Consumer medicine information

Braftovi

Encorafenib

BRAND INFORMATION

Brand name

Braftovi

Active ingredient

Encorafenib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Braftovi.

SUMMARY CMI

BRAFTOVI®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I taking BRAFTOVI?

BRAFTOVI contains the active ingredient encorafenib. BRAFTOVI can be used:

  • in combination with a medicine called binimetinib (MEKTOVI®) to treat adult patients with a type of skin cancer called melanoma, which has spread to other parts of the body, or cannot be removed by surgery; or
  • in combination with a medicine called cetuximab to treat adults with cancer of the large intestine (colorectal cancer) that has been previously treated with other anticancer medicines.

For more information, see Section 1. Why am I taking BRAFTOVI? in the full CMI.

2. What should I know before I take BRAFTOVI?

Do not use if you have ever had an allergic reaction to Braftovi or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I take BRAFTOVI? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BRAFTOVI and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take BRAFTOVI?

  • Melanoma - The recommended dose of BRAFTOVI, when taken in combination with MEKTOVI, is six 75 mg capsules once daily (corresponding to a daily dose of 450 mg).
  • Colorectal cancer - The recommended dose of BRAFTOVI, when taken in combination with cetuximab is four 75 mg capsules once daily (corresponding to a daily dose of 300 mg).
  • Swallow the capsules whole with a full glass of water. BRAFTOVI can be taken with or without food. Avoid grapefruit juice.

More instructions can be found in Section 4. How do I take BRAFTOVI? in the full CMI.

5. What should I know while taking BRAFTOVI?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using BRAFTOVI.
  • Tell your doctor if you are pregnant, think you may be pregnant or are planning to become pregnant before taking BRAFTOVI
  • Tell your doctor if you experience heart, bleeding, eye, liver or problems, or skin changes.
Things you should not do
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.
  • Do not take BRAFTOVI to treat any other complaints unless your doctor tells you to.
Driving or using machines
  • BRAFTOVI can affect your ability to drive or use machines.
Looking after your medicine
  • Keep your BRAFTOVI capsules in their original pack until it is time to take them.
  • Store below 25°C in a cool and dry place.

For more information, see Section 5. What should I know while taking Braftovi? in the full CMI.

6. Are there any side effects?

When BRAFTOVI was taken with binimetinib, very common side effects included fatigue, nausea, diarrhoea, vomiting, problems with vision, stomach pain, joint pain, abnormal blood test results and muscle pain. When BRAFTOVI was taken with cetuximab, very common side effects included fatigue, nausea, diarrhoea, acne type rash, rash, stomach pain, decreased appetite and muscle pain. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

BRAFTOVI®

Active ingredient(s): encorafenib

Consumer Medicine Information (CMI)

This leaflet provides important information about using BRAFTOVI. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using BRAFTOVI.

Where to find information in this leaflet:

1. Why am I taking BRAFTOVI?
2. What should I know before I take BRAFTOVI?
3. What if I am taking other medicines?
4. How do I take BRAFTOVI?
5. What should I know while taking BRAFTOVI?
6. Are there any side effects?
7. Product details

1. Why am I taking BRAFTOVI?

BRAFTOVI contains the active ingredient encorafenib.

BRAFTOVI is an anti-cancer medicine, which belongs to a group of medicines called ‘BRAF inhibitors’.

BRAFTOVI can be used in combination with binimetinib (called MEKTOVI) to treat adult patients who have a type of skin cancer called melanoma, which has spread to other parts of the body, or cannot be removed by surgery, and which has a particular change (mutation) in the gene that produces a protein called BRAF.

BRAFTOVI can also be used in combination with cetuximab to treat adult patients who have previously been treated with other anticancer medicines, and who have a type of large intestine cancer (colorectal cancer), which has spread to other parts of the body, and which has a particular change (mutation) in the gene that produces a protein called BRAF.

BRAFTOVI can only be used to treat patients whose cancer has one of these particular mutations in the BRAF gene.

Before you start treatment, your doctor will have tested your tumour to confirm that it has one of these BRAF mutations.

When BRAFTOVI is used in combination with MEKTOVI or cetuximab, it can slow down or stop the growth of your cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

BRAFTOVI is not recommended for children and adolescents aged under 18 years. The safety and efficacy of this medicine has not been established in this age group.

2. What should I know before I take BRAFTOVI?

BRAFTOVI is to be used in combination with either MEKTOVI or cetuximab, therefore you should also read the CMI for the other medicine you are planning to take.

Warnings

Do not take BRAFTOVI if:

  • you are allergic to encorafenib, or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions such as:
    - heart problems, including alteration of the electrical activity of your heart (QT prolongation)
    - liver problems
    - kidney problems
    - bleeding problems, or if you are taking medicines that may increase your risk of bleeding
    - eye problems
  • take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed. BRAFTOVI is not recommended while breast-feeding. It is not known if BRAFTOVI passes into breastmilk.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with BRAFTOVI and affect how it works. These include:

  • some medicines to treat fungal infections (such as itraconazole, posaconazole, fluconazole)
  • some medicines to treat bacterial infections (such as rifampicin, clarithromycin, telithromycin, erythromycin, penicillin)
  • medicines typically used to treat epilepsy (seizures) (such as phenytoin, carbamazepine)
  • medicines typically used to treat cancer (such as methotrexate, imatinib)
  • medicines typically used to treat high cholesterol (such as rosuvastatin, atorvastatin)
  • a herbal treatment for depression called St. John's wort
  • some medicines for HIV treatment such as ritonavir, amprenavir, raltegravir or dolutegravir
  • birth control medicines containing hormones
  • medicines typically used to treat high blood pressure (such as diltiazem, bosentan, furosemide)
  • medicines used to treat an uneven heartbeat such as amiodarone.

These medicines may be affected by BRAFTOVI or these medicines may affect how well BRAFTOVI works. You may need different amounts of your medicines, or you may need to take different medicines.

Keep a list of the medicines you take so you can show it to your doctor, nurse or pharmacist when you get a new medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect BRAFTOVI.

4. How do I take BRAFTOVI?

Instructions to open the blister:

  • Do not push the capsule through the blister.
  • Separate one blister cell by bending it and gently tearing along the perforations.
  • Carefully peel off the blister foil starting at the corner labelled with an arrow.
  • Gently remove the capsule.

