Encorafenib (Braftovi): Understanding Its Mechanism, Dosing, Clinical Uses, and Role in BRAF V600–Mutated Cancers

Encorafenib (Braftovi) is an oral, selective inhibitor of mutant BRAF kinase, particularly tumors harboring BRAF V600E or V600K mutations. By suppressing constitutive MAPK-pathway activation, encorafenib reduces downstream MEK/ERK signaling and inhibits tumor-cell proliferation and survival.

In contemporary oncology, encorafenib is used almost entirely as part of combination therapy. In the United States, it is FDA approved with binimetinib for BRAF V600E/K-mutated unresectable or metastatic melanoma and BRAF V600E-mutated metastatic NSCLC, and with cetuximab-based therapy for BRAF V600E-mutated metastatic colorectal cancer. Importantly, the 2026 FDA label expanded first-line colorectal cancer treatment to include encorafenib plus cetuximab with fluorouracil-based chemotherapy.

Key Facts

• Generic name: Encorafenib
• Brand name: Braftovi
• Drug class: BRAF kinase inhibitor
• Route: Oral
• Initial US approval: 2018
• Primary target: Mutant BRAF
• Relevant mutations: BRAF V600E and V600K
• Melanoma dose: 450 mg orally once daily with binimetinib
• NSCLC dose: 450 mg orally once daily with binimetinib
• CRC dose: 300 mg orally once daily with cetuximab-based therapy
• Administration: With or without food
• Capsule strength: 75 mg
• Major metabolism: CYP3A4
• Half-life: Approximately 3.5 hours
• Major safety issues: New primary malignancies, cardiomyopathy, hepatotoxicity, hemorrhage, uveitis, QT prolongation
• Current US status: FDA approved for melanoma, colorectal cancer, and NSCLC.

What Is Encorafenib?

Encorafenib is a small-molecule inhibitor of mutant BRAF kinase.

BRAF is part of the:

RAS–RAF–MEK–ERK signaling pathway

which regulates:

• Cell proliferation
• Survival
• Differentiation
• Migration
• Growth

In cancers carrying an activating BRAF V600 mutation, BRAF kinase becomes constitutively active and drives persistent downstream MAPK signaling independently of normal growth-factor control.

The most clinically relevant alterations include:

• BRAF V600E
• BRAF V600K

Encorafenib selectively inhibits mutant BRAF and reduces this abnormal signaling.

What Is the Mechanism of Action of Encorafenib?

1. BRAF V600 Mutation Creates Constitutive Kinase Activation

Normally, BRAF signaling depends on upstream activation through RAS.

A BRAF V600 mutation causes BRAF to remain activated independently of normal regulatory signals.

2. MEK and ERK Become Continuously Activated

Mutant BRAF phosphorylates and activates:

MEK1/2

which activates:

ERK1/2.

Persistent MEK/ERK signaling promotes:

• Tumor-cell proliferation
• Survival
• Invasion
• Resistance to apoptosis

3. Encorafenib Inhibits Mutant BRAF

Encorafenib is an:

ATP-competitive BRAF kinase inhibitor.

It binds to the kinase domain of mutant BRAF and inhibits its catalytic activity.

4. MAPK Signaling Is Suppressed

BRAF inhibition reduces downstream:

• MEK phosphorylation
• ERK phosphorylation

and therefore suppresses MAPK-pathway activity.

5. Tumor Growth Is Reduced

The downstream effects include:

• Reduced tumor-cell proliferation
• Reduced survival signaling
• Increased apoptosis
• Tumor regression in BRAF-dependent cancers

The mechanism can be summarized as:

Encorafenib → mutant BRAF inhibition → reduced MEK/ERK signaling → decreased proliferation and survival → increased apoptosis.

Why Is Encorafenib Used in Combination Therapy?

BRAF inhibition alone can produce meaningful responses, but MAPK signaling can reactivate through multiple resistance mechanisms.

Combination therapy improves pathway suppression.

With Binimetinib

Binimetinib inhibits MEK1/2, directly downstream of BRAF.

