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encorafenib
Encorafenib is an oral, small molecule kinase inhibitor that specifically targets BRAF V600E. BRAF mutations can result in constitutively activated BRAF kinases that may stimulate tumour cell growth. By inhibiting BRAF, encorafenib interferes with the MAPK signalling pathway that regulates the proliferation and survival of cancer cells. In vitro, encorafenib exhibits activity against BRAF V600 E, D, and K mutations, and targets wild-type BRAF and CRAF.
| Bioavailability |
At least 86% |
| Effects with food |
Administration with a high-fat, high-calorie meal ↓ Cmax by 36% but no effect on AUC. |
| T max |
2 hours |
| Time to reach steady state |
15 days |
| PPB |
86% |
Encorafenib is metabolized primarily through CYP3A4 N-dealkylation.
| Half-life |
3.5 hours |
| Feces |
47% (5% unchanged) |
| Urine |
47% (2% unchanged) |
- Melanoma
- Colorectal cancer (CRC)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following adverse events were reported in > 10% of patients with metastatic CRC treated with encorafenib in combination with cetuximab versus either irinotecan and cetuximab or FOLFIRI and cetuximab in a randomized Phase 3 study. It also includes severe or life-threatening adverse effects from other sources. Adverse effects reported with encorafenib in combination with binimetinib for melanoma are denoted with "^".
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | QT interval prolonged (3%) | E | |||
| Tachycardia (6%) | E | ||||
| Venous thromboembolism (6%) | E | ||||
| Dermatological | Hand-foot syndrome (4%) | E | |||
| Other (14%) (melanocytic nevus) | E | ||||
| Photosensitivity (4%) ^ | E | ||||
| Rash, pruritus (29%) | E | ||||
| Gastrointestinal | Abdominal pain (30%) (4% severe) | E | |||
| Anorexia (27%) | E | ||||
| Constipation (15%) | E | ||||
| Diarrhea (33%) | E | ||||
| Nausea, vomiting (34%) | I E | ||||
| General | Fatigue (51%) (7% severe) | E | |||
| Fever (18%) (4% severe) ^ | |||||
| Hematological | Hemorrhage (19%) (2% severe) | E | |||
| Hepatobiliary | ↑ LFTs (<5%) (severe) | E | |||
| Pancreatitis (1%) | E | ||||
| Hypersensitivity | Hypersensitivity (1%) | I E | |||
| Metabolic / Endocrine | Abnormal electrolyte(s) (19%) (↓ Mg, K, Na) | E | |||
| Hyperglycemia (13%) (5% severe) ^ | E | ||||
| Musculoskeletal | Musculoskeletal pain (27%) | E | |||
| Neoplastic | Secondary malignancy (1%) (cutaneous or non-cutaneous) | D L | |||
| Nervous System | Headache (20%) | E | |||
| Insomnia (13%) | E | ||||
| Other (1%) (facial paresis) ^ | E | ||||
| Peripheral neuropathy (12%) | E | ||||
| Ophthalmic | Retinal detachment (20%) ^ | E | |||
| Uveitis (4%) ^ | E | ||||
| Visual disorders (6%) | E | ||||
| Renal | Nephrotoxicity (2%) | E | |||
| Respiratory | Dyspnea (11%) | E | |||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for encorafenib include fatigue, nausea, vomiting, abdominal pain, rash acneiform, anorexia, rash, pruritus, headache, constipation, musculoskeletal pain and skin hyperpigmentation.
When used as a single agent, encorafenib is associated with an increased risk of certain adverse reactions including: hand-foot syndrome, hyperkeratosis, dry skin, erythema, rash, alopecia, pruritus, arthralgia, myopathy, back pain, dysgeusia, and acneiform dermatitis. Grade 3 or 4 dermatologic adverse reactions occurred in 21% of patients receiving single agent encorafenib compared to 2% of patients receiving the combination of encorafenib and binimetinib.
Based on its mechanism of action, encorafenib may promote malignancies associated with RAS activation through mutation or other pathways. New primary malignancies, cutaneous (e.g., cuSCC/KA) and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib.
Fatal cerebral hemorrhage has been reported in patients with new or progressive brain metastases on combination treatment with binimetinib while fatal gastrointestinal hemorrhage has been reported in patients on combination treatment with cetuximab.