How much to take

  • Always take BRAFTOVI exactly as your doctor has prescribed.
  • The recommended dose of BRAFTOVI to treat melanoma, when taken in combination with MEKTOVI, is six 75 mg capsules once daily (corresponding to a daily dose of 450 mg).
  • The recommended dose of BRAFTOVI to treat colorectal cancer, when taken in combination with cetuximab, is four 75 mg capsules once daily (corresponding to a daily dose of 300 mg).
  • Be aware that your dose of BRAFTOVI may change during treatment, depending on your response to treatment.
  • If you have liver or kidney problems, your doctor may start you on a lower dose of BRAFTOVI. If you experience serious side effects (such as skin, heart, liver, eye or bleeding problems), your doctor may lower the dose of BRAFTOVI, or stop treatment temporarily or permanently.
  • Follow the instructions provided and use BRAFTOVI until your doctor tells you to stop.

When to take BRAFTOVI

  • Swallow the capsules whole with a full glass of water.
  • BRAFTOVI can be taken with or without food. Avoid grapefruit juice.
  • If vomiting occurs at any time after taking the capsules, do not take an additional dose. Take the next dose as scheduled.

Continue taking BRAFTOVI for as long as your doctor tells you to. Do not stop unless your doctor advises you to.

If you forget to take BRAFTOVI

If you miss your dose at the usual time, the missed dose is less than 12 hours late, take it as soon as you remember.

If the missed dose is more than 12 hours late, skip that dose and take your next dose at the usual time. Then go back to taking your capsules as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your doctor, nurse or pharmacist for some hints.

If you take too much BRAFTOVI

If you think that you have used too much BRAFTOVI, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while taking BRAFTOVI?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking BRAFTOVI.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking BRAFTOVI.

If you are going to have surgery, tell the surgeon or that you are taking BRAFTOVI.

If you become pregnant while taking BRAFTOVI, tell your doctor immediately.

If you are a woman who could become pregnant, you must use effective birth control (contraception) while you are taking BRAFTOVI, and you must continue to use effective contraception for at least 1 month after taking your last dose.

Birth control medicines containing hormones (such as pills, injections, patches, implants and certain intrauterine devices (IUDs) which release hormones) may not work as well as expected while you are taking BRAFTOVI. You will need to use another reliable method of birth control such as a barrier method (e.g. condom) to prevent falling pregnant while you are taking BRAFTOVI. Ask your doctor, pharmacist or nurse for advice.

Tell your doctor if you are breastfeeding while being treated with BRAFTOVI.

Call your doctor straight away if you experience the following while you are taking BRAFTOVI:

  • Skin changes
    Tell your doctor immediately if you detect any skin changes including new warts, skin soreness, reddish bumps which bleed or don't heal, or any changes in the size or colour of a mole.
BRAFTOVI may cause other types of skin cancer such as cutaneous squamous cell carcinoma. New melanoma lesions may also occur while taking BRAFTOVI.
Your doctor will periodically check for new cancers on your skin and inside your body before, during and after your treatment with BRAFTOVI.
  • Heart problems
    BRAFTOVI may lower the amount of blood pumped by your heart, alter the electrical activity of your heart, or make existing heart problems worse. Your doctor will run tests to check that your heart is working properly before and during your treatment with these medicines.
  • Bleeding problems
    BRAFTOVI may cause serious bleeding problems. Tell your doctor immediately if you have any signs of bleeding.
  • Eye problems
    BRAFTOVI may cause serious eye problems. Your doctor will examine your eyes for any new or worsening problems with your sight while you are taking these medicines.
  • Liver problems
    BRAFTOVI may increase the amounts of liver enzymes in your blood. Your doctor will run blood tests to monitor your liver function before and during treatment.
  • Kidney problems
    BRAFTOVI may alter your kidney activity (often it may cause abnormal blood tests, but more rarely it can cause dehydration and vomiting, or kidney failure). Your doctor will run blood tests to monitor your kidneys before and during treatment. Drink plenty of fluids during treatment. Tell your doctor immediately if you vomit and become dehydrated.

Remind any doctor, dentist or pharmacist you visit that you are using BRAFTOVI. Keep all of your doctor's appointments so that your progress can be checked.

Things you should not do

  • Do not take BRAFTOVI to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if their symptoms seem similar to yours or they have the same condition as you.
  • Do not stop taking your medicine or lower the dosage without checking with your doctor.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how BRAFTOVI affects you.

BRAFTOVI can affect your ability to drive or use machines. If you experience any problems with your vision, or any other side-effects that may affect your ability, avoid driving or using machines. Talk to your doctor if you are not sure if you should drive.

Looking after your medicine

  • Keep your BRAFTOVI capsules in their original pack until it is time to take them.
  • Keep your BRAFTOVI capsules in a place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on windowsills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

When BRAFTOVI was taken with MEKTOVI by patients with melanoma, the following side effects were reported.

Less serious side effects

Less serious side effectsWhat to do
Head and neurology related:
  • problems with nerves that can cause pain, loss of sensation or tingling in hands and feet
  • headache
  • dizziness
  • fever
  • fatigue
  • changes in the way things taste
  • weakness and paralysis of the face muscles (facial paresis)
Bleeding related:
  • reduced red blood cell count (anaemia)
  • bleeding at various sites in the body
  • blood clots
Heart related:
  • high blood pressure
  • abnormal blood test results related to blood creatine kinase, indicating damage to the heart and muscle
Eyes related:
  • problems with your vision (visual impairment)
  • inflammation of the eye (uveitis)
Gastrointestinal related:
  • stomach pain
  • diarrhoea
  • being sick (vomiting)
  • feeling sick (nausea)
  • constipation
  • abnormal blood test results for liver function
  • inflammation of the colon (colitis)
  • kidney failure
  • abnormal kidney test results (creatinine elevations)
  • abnormal blood test results for liver function (blood alkaline phosphatase)
  • abnormal blood test results for pancreas function (amylase, lipase)
  • inflammation of the pancreas (pancreatitis) causing severe abdominal pain
Muscle related:
  • joint pain (arthralgia)
  • muscle pain (myalgia), weakness or spasm
  • back pain
  • pain in the hands and feet
Skin and hair related:
  • itching
  • dry skin
  • abnormal hair loss or thinning (alopecia)
  • thickening of the outer layers of the skin
  • some types of benign (non-cancerous) skin tumours such as skin papilloma
  • type of skin cancer such as basal cell carcinoma
  • redness, chapping or cracking of the skin
  • inflammation of the fatty layer under the skin, symptoms include tender skin nodules
  • skin rash with flat discoloured area or raised bumps like acne (dermatitis acneiform)
  • redness, skin peeling or blisters on hands and feet (called palmar-plantar erythrodysaesthesia or hand and foot syndrome)
  • increased skin sensitivity to sunlight
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do