Therefore:

Encorafenib + binimetinib

provides dual blockade of:

BRAF → MEK → ERK signaling.

This strategy:

• Improves response durability
• Prolongs progression-free survival
• Improves overall survival
• Reduces some paradoxical BRAF inhibitor toxicities

It is used in:

• BRAF V600E/K melanoma
• BRAF V600E NSCLC

With Cetuximab in Colorectal Cancer

BRAF inhibition alone is relatively ineffective in BRAF V600E-mutated colorectal cancer because blockade of BRAF triggers feedback activation of:

EGFR signaling.

Cetuximab inhibits EGFR and helps prevent this feedback reactivation.

Therefore:

Encorafenib + cetuximab

became an established targeted approach in BRAF V600E-mutated metastatic CRC.

The combination can now also be given with:

• mFOLFOX6
• FOLFIRI

in first-line metastatic disease.

What Is the Dose of Encorafenib?

The recommended dose depends on the cancer type and combination partner.

Melanoma

For BRAF V600E- or V600K-mutated unresectable or metastatic melanoma:

450 mg orally once daily

in combination with binimetinib.

This equals:

Six 75 mg capsules once daily. 

NSCLC

For BRAF V600E-mutated metastatic NSCLC:

450 mg orally once daily

with binimetinib.

Treatment continues until:

• Disease progression
• Unacceptable toxicity.

Colorectal Cancer

For BRAF V600E-mutated metastatic CRC:

300 mg orally once daily

in combination with cetuximab.

Current FDA-approved combinations include:

• Cetuximab alone after prior therapy
• Cetuximab + mFOLFOX6
• Cetuximab + FOLFIRI

The latter fluorouracil-based combinations can be used in metastatic CRC according to the 2026 label.

How Is Encorafenib Administered?

Encorafenib is available as:

75 mg capsules.

It may be taken:

With or without food.

A high-fat meal reduces peak concentration but does not meaningfully alter total exposure, which supports administration without food restrictions.

Capsules should be taken consistently once daily.

What If a Dose Is Missed?

If a dose is missed:

Take it when remembered unless the next dose is due within 12 hours.

If the next dose is due within 12 hours:

Skip the missed dose.

Do not make up the missed dose.

If vomiting occurs after taking encorafenib:

Do not take an additional dose.

Take the next scheduled dose at the usual time.

How Are Encorafenib Dose Reductions Made?

Dose reductions depend on the indication.

Melanoma or NSCLC

Starting dose:

450 mg once daily

First reduction:

300 mg once daily

Second reduction:

225 mg once daily

If the patient cannot tolerate:

225 mg once daily

encorafenib should generally be permanently discontinued.

If binimetinib is temporarily withheld:

Reduce encorafenib to a maximum of 300 mg once daily until binimetinib is resumed.

Dose Reductions in Colorectal Cancer

Starting dose:

300 mg once daily

First reduction:

225 mg once daily

Second reduction:

150 mg once daily

If the patient cannot tolerate:

150 mg once daily

treatment should generally be permanently discontinued.

What Are the Important Drug Interactions With Encorafenib?

Strong or Moderate CYP3A4 Inhibitors

Encorafenib is primarily metabolized by:

CYP3A4.

Strong or moderate CYP3A4 inhibitors can substantially increase encorafenib exposure.

For example:

• Posaconazole increased AUC by approximately 183%
• Diltiazem increased AUC by approximately 83%. 

These combinations should generally be avoided.

If unavoidable:

Dose reduction is required according to the prescribing information.

CYP3A4 Inducers

Strong CYP3A4 inducers should generally be avoided because they may reduce encorafenib exposure.

Moderate induction also lowers exposure.

For example, modafinil reduced steady-state:

• AUC by approximately 24%
• Cmax by approximately 20%.

CYP3A4 Substrates

Encorafenib can act as a CYP3A4 inducer and substantially reduce exposure to sensitive CYP3A4 substrates.

In a drug-interaction study, midazolam exposure fell markedly during repeated encorafenib therapy.

