is Encorafenib?

Encorafenib is a targeted cancer therapy, particularly for cells with genetic alterations such as a BRAF-V600E mutation. This oral small-molecule drug suppresses the mitogen-activated protein kinase (MAPK) signaling pathway, which supports cell growth and proliferation.

NOTE: Encorafenib and binimetinib are used together for certain cancers, particularly BRAF V600E mutation-positive melanoma, because the combination suppresses signaling more effectively by targeting both BRAF and MEK pathways. This synergy reduces the risk of cancer cell resistance and improves treatment efficacy. 

How Does It Work?

• It suppresses cellular signaling by inhibiting mutated BRAF serine-threonine kinases, such as BRAF-V600E.
• It can inhibit normal (wild-type) BRAF and CRAF kinases.
• JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 are among the other kinases it inhibits to stop signaling in cancer cells.

These mechanisms aim to slow cancer cell growth while minimizing effects on healthy cells.

The image above shows intracellular signaling pathways and the effects of various inhibitors on them. Beginning with the EGFR receptor, it details critical cellular pathways such as RAS-RAF-MEK-ERK and PI3K-AKT-mTOR after signals are received at the cell surface.

• BRAF inhibitors (encorafenib, vemurafenib, dabrafenib) and MEK inhibitors (binimetinib, trametinib) aim to halt cell proliferation by targeting the RAS-RAF-MEK-ERK pathway.
• EGFR inhibitors (cetuximab, panitumumab) and PI3K inhibitors (alpelisib, inavolisib) inhibit different points in signaling.

Suppressing these pathways with various drugs is therefore used to change gene expression and stop cancer cell growth and proliferation.

FDA (US Food and Drug Administration) Approval History

1. 20 December 2024: Encorafenib, Cetuximab, and mFOLFOX6 Received Accelerated FDA Approval for First-Line BRAF V600E-Mutant Metastatic Colorectal Cancer
2. 11 October 2023: The FDA approved Braftovi (encorafenib) plus Mektovi (binimetinib) for metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation.
3. 8 April 2020: The FDA approved Braftovi (encorafenib) plus cetuximab for previously treated BRAF V600E-mutant metastatic colorectal cancer (CRC).
4. 27 June 2018: The FDA approved Braftovi (encorafenib) plus Mektovi (binimetinib) for BRAF mutations in unresectable or metastatic melanoma.

Licensing in Turkey

The conditions / therapeutic indications for which encorafenib is licensed in Turkey are stated as follows:

Therapeutic Indications:

Encorafenib:

• With binimetinib, it is indicated for adults with unresectable or metastatic malignant melanoma with a BRAF V600 mutation who have not previously received any RAF pathway inhibitor and have an ECOG performance score of 0 or 1.
• With cetuximab, it is indicated for adults with BRAF V600E-mutant metastatic colorectal cancer (CRC) who have an ECOG performance score of 0 or 1 and have received at least one prior line of systemic therapy.

Is Encorafenib Reimbursed?

Braftovi is not yet reimbursed in Turkey.

Price: As of August 2025, the pharmacy retail price of BRAFTOVİ 75 mg hard capsules is 64,904.05 ₺

Resistance Mechanism

Possible resistance mechanisms during encorafenib treatment include:

1. Upregulation of MAPK Signaling: Cancer cells may develop resistance by upregulating (increasing) the MAPK signaling pathway.
2. Activation of Alternative Cellular Signaling Pathways: Fibroblast growth factor receptors (FGFR), epidermal growth factor receptors (EGFR), and other pathways such as PI3K/Akt can be activated or induced, reducing drug sensitivity.
3. Reactivation of Ras/Raf Signaling: Cancer cells may reactivate this pathway to evade treatment.

These resistance mechanisms allow cancer cells to continue growing and spreading. Treatment strategies are being developed to prevent or target them.