Heart related:
BRAFTOVI can affect the strength with which your heart pumps blood into your arteries or makes existing heart problems worse. Signs and symptoms can include:

  • feeling dizzy, tired or lightheaded
  • shortness of breath
  • feeling like your heart is pounding, racing or beating irregularly
  • swelling in the legs
Bleeding related:
  • headaches, dizziness or weakness
  • coughing up of blood or blood clots
  • vomit containing blood or that looks like “coffee grounds”
  • red or black stools that look like tar
  • passing blood in the urine
  • stomach (abdominal) pain
  • unusual vaginal bleeding
  • blood clots
Allergy related:
  • swelling of the hands or feet (peripheral oedema), localised swelling
  • allergic reaction that may include swelling of the face and difficulty breathing
Other skin cancers related:
  • BRAFTOVI may cause other types of skin cancer such as cutaneous squamous cell carcinoma or new melanomas. Usually these skin cancers can be removed with surgery.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What BRAFTOVI contains

Active ingredient
(main ingredient)		50 or 75 mg of encorafenib
Other ingredients
(inactive ingredients)

Capsule fill:

  • copovidone
  • poloxamer
  • microcrystalline cellulose
  • succinic acid
  • crospovidone
  • colloidal anhydrous silica
  • magnesium stearate
Capsule shell:
  • gelatin
  • titanium dioxide
  • iron oxide red
  • iron oxide yellow
  • iron oxide black
Printing ink:
  • shellac
  • iron oxide black
  • propylene glycol
Potential allergensNo

Do not take this medicine if you are allergic to any of these ingredients.

What BRAFTOVI looks like

BRAFTOVI 50 mg hard capsules are supplied in blister packs of 28 capsules (7 strips of 4 capsules).

The 50 mg capsules have an orange opaque cap and a flesh-coloured opaque body, with a stylised “A” printed on the cap and “LGX 50 mg” printed on the body.

50 mg: AUST R 295764

BRAFTOVI 75 mg hard capsules are supplied in blister packs of 42 capsules (7 strips of 6 capsules).

The 75 mg capsules have a flesh-coloured opaque cap and a white opaque body, with a stylised “A” printed on the cap and “LGX 75 mg” printed on the body.

75 mg: AUST R 295441

Who distributes BRAFTOVI

Pierre Fabre Australia Pty Limited
Level 7, 32 Walker St
North Sydney, NSW 2060

® = Registered Trademark

This leaflet was prepared in November 2021.

Internal document code
(Aus Braftovi CMI v8 based on Aus Braftovi PI v11)

Published by MIMS December 2022

BRAND INFORMATION

Brand name

Braftovi

Active ingredient

Encorafenib

Schedule

S4

 

1 Name of Medicine

Encorafenib.

2 Qualitative and Quantitative Composition

Each Braftovi 50 mg hard capsule contains encorafenib 50 mg.
Each Braftovi 75 mg hard capsule contains encorafenib 75 mg.
For the list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Braftovi 50 mg hard capsules.

Swedish orange opaque cap and flesh-coloured opaque body, printed with a stylised "A" on the cap and "LGX 50 mg" on the body. The length of the capsule is approximately 22 mm.

Braftovi 75 mg hard capsules.

Flesh-coloured opaque cap and white opaque body, printed with a stylised "A" on the cap and "LGX 75 mg" on the body. The length of the capsule is approximately 23 mm.

4 Clinical Particulars

4.1 Therapeutic Indications

Melanoma.

Encorafenib, in combination with binimetinib, is indicated for the treatment of adult patients who have unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by a validated test.

Colorectal cancer.

Encorafenib, in combination with cetuximab, is indicated for the treatment of adult patients who have metastatic colorectal cancer (mCRC) with a BRAF V600E mutation as detected by a validated test, and who have received prior systemic therapy.

4.2 Dose and Method of Administration

Treatment with encorafenib should only be initiated and supervised by a physician experienced in the use of anti-cancer medicines.

Patient selection.

Prior to treatment with encorafenib, the BRAF V600 mutation status of a patient's melanoma or colorectal cancer must be confirmed by a validated test, conducted by an experienced laboratory (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The efficacy and safety of encorafenib have only been established in patients who have melanoma with a BRAF V600E or V600K mutation or colorectal cancer with a BRAF V600E mutation. Encorafenib should not be used in patients who have wild-type BRAF malignant melanoma or wild type BRAF colorectal cancer.

Dosage.

Melanoma.

The recommended dose of encorafenib is 450 mg (six 75 mg capsules) once daily when used in combination with binimetinib.
For information on binimetinib dosage, see Section 4.2 Dose and Method of Administration of the binimetinib Product Information (PI).

Colorectal cancer.

The recommended dose of encorafenib is 300 mg (four 75 mg capsules) once daily, when used in combination with cetuximab.
For information on cetuximab dosage, see Section 4.2 Dose and Method of Administration of the cetuximab PI.

Administration.

Encorafenib capsules should be swallowed whole with water, with or without food. The concomitant administration of encorafenib with grapefruit juice should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Duration of treatment.

Treatment should continue until the patient no longer derives benefit or unacceptable toxicity develops.

Missed dose.

If a dose of encorafenib is missed, the patient should only take the missed dose if it is more than 12 hours until the next scheduled dose.

Vomiting after administration.

If a patient vomits after taking encorafenib, the patient should not take an additional dose. The patient should take the next scheduled dose.

Dose modification.

The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation. Recommended encorafenib dose levels for dose reduction are different in melanoma (Table 1) compared to mCRC (Table 2). Dose modification recommendations in case of adverse reactions (regardless of treatment indication) are presented in Table 3.

Melanoma.

If treatment-related toxicities occur when encorafenib is used in combination with binimetinib, dose modification should generally be undertaken for both drugs.
The following adverse reactions are more likely to be related to binimetinib than encorafenib: retinal pigment epithelial detachment (RPED), retinal vein occlusion (RVO), interstitial lung disease/pneumonitis, cardiac dysfunction, creatine phosphokinase (CK) elevation, rhabdomyolysis and venous thromboembolism. If one of these toxicities occurs, consider dose modification of binimetinib alone.
For information on dosage and recommended dose modifications for binimetinib, see Section 4.2 Dose and Method of Administration of the binimetinib PI.
Recommended dose levels for encorafenib dose reduction (when used in combination with binimetinib for the treatment of melanoma) are presented in Table 1.
If encorafenib is temporarily interrupted, interrupt binimetinib.
If binimetinib is temporarily interrupted, reduce encorafenib to 300 mg once daily during the time of binimetinib dose interruption. Administration of encorafenib at a dose of 450 mg once daily as a single agent is not well tolerated, and not recommended.
If encorafenib is permanently discontinued, then discontinue binimetinib.
If binimetinib is permanently discontinued, encorafenib may be continued at a reduced dose of 300 mg, depending on the individual clinical benefit.