This may be clinically important for:

• Hormonal contraceptives
• Other sensitive CYP3A4 substrates

Hormonal contraceptive effectiveness may therefore be reduced.

Transporter Interactions

Encorafenib inhibits transporters including:

• OATP1B1
• OATP1B3
• BCRP

Rosuvastatin exposure increased when administered with encorafenib/binimetinib.

Dose adjustment of sensitive transporter substrates may therefore be required.

Does Encorafenib Require Renal or Hepatic Dose Adjustment?

Renal Impairment

No dose adjustment is recommended for:

Mild-to-moderate renal impairment

defined approximately as:

CrCl 30 to <90 mL/min.

A recommended dose has not been established in:

Severe renal impairment, CrCl <30 mL/min. 

Hepatic Impairment

No adjustment is recommended for:

Mild hepatic impairment — Child-Pugh A.

A recommended dose has not been established for:

• Child-Pugh B
• Child-Pugh C.

What Is the Pharmacokinetic Profile of Encorafenib?

Absorption

The median time to peak plasma concentration is approximately:

2 hours.

At least:

86%

of the administered dose is absorbed. Access Data FDA

Food Effect

A high-fat meal decreased Cmax by approximately:

36%

but did not affect AUC.

Therefore encorafenib can be administered:

With or without food. 

Protein Binding

Encorafenib is approximately:

86% protein bound.

Volume of Distribution

Approximate apparent volume of distribution:

164 L.

Half-Life

The terminal half-life is approximately:

3.5 hours. 

Metabolism

Encorafenib is metabolized primarily through:

• CYP3A4: ~83%
• CYP2C19: ~16%
• CYP2D6: ~1%. 

Excretion

After radiolabeled dosing:

• Approximately 47% was recovered in feces
• Approximately 47% in urine

Only small fractions were recovered unchanged.

What Are the Clinical Uses of Encorafenib?

1. BRAF V600E/K-Mutated Unresectable or Metastatic Melanoma

Encorafenib is FDA approved:

In combination with binimetinib

for patients with unresectable or metastatic melanoma with:

• BRAF V600E
• BRAF V600K

mutations.

2. BRAF V600E-Mutated Metastatic Colorectal Cancer

Encorafenib is FDA approved:

With cetuximab

after prior therapy.

The 2026 label also includes:

Encorafenib + cetuximab + fluorouracil-based chemotherapy

for adults with BRAF V600E-mutated metastatic CRC.

Approved chemotherapy backbones include:

• mFOLFOX6
• FOLFIRI.

3. BRAF V600E-Mutated Metastatic NSCLC

Encorafenib is FDA approved:

In combination with binimetinib

for adults with metastatic NSCLC harboring:

BRAF V600E. 

What Did Encorafenib Clinical Trials Show?

COLUMBUS — BRAF V600-Mutated Melanoma

The pivotal phase III COLUMBUS trial evaluated encorafenib plus binimetinib in patients with BRAF V600-mutated advanced melanoma.

A total of:

577 patients

were randomized to:

• Encorafenib 450 mg once daily + binimetinib 45 mg twice daily
• Encorafenib 300 mg once daily
• Vemurafenib 960 mg twice daily.

Progression-Free Survival

Median PFS was:

• 14.9 months with encorafenib + binimetinib
• 7.3 months with vemurafenib

Hazard ratio:

0.54

P < 0.0001.

Overall Survival

Median OS was:

• 33.6 months with encorafenib + binimetinib
• 16.9 months with vemurafenib.

Objective Response Rate

ORR was approximately:

• 63% with encorafenib + binimetinib
• 40% with vemurafenib.

Long-Term Outcomes

At 5 years:

• PFS rate: 23%
• OS rate: 35%

with encorafenib + binimetinib.

For vemurafenib:

• 5-year PFS: 10%
• 5-year OS: 21%

BEACON CRC — Previously Treated BRAF V600E-Mutated mCRC

The phase III BEACON CRC study established encorafenib plus cetuximab as an important targeted therapy for previously treated BRAF V600E-mutant metastatic colorectal cancer.