Absorption

• Oral bioavailability is 86%.
• Peak plasma concentration is reached approximately 2 hours after dosing.
• High-fat foods reduce maximum concentration (Cmax), but total drug bioavailability (AUC) is unaffected.

Distribution

Encorafenib's distribution properties are described below:

1. Plasma Protein Binding: 86% of encorafenib binds to plasma proteins, which may affect the active circulating concentration.
2. Steady-State Concentration: Steady-state drug levels are reached approximately 15 days after treatment begins.

Metabolism

• It is metabolized in the liver by the microsomal enzymes CYP3A4, CYP2C19, and CYP2D6.
• Drug metabolites are excreted in equal proportions through feces and urine (47%).
• Mean terminal half-life is approximately 3.5 hours.

Dosing

1. Melanoma: The recommended dose is 450 mg orally once daily, with binimetinib.
2. Colorectal Cancer: 300 mg orally once daily, with cetuximab.
3. Non-Small Cell Lung Cancer: 450 mg encorafenib orally once daily and 45 mg binimetinib orally twice daily.

Drug Interactions

1. CYP3A4 Inhibitors: Drugs such as ketoconazole, itraconazole, clarithromycin, and atazanavir may slow encorafenib metabolism and increase toxicity risk.
2. CYP3A4 Inducers: Drugs such as rifampin, phenytoin, and carbamazepine may accelerate encorafenib metabolism and reduce efficacy.
3. Hormonal Contraceptives: Concomitant use with CYP3A4 substrates may reduce the effectiveness of hormonal contraceptives and increase toxicity.

Conditions Requiring Caution

1. Skin Examinations: Because of potential skin adverse effects (such as cutaneous squamous cell carcinoma and keratoacanthoma), skin examinations should be performed at the start of treatment, every 2 months during treatment, and for up to 6 months after treatment is discontinued.
2. Signs of Non-Cutaneous Malignancy: Patients should be closely monitored for malignancies outside the skin.
3. Blood Glucose Control: Serum glucose levels should be monitored regularly in patients with diabetes or hyperglycemia.
4. Ocular Reactions: Patients should be monitored for ophthalmic adverse effects such as uveitis and iritis.
5. BRAF Mutation Testing: Before treatment is started, the presence of a BRAF-V600E mutation should be confirmed using an FDA-approved test.
6. Hepatic and Renal Impairment: No dose adjustment is required in patients with mild hepatic or renal impairment. However, caution is required in cases of moderate or severe impairment, and a clinical assessment should be performed before treatment is administered.
7. CYP3A4 Drug Interactions: The dose adjustment guidelines should be consulted when the drug is used with moderate or strong CYP3A4 inhibitors.
8. Pregnancy and Breastfeeding: Encorafenib is classified as pregnancy category D . It should not be used during pregnancy or breastfeeding.

Adverse Effects

Adverse effects have been reported as follows, from most common to least common:

1. Skin Toxicity: Cutaneous squamous cell carcinomas and keratoacanthomas occur in approximately 3% of patients. The average time to first occurrence is 6 months. A new primary melanoma may also develop.
2. Skin Reactions: Reactions such as hyperkeratosis, rash, dry skin, hair loss (alopecia), and itching (pruritus) are common.
3. Fatigue: Fatigue is one of the most frequently reported adverse effects during treatment.
4. Bleeding: Gastrointestinal bleeding complications and intracranial bleeding in patients with metastatic brain disease may occur.
5. Musculoskeletal Reactions: Arthralgia (joint pain) and myalgia (muscle pain) may occur.
6. Ocular Adverse Effects: Ophthalmic adverse effects, including uveitis, iritis, and photophobia, may develop.
7. Gastrointestinal Adverse Effects: Nausea, vomiting, abdominal pain, and constipation are the most common gastrointestinal adverse effects.
8. QTc Prolongation: It may prolong the QTc interval and affect heart rhythm.
9. Hyperglycemia: An increase in blood glucose levels (hyperglycemia) may develop.