Colorectal cancer.

For information on dosage and recommended dose modifications for cetuximab, see Section 4.2 Dose and Method of Administration of the cetuximab PI.
Recommended dose levels for encorafenib dose reduction (when used in combination with cetuximab for the treatment of mCRC) are presented in Table 2.
If encorafenib is permanently discontinued, cetuximab should be discontinued.
If cetuximab is permanently discontinued, encorafenib should be discontinued.

All indications.

Dose modification recommendations in case of adverse reactions (regardless of treatment indication) are presented in Table 3.

Special populations.

Hepatic impairment.

Patients with mild to severe hepatic impairment may have increased encorafenib exposure (see Section 5.2 Pharmacokinetic Properties). Administration of encorafenib should be undertaken with caution at a dose of 300 mg once daily in patients with mild hepatic impairment (Child-Pugh Class A). No dosing recommendation can be made in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment.

Renal impairment.

No dose adjustment is required for patients with mild or moderate renal impairment based on a population pharmacokinetics (PK) analysis. There are no clinical data with encorafenib in patients with severe renal impairment. Therefore, the potential requirement for dose adjustment cannot be determined for patients with severe renal impairment (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Elderly patients (65 years and older).

No dose adjustment is required for elderly patients (see Section 5.2 Pharmacokinetic Properties).

Children and adolescents (< 18 years).

The safety and efficacy of encorafenib have not been established in patients below the age of 18 years. There are no data available.

4.3 Contraindications

Hypersensitivity to the active substance encorafenib or to any of the excipients (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

Before initiating treatment with encorafenib in combination with binimetinib, or encorafenib in combination with cetuximab, the PI for the relevant combination partner drug must be reviewed. Information on warnings and precautions specific to binimetinib or cetuximab treatment are described in those documents.

Assessment of BRAF mutation status.

When assessing the BRAF mutation status of the tumour, it is important that a well-validated and robust test is used to minimise false-positive and false-negative determinations. In vitro experiments have demonstrated paradoxical activation of MAP-kinase signalling and increased cell proliferation in melanoma BRAF wild-type cell lines when they are exposed to BRAF inhibitors. Giving BRAF inhibitors to patients who have BRAF wild-type tumours may lead to accelerated tumour growth.

Melanoma that has progressed on a BRAF inhibitor.

There are limited data on the use of the combination of encorafenib with binimetinib in patients who previously progressed on a prior BRAF inhibitor treatment for unresectable or metastatic melanoma with a BRAF V600 mutation. These data show that the efficacy of the combination would be lower in these patients.

Patients with melanoma who have brain metastases.

There are limited efficacy data on the use of the combination of encorafenib and binimetinib in patients with a BRAF V600 mutant melanoma with brain metastases (see Section 5.1 Pharmacodynamic Properties).

New primary malignancies.

New primary malignancies (cutaneous and non-cutaneous) have been observed in patients treated with BRAF inhibitors, whether administered as a single agent or used in combination.

Cutaneous malignancies.

Cutaneous malignancies such as cutaneous squamous cell carcinoma including keratoacanthoma have been observed in patients treated with BRAF-inhibitors including encorafenib. New primary melanoma has been observed in patients treated with BRAF-inhibitors including encorafenib (see Section 4.8 Adverse Effects (Undesirable Effects)).
Dermatological evaluations should be performed prior to initiation of therapy with encorafenib, every 2 months while on therapy, and for up to 6 months following treatment discontinuation. Suspicious skin lesions should be managed by excision and dermatopathological evaluation. Patients should be instructed to immediately inform their physicians if new skin lesions develop. Encorafenib should be continued without any dose modification.

Non-cutaneous malignancies.

Based on its mechanism of action, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms. Patients receiving encorafenib should undergo a head and neck examination, chest/abdomen computerised tomography (CT) scan, anal and pelvic examinations (for women) and full blood counts prior to initiation, during and at the end of treatment as clinically appropriate. Consider permanently discontinuing encorafenib in patients who develop RAS mutation-positive non-cutaneous malignancies. Benefits and risks should be carefully considered before administering encorafenib to patients with a prior or concurrent cancer associated with RAS mutation.

Haemorrhage.

Haemorrhages, including major haemorrhagic events, can occur with encorafenib (see Section 4.8 Adverse Effects (Undesirable Effects)). The risk of haemorrhage may be increased with concomitant use of anticoagulant and antiplatelet therapy. The occurrence of Grade ≥ 3 haemorrhagic events can be managed with dose interruption, or treatment discontinuation and as clinically indicated (see Section 4.2 Dose and Method of Administration).

Ocular toxicities.

Ocular toxicities including uveitis, iritis and iridocyclitis can occur when encorafenib is administered (see Section 4.8 Adverse Effects (Undesirable Effects)). Some ocular toxicities (RPED and RVO) are more likely to be related to coadministered binimetinib (see Section 4.2 Dose and Method of Administration).
Patients should be assessed at each visit for symptoms of new or worsening visual disturbances. If symptoms of new or worsening visual disturbances including diminished central vision, blurred vision or loss of vision are identified, a prompt ophthalmological examination is recommended. Dose modification advice for ocular toxicities is described in Dose and Method of Administration.

QT prolongation.

QT prolongation has been observed in patients treated with BRAF-inhibitors. A thorough QT study to evaluate the QT prolongation potential of encorafenib has not been conducted. Encorafenib may cause mild increases in heart rate and small increases in QTc interval (see Section 5.1 Pharmacodynamic Properties).
There are insufficient data to exclude a clinically significant, exposure-dependent QT prolongation.
Due to the potential risk for QT prolongation, correct serum electrolyte abnormalities (including magnesium, potassium and calcium) and review other risk factors for QT prolongation (e.g. control of congestive heart failure and bradyarrhythmias, and concurrent administration of other medicinal products associated with QT prolongation) before treatment initiation and during treatment.
Perform an electrocardiogram (ECG) before initiation of encorafenib, one month after initiation, and then at approximately 3-month intervals or more frequently, as clinically indicated, while on treatment. The occurrence of QTc prolongation can be managed with dose reduction, treatment interruption or treatment discontinuation with correction of abnormal electrolytes and control of risk factors (see Section 4.2 Dose and Method of Administration).

Left ventricular dysfunction.