Patients were randomized to:

• Encorafenib + binimetinib + cetuximab
• Encorafenib + cetuximab
• Control chemotherapy + cetuximab

Updated results showed:

Median Overall Survival

• Encorafenib + cetuximab: 9.3 months
• Control: 5.9 months

Hazard ratio:

0.61.

Objective Response Rate

• Encorafenib + cetuximab: 19.5%
• Control: 1.8%.

These findings established:

Encorafenib + cetuximab

as a standard targeted option after prior therapy.

BREAKWATER — First-Line BRAF V600E-Mutated mCRC

The phase III BREAKWATER trial moved encorafenib into the first-line metastatic colorectal cancer setting.

It evaluated:

Encorafenib + cetuximab + mFOLFOX6

versus standard chemotherapy.

Objective Response Rate

At the initial analysis:

• EC + mFOLFOX6: 60.9%
• Standard care: 40.0%

Odds ratio:

2.44.

Median duration of response was:

• 13.9 months
• 11.1 months, respectively.

Later analyses confirmed significant improvement in:

• Progression-free survival
• Overall survival

with first-line encorafenib/cetuximab plus chemotherapy.

The 2026 FDA label now includes encorafenib with cetuximab plus:

• mFOLFOX6
• FOLFIRI

for BRAF V600E-mutated metastatic CRC.

PHAROS — BRAF V600E-Mutated Metastatic NSCLC

The phase II PHAROS trial evaluated:

Encorafenib 450 mg once daily + binimetinib 45 mg twice daily

in BRAF V600E-mutated metastatic NSCLC.

The trial included:

• 59 treatment-naïve patients
• 39 previously treated patients.

Treatment-Naïve Patients

Updated 2025/2026 results showed:

Objective Response Rate
75%.

Median Duration of Response
40.0 months.

Median Progression-Free Survival
30.2 months.

3-Year Overall Survival Probability
53%.

Previously Treated Patients
ORR
46%.

Median Duration of Response
16.7 months.

Median PFS
9.3 months.

Median OS
22.7 months.

These results confirmed durable activity, especially in treatment-naïve disease.

What About Brain Metastases?

BRAF-mutated melanoma and NSCLC can both involve the central nervous system.

The pivotal COLUMBUS population included relatively few patients with baseline brain metastases, so the study was not designed as a dedicated intracranial-efficacy trial.

For NSCLC, encorafenib plus binimetinib is used as a systemic targeted option in BRAF V600E-mutated metastatic disease, including selected patients with CNS involvement, although the intracranial evidence base is less extensive than for some driver-specific agents such as modern ALK or EGFR inhibitors.

Is Encorafenib FDA Approved?

Yes.

Encorafenib received its initial US approval in:

2018.

Its current FDA-approved indications include:

Melanoma

Encorafenib + binimetinib for BRAF V600E/K-mutated unresectable or metastatic melanoma.

Colorectal Cancer

Encorafenib + cetuximab after prior therapy.

Encorafenib + cetuximab + fluorouracil-based chemotherapy for BRAF V600E-mutated metastatic CRC.

NSCLC

Encorafenib + binimetinib for BRAF V600E-mutated metastatic NSCLC.

What Is the Current Clinical Role of Encorafenib?

Melanoma

Encorafenib plus binimetinib is an established BRAF/MEK-targeted regimen for:

BRAF V600E/K-mutated advanced melanoma.

COLUMBUS demonstrated durable long-term disease control, with approximately:

35% of patients alive at 5 years.

Treatment selection between targeted therapy and immunotherapy depends on:

• Tumor burden
• Symptoms
• LDH
• CNS disease
• Prior immune checkpoint therapy
• Need for rapid tumor response

Colorectal Cancer

The role of encorafenib in colorectal cancer has expanded substantially.

Historically:

Encorafenib + cetuximab

was used after prior therapy based on BEACON CRC.

In 2026, the FDA label also supports first-line:

Encorafenib + cetuximab + fluorouracil-based chemotherapy

based on BREAKWATER.