Uveitis, including iritis and iridocyclitis, has been observed in patients on combination treatment with binimetinib for melanoma.
Encorafenib has been associated with serious cardiovascular adverse effects. In clinical trials, dose-dependent QTc prolongation occurred in 0.7% and 3.2% of patients who received encorafenib in combination with binimetinib and cetuximab, respectively. Venous thromboembolism, including pulmonary embolism, has also occurred while on combination treatment.
Refer to protocol by which the patient is being treated.
Screen for hepatitis B virus in all cancer patients starting systemic treatment. Refer to the hepatitis B virus screening and management guideline.
BRAF V600 or V600E mutation should be confirmed by a validated test prior to starting encorafenib.
Correct electrolyte imbalances prior to and during treatment.
A dermatologic evaluation should be performed prior to initiating treatment.
Various dosing and schedules are used depending on the indication. Refer to the product monograph or related regimen monographs for details.
Melanoma (in combination with binimetinib):
Oral: 450 mg Daily
Colorectal Cancer (in combination with cetuximab):
Oral: 300 mg Daily
Table 1 - Encorafenib Dose with CYP3A4 Inhibitors
Refer to Interactions Section for details on dosing modifications with CYP 3A4 inhibitors.
| Planned Dose (mg daily) | Encorafenib Dose* (mg daily) | |
| with Strong CYP3A4 inhibitor | with Moderate CYP3A4 inhibitor | |
| 450 | 150 | 225 |
| 300 | 75 | 150 |
| 225 | 75 | 75 |
| 150 | 75^ | 75 |
*Resume previous dose after the inhibitor has been discontinued for 3 to 5 half-lives.
^Monitor patients for adverse reactions and use clinical judgment; encorafenib exposure at 75mg daily (with a strong CYP3A4 inhibitor) is expected to be similar to the exposure at the 225mg daily dose (in the absence of a CYP3A4 inhibitor).
Table 2 - Dose Levels
| Dose Level | Encorafenib Dose (mg daily) | |
| Melanoma | Colorectal Cancer | |
| 0 | 450 | 300 |
| -1 | 300 | 225 |
| -2 | 225 | 150 |
| -3 | Discontinue | Discontinue |
Table 3 - Dose Modifications
Also refer to the binimetinib, cetuximab and panitumumab product monographs for dose modifications of these drugs.
| Toxicity / Severity | Action# | |
|
Non-cutaneous malignancy |
Discontinue if RAS mutation-positive. | |
| Any new or worsening visual disturbance | Refer to ophthalmologist. | |
| Uveitis | Grade 1 not responding to ocular therapy |
Hold encorafenib for up to 6 weeks. If improves to Grade < 1, resume at same dose. |
| Grade 2 not responding to ocular therapy |
Hold encorafenib for up to 6 weeks. If improves to Grade < 1, resume at 1 dose level ↓. |
|
| Grade 3 | ||
| Grade 4 | Discontinue. | |
| QT Prolongation |
QTcF > 500 ms |
Hold until QTcF < 500 ms, then resume at 1 dose level ↓. If > 1 recurrence, discontinue. |
| QTcF > 500 ms AND > 60 ms increase from baseline |
Discontinue. | |
Increase in AST or ALT |
Grade 2, without improvement for 2 weeks |
Hold until Grade < 1 or baseline. Resume at same dose. |
| Grade 3 or 4 | See Other Adverse Reactions below. | |
| Hand-foot Syndrome | Grade 2, without improvement for 2 weeks |
Hold until < Grade 1. Resume at same dose for first occurrence. Resume at same dose or with 1 dose level ↓ if recurrent. |
| Grade 3 |
Hold until < Grade 1. Resume with 1 dose level ↓. |
|
|
Other Dermatologic Reactions* |
Grade 2, without improvement for 2 weeks |
Hold until Grade < 1. Resume at same dose. |
| Grade 3 |
Hold until Grade < 1. Resume at same dose for first occurrence. Resume at 1 dose level ↓ if recurrent. |
|
| Grade 4 | Discontinue. | |
| Other Adverse Reactions* (including hemorrhage) | Grade 2, recurrent |
Hold for up to 4 weeks. If improves to Grade < 1 or baseline, resume at 1 dose level ↓. Discontinue if no improvement. |
| Grade 3, 1st occurrence | ||
| Grade 3, recurrent | Consider discontinuing. | |
| Grade 4, 1st occurrence |
Discontinue If improves to Grade < 1 or baseline, resume at 1 dose level ↓. Discontinue if no improvement. |
|
| Grade 4, recurrent | Discontinue. | |
#Encorafenib, when given in combination, may require dose reductions or discontinuation if other drugs are held or discontinued. Refer to the regimen monographs for more information.