Left ventricular dysfunction (LVD), defined as symptomatic or asymptomatic decreases in ejection fraction has been reported when encorafenib is used in combination with binimetinib.
Assess LVEF (left ventricular ejection fraction) by echocardiogram or multi-gated acquisition (MUGA) scan before initiating encorafenib in combination with binimetinib, one month after initiation and then at approximately 3-month intervals or more frequently as clinically indicated while on treatment. If LVD occurs during treatment, see Section 4.2 Dose and Method of Administration of binimetinib PI.
The safety of encorafenib in combination with binimetinib has not been established in patients with a baseline LVEF that is either below 50% or below the institutional lower limit of normal. In these patients, binimetinib should be used with caution. For any symptomatic LVD, Grade 3 or 4 LVEF decrease or for absolute decrease of LVEF from baseline of ≥ 10%, binimetinib, and encorafenib should be discontinued and LVEF should be evaluated every 2 weeks until recovery.

Hepatic impairment.

As encorafenib is primarily metabolised and eliminated via the liver, patients with mild to severe hepatic impairment may have increased encorafenib exposure over the range of inter-subject variability exposure (see Section 5.2 Pharmacokinetic Properties).
In the absence of clinical data, encorafenib is not recommended in patients with moderate or severe hepatic impairment.
Administration of encorafenib should be undertaken with caution at a dose of 300 mg once daily in patients with mild hepatic impairment (see Section 4.2 Dose and Method of Administration).
Closer monitoring of encorafenib related toxicities in patients with mild hepatic impairment is recommended, including clinical examination and liver function tests, with assessment of ECGs as clinically appropriate during treatment.

Renal impairment.

There are no data available in patients with severe renal impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). Encorafenib should be used with caution in patients with severe renal impairment.
Creatinine elevation has been commonly reported with encorafenib as single agent or in combination with binimetinib or cetuximab. Observed cases of renal failure including acute kidney injury and renal impairment were generally associated with vomiting and dehydration. Other contributing factors included diabetes and hypertension. Blood creatinine should be monitored as clinically indicated and creatinine elevation managed with dose modification or discontinuation (see Section 4.2 Dose and Method of Administration, Table 3). Patients should ensure adequate fluid intake during treatment.

Use in the elderly.

Please see Section 5.2 Pharmacokinetic Properties; Section 4.8 Adverse Effects (Undesirable Effects).

Paediatric use.

The safety and efficacy of encorafenib in children and adolescents aged < 18 years have not been established. There are no data available.

Effects on laboratory tests.

Liver function abnormalities (AST, ALT elevations) have been observed with encorafenib (see Section 4.8 Adverse Effects (Undesirable Effects)). Liver laboratory values should be monitored before initiation of encorafenib and at least monthly during the first 6 months of treatment and then as clinically indicated. Liver function abnormalities should be managed with dose reduction, treatment interruption, or treatment discontinuation (see Section 4.2 Dose and Method of Administration).

Effects of other medicinal products on encorafenib.

Concurrent use of strong CYP3A inhibitors during treatment with encorafenib should be avoided. If concomitant use with a strong CYP3A inhibitor is necessary, patients should be carefully monitored for safety (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Caution should be exercised if a moderate CYP3A inhibitor is co-administered with encorafenib.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No drug-drug interaction was identified between encorafenib and cetuximab, or between encorafenib and binimetinib.

Effects of other medicinal products on encorafenib.

Encorafenib is metabolised by CYP3A4, CYP2C19 and CYP2D6. In vitro, CYP3A4 was predicted to be the major enzyme contributing to total oxidative clearance of encorafenib in human liver microsomes (~83.3%), followed by CYP2C19 and CYP2D6 (~16.0% and 0.71%, respectively).

CYP3A4 inhibitors.

Co-administration of strong (posaconazole) and moderate (diltiazem) CYP3A4 inhibitors with single doses of encorafenib in healthy volunteers resulted in an increase in overall (AUC, 3- and 2-fold higher, respectively) and peak (Cmax, 68.3% and 44.6% higher, respectively) encorafenib exposure.
Concomitant administration of encorafenib with strong CYP3A4 inhibitors should be avoided (due to increased encorafenib exposure and potential increase in toxicity). Examples of strong CYP3A4 inhibitors include, but are not limited to, ritonavir, itraconazole, clarithromycin, telithromycin, posaconazole and grapefruit juice. Moderate CYP3A4 inhibitors should be co-administered with caution. Examples of moderate CYP3A4 inhibitors include, but are not limited to, amiodarone, erythromycin, fluconazole, diltiazem, amprenavir and imatinib.
The safety and tolerability of encorafenib should be carefully monitored for patients in whom concomitant use of a strong or moderate CYP3A4 inhibitor is deemed necessary.

CYP3A4 inducers.

The effect of co-administering a strong CYP3A4 inducer on encorafenib exposure has not been studied in a dedicated trial however, a reduction in encorafenib exposure is likely and may result in compromised efficacy of encorafenib. Examples of strong CYP3A4 inducers include, but are not limited to carbamazepine, rifampicin, phenytoin and St. John's wort. Alternative agents with no to moderate CYP3A induction should be considered.
Repeat dose administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily with modafinil, a moderate CYP3A inducer, decreased encorafenib steady-state AUC by 24% and Cmax by 20%, compared to no co-administration with modafinil.

P-gp inhibitors and inducers.

Encorafenib is a substrate of P-glycoprotein (P-gp). While oral bioavailability might not be significantly affected by P-gp inhibitors or inducers because of the predicted high intestinal permeability, distribution into the central nervous system may be increased by P-gp inhibitors.

Effects of encorafenib on other medicinal products.

CYP and UGT substrates.