This represents a major change in the management of:

BRAF V600E-mutated metastatic colorectal cancer.

NSCLC

Encorafenib plus binimetinib is a targeted treatment option for:

BRAF V600E-mutated metastatic NSCLC.

Longer follow-up from PHAROS showed particularly durable responses in treatment-naïve disease, with median PFS around:

30.2 months.

Read more: OncoDaily’s coverage of the ESMO 2026 metastatic colorectal cancer guideline, including first-line encorafenib + cetuximab + FOLFOX/FOLFIRI for BRAF V600E-mutated mCRC.

Watch more: Explore OncoDaily’s discussion on colorectal cancer and the evolving role of targeted therapy in molecularly defined disease.

What Are the Major Side Effects of Encorafenib?

The toxicity profile depends on the combination partner.

With Binimetinib

Common adverse effects in melanoma include:

• Fatigue
• Nausea
• Vomiting
• Abdominal pain
• Arthralgia

In NSCLC, common adverse effects include:

• Fatigue
• Nausea
• Diarrhea
• Musculoskeletal pain
• Vomiting
• Abdominal pain
• Visual impairment
• Constipation
• Dyspnea
• Rash
• Cough.

New Primary Malignancies

BRAF inhibitors can paradoxically stimulate MAPK signaling in:

BRAF wild-type cells

and can promote new malignancies.

These may include:

• Cutaneous squamous-cell carcinoma
• Keratoacanthoma
• New primary melanoma
• Noncutaneous malignancies

Patients require:

Dermatologic examination before treatment, during treatment, and after discontinuation. 

Tumor Promotion in BRAF Wild-Type Tumors

Encorafenib should not be used in:

Wild-type BRAF melanoma, CRC, or NSCLC.

Paradoxical pathway activation can increase proliferation in certain BRAF wild-type cells.

Cardiomyopathy

When encorafenib is combined with binimetinib, cardiac dysfunction may occur.

LVEF should be assessed:

• Before treatment
• After approximately 1 month
• Every 2–3 months thereafter.

Clinically meaningful reductions in LVEF may require:

• Treatment interruption
• Dose reduction
• Permanent discontinuation

Hepatotoxicity

Encorafenib plus binimetinib can cause elevated:

• ALT
• AST
• Bilirubin

Liver function tests should be obtained:

• Before treatment
• During treatment
• As clinically indicated.

Hemorrhage

Major hemorrhagic events can occur, particularly with:

Encorafenib + binimetinib.

Patients should be monitored for:

• Gastrointestinal bleeding
• Intracranial hemorrhage
• Other significant bleeding.

Uveitis and Ocular Toxicity

Encorafenib can cause:

Uveitis.

Patients should have ophthalmologic evaluation:

• At regular intervals
• Whenever visual symptoms occur.

Symptoms requiring evaluation include:

• Eye pain
• Photophobia
• Blurred vision
• Visual disturbance

QT Prolongation

Encorafenib can prolong the:

QT interval.

Monitoring should include:

• Potassium
• Magnesium
• Calcium
• ECG in patients at increased risk

Electrolyte abnormalities should be corrected before and during treatment.

Encorafenib should be withheld for:

QTc ≥500 ms. 

Embryo-Fetal Toxicity

Encorafenib can cause fetal harm.

Women of reproductive potential should use:

Effective nonhormonal contraception

because encorafenib may reduce the effectiveness of hormonal contraceptives.

What Monitoring Is Required?

Monitoring should be individualized according to the combination regimen but generally includes:

• Confirm BRAF mutation before therapy
• Dermatologic examination
• LVEF when used with binimetinib
• ALT
• AST
• Bilirubin
• Signs of hemorrhage
• Visual symptoms
• Ophthalmologic review
• ECG when clinically indicated
• Potassium
• Magnesium
• Calcium
• Symptoms of secondary malignancies
• Drug-interaction review
• CYP3A4 inhibitors and inducers
• Concomitant medications affected by CYP3A4 induction

When combined with chemotherapy or cetuximab, additional monitoring should follow the safety profile of those agents.