*Excluding new primary cutaneous malignancies, other ocular events, ILD/pneumonitis, cardiac dysfunction, CPK elevation, rhabdomyolysis, and VTE.
For increased AST/ALT during treatment, refer to dose modifications table above.
| Hepatic Impairment | Encorafenib Starting Dose |
| Mild (Child-Pugh Class A) | 300 mg Daily |
| Moderate (Child-Pugh Class B) | No data available. |
| Severe (Child-Pugh Class C) |
| Creatinine Clearance (mL/min) | Encorafenib Starting Dose |
| > 30 | No dose adjustment recommended |
| < 30 | No data available. |
No dose adjustment required for patients > 65 years. No clinically relevant differences in the safety or effectiveness were observed in patients > 65 years compared to younger patients on combination treatment with binimetinib. There is insufficient data with the use of encorafenib and cetuximab in patients > 65 years or older to assess differences in efficacy or safety compared to younger patients.
Sex does not have a clinically meaningful effect on the pharmacokinetics of encorafenib.
The safety and effectiveness of encorafenib in children < 18 years have not been established.
-
Administer encorafenib with or without food.
-
Capsules should be swallowed whole with water. Do not crush, dissolve, or open capsules.
-
Grapefruit, starfruit, Seville oranges, their juices or products should be avoided during encorafenib treatment.
-
If a dose is missed, patient may take within 12 hours of the missed dose. If more than 12 hours has elapsed from the missed dose, the dose should be skipped and taken at the next scheduled time. Extra capsules should not be taken to make up for a missed dose.
-
Do not take an additional dose if vomiting occurs after taking encorafenib.
-
Store at 15 - 30°C in the original bottle. Protect from moisture and do not remove the desiccant.
- Patients who have a hypersensitivity to this drug or any of its components
- Patients must have a validated test to confirm BRAF V600/E mutation before treatment; paradoxical activation of MAP-kinase signaling may occur when BRAF wild-type cells are exposed to BRAF inhibitors, such as encorafenib.
- Exercise caution in patients with diabetes or with risk factors for QT prolongation, including known long QT syndromes, bradyarrhythmias, heart failure, and taking other QT prolonging agents.
- Patients were excluded from clinical trials if they have a history of Gilbert’s syndrome, abnormal LVEF, prolonged QTc (>480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. Consider benefits vs risks of using encorafenib in these patients.
- Use caution when driving or operating a vehicle or potentially dangerous machinery as vision problems have been reported.
Other Drug Properties:
-
Carcinogenicity:
New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with encorafenib.
-
Genotoxicity:
No
-
Embryotoxicity:
Yes
-
Fetotoxicity:
Yes
Encorafenib is not recommended for use in pregnancy. Adequate non-hormonal contraception should be used by patients and their partners during treatment, and for at least 2 weeks after the last dose.
-
Excretion into breast milk:
Unknown
Breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose
-
Fertility effects:
Probable
No fertility data in humans. Adverse effects on male reproductive organs have been seen in animals.
Encorafenib is metabolized mainly by CYP3A4, with lesser contribution from CYP2C19 and CYP2D6, and is a substrate of P-gp in vitro.
In vitro, encorafenib is a reversible inhibitor of UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, and CYP3A, a time-dependent inhibitor of CYP3A4, and an inhibitor of P-gp, OCT1, OCT2, and OAT1, and OAT3.
Encorafenib is a strong inducer of CYP3A4 at steady-state, and also induced CYP1A2, CYP2B6, and CYP2C9 in vitro.
Coadministration with sensitive CYP2C19, CYP2B6, or CYP2C9 substrates may result in increased toxicity or decreased efficacy of these agents.
Coadministration of encorafenib (UGT1A1 inhibitor) with binimetinib (UGT1A1 substrate) had no effect on binimetinib exposure. Coadministration of encorafenib with cetuximab had no clinically relevant effect on pharmacokinetics.