Encorafenib is a strong inducer of CYP3A4. In vitro, encorafenib is a relatively potent reversible inhibitor of UGT1A1, CYP2B6, CYP2C9 and CYP3A4/5, a relatively less potent inhibitor of CYP1A2, CYP2C8, CYP2C19 and CYP2D6 and a time-dependent inhibitor of CYP3A4. Encorafenib induced CYP1A2, CYP2B6, CYP2C9 and CYP3A4 in human primary hepatocytes.
Repeat dose administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily with a single dose of CYP probe substrate cocktail:
reduced midazolam 2 mg (CYP3A4 substrate) AUC by 82% and Cmax by 74%;
decreased omeprazole 20 mg (CYP2C19 substrate) AUC by 17% and did not change Cmax;
increased caffeine 50 mg (CYP1A2 substrate) AUC by 27% and Cmax by 13%;
decreased the ratio of losartan metabolite E3174 to losartan (CYP2C9 substrate) concentrations in urine by 28%;
did not change the ratio of dextromethorphan metabolite (dextrorphan) to dextromethorphan (CYP2D6 substrate) concentrations in urine.
These results indicate strong induction of CYP3A4, mild inhibition of CYP1A2 and CYP2C9 and no impact on pharmacokinetics of CYP2C19 and CYP2D6 substrates.
A single dose of encorafenib 450 mg and binimetinib 45 mg reduced bupropion 75 mg (CYP2B6 substrate) AUC and Cmax by ≤ 25% and repeated administration of encorafenib 450 mg daily and binimetinib 45 mg twice daily reduced bupropion AUC and Cmax by ≤ 26% indicating a lack of moderate or strong inhibition or induction.
For UGT1A1 substrates that undergo gut extraction, a minor to moderate interaction with encorafenib is expected.
Use caution when co-administering encorafenib with agents that are substrates of CYP3A4 (e.g. hormonal contraceptives) as it may result in loss of efficacy of those agents. If the coadministration of narrow therapeutic index CYP3A4 substrates cannot be avoided, adjust the dose of these substrates in accordance with their approved Product Information. Use caution when co-administering encorafenib with agents that are substrates of UGT1A1 as it may result in increased toxicity of those agents. While binimetinib is a UGT1A1 substrate, it does not undergo gut extraction. Co-administration of encorafenib with binimetinib does not affect binimetinib exposure.

Transporter substrates.

Encorafenib is an inhibitor of OATP1B1, OATP1B3 and/or BCRP. Repeated administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily with a single dose of rosuvastatin (a OATP1B1, OATP1B3 and BCRP substrate) increased rosuvastatin Cmax by 2.7-fold and AUC by 1.6-fold indicating a mild inhibition of OATP1B1, OAPTP1B3 and/or BCRP transporters. Coadministration of encorafenib with OATP1B1, OATP1B3 and/or BCRP substrates (such as rosuvastatin, atorvastatin, methotrexate) can result in increased concentrations.
In vitro, encorafenib potentially inhibits a number of other transporters at the expected clinical concentrations. Agents that are substrates of renal transporters OCT2, OAT1, OAT3 (such as furosemide, penicillin) or agents that are substrates of hepatic transporters OCT1 (such as bosentan) or substrates of P-gp (e.g. posaconazole) may also have increased exposure.
Therefore, these agents, substrates of transporters (OCT1, OCT2, OAT1, OAT3, OATP1B1, OATP1B3, BCRP and P-gp) should be co-administered with caution.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effect of encorafenib on fertility in humans. Fertility studies were not conducted with encorafenib. In the sub-acute 28-day and subchronic 13-week rat toxicology studies, encorafenib treatment at 20 mg/kg/day (similar to the human exposure at 450 mg daily based on unbound AUC) resulted in decreased testes and epididymis weights with tubular degeneration and oligospermia. In the 13-week study, partial reversibility was noted at the highest dose level (60 mg/kg/day).
Based on findings in male rats, the use of encorafenib may affect fertility in males of reproductive potential. As the clinical relevance of this is unknown, male patients should be informed of the potential risk for impaired spermatogenesis.

Women of childbearing potential.

Women of childbearing potential should be advised to use effective contraception during treatment with encorafenib and for at least 1 month after the last dose. Encorafenib may decrease the efficacy of hormonal contraceptives (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Therefore, female patients using hormonal contraception are advised to use an additional or alternative method such as a barrier method (e.g. condom) during treatment with encorafenib and for at least 1 month following the last dose.
(Category D)
There are no data on the use of encorafenib in pregnant women. However, studies in animals have demonstrated reproductive toxicity. The embryo-foetal development study in rats indicated that encorafenib induced foetal toxicity with lower foetal weights and delays in skeletal development (incomplete ossification of the bones of the skull and thoracic vertebra) at 20 mg/kg/day (2 times the human exposure at 450 mg daily based on unbound AUC). The embryo-foetal development study in rabbits indicated that encorafenib induced maternal toxicity and foetal toxicity with lower foetal weights, delays in skeletal development (incomplete ossification of the bones of the skull and thoracic vertebra) and visceral malformations (dilation of the aortic arch and ascending aorta, misshapen globular hearts, cardiac interventricular septal defects, small lung lobes and asplenia) at 75 mg/kg/day (14 times the human exposure at 450 mg daily based on total AUC) and delayed ossification (thoracic vertebra) at 25 mg/kg/day (7 times the human exposure).
Encorafenib should not be administered during pregnancy unless the benefits for the mother outweigh the risks for the foetus. If encorafenib is used during pregnancy or if the patient becomes pregnant while taking encorafenib, the patient should be informed of the potential hazard to the foetus.
 It is not known if encorafenib or its metabolites are excreted in human milk. Because many drugs are excreted in breast milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue encorafenib taking into account the benefit of breastfeeding for the child and the benefit of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

Visual disturbances have been reported in some patients treated with encorafenib during clinical trials. Patients should be advised not to drive or operate machinery if they experience visual disturbances or any other adverse effects that may affect their ability to drive or operate machinery (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

Melanoma studies.

Encorafenib 450 mg once daily with binimetinib 45 mg twice daily.

The safety of encorafenib (450 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) was evaluated in 274 patients with BRAF V600 mutant unresectable or metastatic melanoma (hereafter referred to as the pooled Combo 450 population), who received this regimen across two Phase II studies (CMEK162X2110 and CLGX818X2109) and one Phase III study (CMEK162B2301, the "COLUMBUS" study; see Section 5.1 Pharmacodynamic Properties, Clinical trials). In the pooled Combo 450 population (n=274), the most common adverse reactions (≥ 25%) occurring in patients treated with encorafenib administered with binimetinib were fatigue, nausea, diarrhoea, vomiting, retinal detachment, abdominal pain, arthralgia, blood CK increase and myalgia.

Encorafenib 300 mg once daily with binimetinib 45 mg twice daily.

The safety of encorafenib (300 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) was evaluated in 257 patients with BRAF V600 mutant unresectable or metastatic melanoma (hereafter referred to as the Combo 300 population) who received this regimen in Part 2 of the COLUMBUS study. The most common adverse reactions (≥ 25%) occurring in patients treated with encorafenib 300 mg administered with binimetinib were fatigue, nausea and diarrhoea.

Encorafenib 300 mg once daily as a single agent.

The safety profile of encorafenib as a single agent (at a dose of 300 mg once daily) is based on data from three clinical studies (Columbus Part 1, CLGX818X2102 and CLGX818X2101) that included 217 patients with unresectable or metastatic BRAF V600-mutant melanoma (hereafter referred to as the pooled encorafenib 300 mg population). The most common adverse drug reactions (ADRs) (≥ 25%) reported with encorafenib monotherapy at this dose were hyperkeratosis, alopecia, PPES fatigue, rash, arthralgia, dry skin, nausea, myalgia, headache, vomiting and pruritus.
Colorectal cancer studies.

Encorafenib 300 mg once daily with cetuximab.

The safety of encorafenib (300 mg orally once daily) in combination with cetuximab (dosed as per its PI) was evaluated in 216 patients with BRAF V600E-mutant metastatic colorectal cancer who received this regimen in the phase III study ARRAY-818-302 "BEACON CRC" (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The most common ADRs (> 25%) reported in this population were: fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletal pain, decreased appetite, rash and vomiting.

Tabulated summary of adverse reactions.

Melanoma studies.

Adverse reactions that occurred in patients with melanoma in the Combo 450 population (n=274) and in the pooled encorafenib 300 mg population (n=217) are listed in Table 4, by MedDRA body system organ class (SOC).

Colorectal cancer studies.

Adverse reactions in patients who received encorafenib 300 mg in combination with cetuximab in the BEACON CRC study (n=216) are listed in Table 5, by MedDRA body system organ class (SOC).
The rate of all study drug discontinuation due to any adverse reaction was 1.9% in patients treated with encorafenib 300 mg in combination with cetuximab.

Adverse events.

Adverse events in the COLUMBUS study (melanoma).

Table 6 summarises the most common treatment-emergent adverse events (AEs) (≥ 10% any grade or ≥ 2% grade 3 or 4) occurring in patients in Part I of the phase III randomised, active-controlled, open-label, multicentre trial (COLUMBUS) in patients with unresectable or metastatic BRAF V600 E or K mutant melanoma. The COLUMBUS study excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion.
In Part 1 of the COLUMBUS study, serious adverse events (SAEs) regardless of relationship to study therapy were reported in 35.9% of patients with melanoma treated with encorafenib 450 mg in combination with binimetinib (Combo 450), 34.9% of patients treated with encorafenib single agent 300 mg (Enco 300) and in 38.2% of patients treated with vemurafenib.
Permanent discontinuations due to AEs were reported in 14.6% of patients treated in the Combo 450 arm, 15.1% of patients treated in the Enco 300 arm and 16.1% of patients treated in the vemurafenib arm.

Adverse events in the BEACON CRC study (colorectal cancer).

Table 7 summarises the most common (incidence of at least 10%) treatment-emergent adverse events (AEs) occurring in patients in the BEACON CRC study. The BEACON CRC study excluded patients with a history of Gilbert's syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 ms), uncontrolled hypertension, and history or current evidence of retinal vein occlusion.
Serious adverse events (SAEs) regardless of relationship to study therapy were reported in 40% of patients who received encorafenib 300 mg in combination with cetuximab. Adverse events leading to dose interruptions of Braftovi occurred in 39% of patients receiving Braftovi in combination with cetuximab; the most common were vomiting (6%), diarrhoea (4%) nausea (4%), pyrexia (3%), and fatigue (2%), Adverse events leading to dose reductions of Braftovi occurred in 10% of patients receiving Braftovi in combination with cetuximab; the most common were fatigue (1.4%), musculoskeletal pain (1.4%), and peripheral neuropathy (1.4%). Permanent discontinuations due to AEs were reported in 11% of patients who received encorafenib 300 mg in combination with cetuximab. None of the adverse events leading to permanent discontinuation of Braftovi occurred in more than 2 patients (0.9%).

Description of selected adverse reactions.

Cutaneous malignancies. Cutaneous squamous cell carcinoma.

Melanoma studies.

In the pooled Combo 450 population, cuSCC including keratoacanthomas was observed in 3.3% (9/274) of patients. The median time to onset of the first event of cuSCC (all grades) was 6.5 months (range 1 to 22.8 months).
In the pooled encorafenib 300 mg population, cuSCC was reported in 7.4% (16/217) patients. For patients in the COLUMBUS study who developed cuSCC, the median time to onset of the first event of cuSCC (all grades) was 2.3 months (range 0.3 to 12.0 months).

Colorectal cancer studies.

In patients treated with encorafenib 300 mg in combination with cetuximab, cuSCC including keratoacanthoma was observed in 1.4% (3/216) of patients. The times to first event of cuSCC (all grades) were 0.5, 0.6 and 3.6 months for these 3 patients.
New primary melanoma.

Melanoma studies.

In the pooled encorafenib 300 population, new primary melanoma events occurred in 4.1% of patients (9 /217) and were reported as Grade 1 in 1.4% (3/217) of patients, Grade 2 in 2.1% (4/217) of patients, Grade 3 in 0.5% (1/217) of patients and Grade 4 in 0.5% (1/217) of patients.

Colorectal cancer studies.

In patients treated with encorafenib 300 mg in combination with cetuximab, new primary melanoma events occurred in 1.9% of patients (4/216) and were reported as Grade 2 in 0.9% (2/216) of patients and Grade 3 in 0.9% (2/216) of patients.
Ocular events.

Melanoma studies.

In the pooled Combo 450 population, RPED was reported in 29.6% (81/274) of patients. RPED was Grade 1 (asymptomatic) in 21.2% (58/274) of patients, Grade 2 in 5.8% (16/274) and Grade 3 in 1.8% (5/274). Most of these events were reported as retinopathy (9.5%, 26/274), retinal detachment (6.6%, 18/274), subretinal fluid (6.2%, 17/274), macular oedema (5.1%, 14/274) and chorioretinopathy (3.3%, 9/274); and led to dose interruptions or dose modifications in 4.7% (13/274) of patients. RPED was generally reversible. The median time to onset of the first event of RPED (all grades) was 1.5 months (0.03 to 17.5 months).
Uveitis was reported in 4.4% (12/274) of patients and was Grade 1 in 0.4% (1/274), Grade 2 in 3.6% (10/274) and Grade 3 in 0.4% (1/274). Visual impairment, including blurred vision and reduced visual acuity, occurred in 21.5% (59/274) of patients. Uveitis and visual impairment were generally reversible.
Left ventricular dysfunction.

Melanoma studies.

LVD was reported when encorafenib is used in combination with binimetinib in patients with melanoma (see Section 4.8 Adverse Effects (Undesirable Effects) of binimetinib PI).
Haemorrhage.

Melanoma studies.