Coadministration of a proton pump inhibitor (i.e., rabeprazole) had no effect on encorafenib exposure.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| Strong CYP3A4 inhibitors (e.g., itraconazole, posaconazole, clarithromycin, ritonavir) | ↑ encorafenib exposure (↑ AUC 3-fold and ↑ Cmax by 68% with posaconazole) | ↓ metabolism of encorafenib | Avoid if possible. Reduce encorafenib dose if used in combination. See Table 1 in Dosing section. |
| Moderate CYP3A4 (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ encorafenib exposure (↑ AUC 2-fold and ↑ Cmax by 45% with diltiazem) | ↓ metabolism of encorafenib | Avoid if possible. Reduce encorafenib dose if used in combination. See Table 1 in Dosing section. |
| Strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort) | ↓ encorafenib exposure | ↑ metabolism of encorafenib | Avoid concomitant use. |
| Moderate CYP3A4 inducers (e.g., bosentan, efavirenz, etravirine, modafinil) | ↓ encorafenib exposure | ↑ metabolism of encorafenib | Avoid concomitant use. If unavoidable, no change in encorafenib dose when used in combination. |
| CYP3A4 substrates (e.g., hormonal contraceptives, atorvastatin, midazolam) | ↓ AUC and Cmax of substrate | Encorafenib is an inducer of CYP3A4. | Avoid concomitant use with substrates where a minimal decrease in concentration may lead to therapeutic failure. If coadministration of a sensitive substrate cannot be avoided, adjust substrate dose based on its product monograph recommendations. |
| CYP1A2 substrates (e.g., caffeine) | ↑ risk of toxicity | Encorafenib is a reversible inhibitor of CYP1A2. | Caution, monitor for substrate toxicity. |
| Drugs that prolong QT Interval (e.g., amiodarone, furosemide) | ↑ risk of toxicity | Additive | Avoid concomitant use with QT/QTc prolonging agent. |
| OATP1B1, OATP1B3 or BCRP substrates (e.g., rosuvastatin) | ↑ substrate exposure (↑ AUC 1.6-fold and ↑ Cmax 2.7-fold of rosuvastatin) | Encorafenib is an inhibitor of OATP1B1, OATP1B3 and/or BCRP. | Caution, monitor for substrate toxicity. Consider dose adjustment of substrate. |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Refer to the hepatitis B virus screening and management guideline for monitoring during and after treatment.
| Monitor Type | Monitor Frequency |
|---|---|
Liver function tests |
Baseline, monthly, and as clinically indicated |
Renal function tests and electrolytes, including potassium and magnesium |
Baseline, monthly, and as clinically indicated |
CBC |
Baseline, and as clinically indicated |
Skin examination for any new cutaneous malignancies |
Baseline, every 2 months during treatment, and continue for up to 6 months after the last dose |
ECG (especially in patients at risk for QT prolongation) |
Baseline and as clinically indicated |
Clinical toxicity assessment for bleeding, thromboembolism, hypersensitivity, fatigue, hyperglycemia, new primary non-cutaneous malignancies, rash, ocular, and GI effects |
At each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Exceptional Access Program (EAP Website)
- encorafenib - In combination with cetuximab or panitumumab in previously treated BRAF V600E-mutated metastatic colorectal cancer, according to clinical criteria
- encorafenib - For the treatment of patients with locally advanced unresectable or metastatic melanoma with a BRAF V600 mutation, according to clinical criteria.
Heinzerling L, Eigentler TK, Fluck M, et al. Tolerability of BRAF/MEK inhibitor combinations: adverse event evaluation and management. ESMO Open. 2019 May 23;4(3):e000491.
Hesketh, P. et al. Antiemetics: ASCO Guideline Update. Journal of Clinical Oncology 2020 38:24, 2782-2797.
Kopetz, S. et al. Encorafenib, Binimetinib, and Cetuximab in BRAF V600E–Mutated Colorectal Cancer. N Engl J Med 2019.
Product Monograph: Braftovi® (encorafenib). Pfizer Canada ULC. February 23, 2024.
Proietti I. et al. BRAF Inhibitors: Molecular Targeting and Immunomodulatory Actions. Cancers (Basel). 2020 Jul 7;12(7):1823.
Summary of Product Characteristics: Braftovi. Pierre Fabre Limited. September 14, 2022.
April 2024 Modified Interactions section
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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