Haemorrhagic events have been observed in 17.9% (49/274) of patients in the pooled Combo 450 population. Most of these events were Grade 1 or 2 (14.6%) and 3.3% were Grade 3 or 4 events. Few patients required dose interruptions or dose reductions (0.7% or 2/274).
Haemorrhagic events led to discontinuation of treatment in 1.1% (3/274) of patients. The most frequent haemorrhagic events were haematuria in 3.3% (9/274) of patients, rectal haemorrhage in 2.9% (8/274) and haematochezia in 2.9% (8/274) of patients. Fatal gastric ulcer haemorrhage, with multiple organ failure as a concurrent cause of death, occurred in one patient. Cerebral haemorrhage occurred in 1.5% (4/274) of patients; with fatal outcome in 3 patients. All events occurred in the setting of new or progressive brain metastases.
In the Combo 300 population of the COLUMBUS study, haemorrhagic events were observed in 6.6% (17/257) of patients and were Grade 3 or 4 in 1.6% (4/257) of patients.

Colorectal cancer studies.

Haemorrhagic events were observed in 21.3% (46/216) of patients treated with encorafenib 300 mg in combination with cetuximab; 1.4% (3/216) of patients were Grade 3 events and one fatal case was reported. Dose interruptions or dose reductions were required in 1.9% (4/216) of patients. Haemorrhagic events led to treatment discontinuation in 1 patient (0.5%).
The most frequent haemorrhagic events were epistaxis in 6.9% (15/216) of patients, haematochezia in 2.8% (6/216), rectal haemorrhage in 2.8% (6/216) of patients and haematuria in 2.8% (6/216) of patients.
Hypertension.

Melanoma studies.

Hypertension was reported when encorafenib was used in combination with binimetinib in melanoma patients (see Section 4.8 Adverse Effects (Undesirable Effects) of binimetinib PI).
Venous thromboembolism.

Melanoma studies.

VTE was reported when encorafenib was used in combination with binimetinib in melanoma patients (see Section 4.8 Adverse Effects (Undesirable Effects) of binimetinib PI).
Pancreatitis.

Melanoma studies.

In the pooled Combo 450 population, pancreatic enzyme elevation, mostly asymptomatic, was reported. Amylase and lipase elevations have been reported in 3.3% (9/274) and 51% (14/274) of patients, respectively. Pancreatitis adverse reactions were reported in 0.7% (2/274) of patients. Both patients experienced Grade 3 events. Pancreatitis led to dose interruption in 0.4% (1/274) of patients.

Colorectal cancer studies.

In the population treated with encorafenib 300 mg in combination with cetuximab, pancreatitis grade 3 with lipase and amylase increased events were reported in 1 patient (0.5%). Pancreatitis recurred on re-challenge twice, despite dose reductions each time, and led to permanent discontinuation.
Dermatological reactions. Rash.

Melanoma studies.

In the pooled Combo 450 population, rash occurred in 19.7% (54/274) of patients. Most of the events were mild, with Grade 3 or 4 events reported in 0.7% (2/274) of patients. Rash led to discontinuation in 0.4% (1/274) patients and to dose interruption or dose modification in 1.1% (3/274) of patients.
In the pooled encorafenib 300 mg population, rash was reported in 43.3% (94/217) of patients. Most of the events were mild, with Grade 3 or 4 events reported in 4.6% (10/217) of patients who received encorafenib as a single agent. Rash led to discontinuation in 0.5% (1/217) of patients and to dose interruption or dose modification in 7.4% (16/217) of patients.

Colorectal cancer studies.

In patients treated with encorafenib 300 mg in combination with cetuximab, rash occurred in 30.6% (66/216) of patients. Most events were mild, with Grade 3 event reported in 0.5% (1/216) of patients. Rash led to dose interruption in 0.5% (1/216) of patients.
Palmar-plantar erythrodysaesthesia syndrome.

Melanoma studies.

PPES was reported in 6.2% (17/274) of patients in the pooled Combo 450 population. All the PPES adverse reactions were either Grade 1 (3.3%) or Grade 2 (2.9%). Dose interruption or dose modification occurred in 1.1% (3/274) of patients.
In the pooled encorafenib 300 mg population, PPES was reported in 51.6% (112/217) of patients. Most of the events were mild to moderate: Grade 1 in 12.4% (27/217) of patients; Grade 2 in 26.7% (58/217) and Grade 3 in 12.4% (27/217) of patients. PPES led to discontinuation in 4.1% (9/217) of patients and to dose interruption or dose modification in 23.0% (50/217) of patients.

Colorectal cancer studies.

In the population treated with encorafenib 300 mg in combination with cetuximab, PPES was reported in 5.1% (11/216) of patients. Most of PPES adverse reactions were either Grade 1 in 3.7% (8/216). Grade 2 events were reported in 0.9% (2/216) of patients, and Grade 3 in 0.5% (1/216) of patients. No dose interruption, dose modification or treatment discontinuation was required.
Dermatitis acneiform.

Melanoma studies.

Dermatitis acneiform was reported when encorafenib was used in combination with binimetinib (see Section 4.8 Adverse Effects (Undesirable Effects) of binimetinib PI).

Colorectal cancer studies.

In patients treated with encorafenib 300 mg in combination with cetuximab, dermatitis acneiform occurred in 33.3% (72/216) of patients and was mostly Grade 1 (25.5% (55 /216) of patients), or 2 (6.9% (15 /216) of patients). Dose reduction or interruption was reported in 2.3% (5/216) of patients. No treatment discontinuation was reported. Dermatitis acneiform was generally reversible.
Photosensitivity.

Melanoma studies.

In the pooled Combo 450 population, photosensitivity was observed in 4.0% (11/274) of patients. Most events were Grade 1 or 2, with Grade 3 reported in 0.4% (1/274) of patients and no event led to discontinuation. Dose interruption or dose modification was reported in 0.4% (1/274) of patients.
In the pooled encorafenib 300 population, photosensitivity was reported in 4.1% (9/217) of patients. All events were Grade 1-2. No event required discontinuation, dose modification or interruption.
Facial paresis.

Melanoma studies.

In the pooled Combo 450 population, facial paresis occurred in 0.7% (2/274) of patients including Grade 3 in 0.4% (1/274) of patients. The events were reversible, and no event led to treatment discontinuation. Dose interruption or modification was reported in 0.4% (1/274) of patients.
In the pooled encorafenib 300 population, facial paresis was observed in 7.4% (16/217) of patients. Most events were mild to moderate: Grade 1 in 2.3% (5/217); Grade 2 in 3.7% (8/217) and Grade 3 in 1.4% (3/217) of patients. The median time to onset of the first event of facial paresis was 0.3 months (range 0.1 to 12.1 months). Facial paresis was generally reversible and led to treatment discontinuation in 0.9% (2/217). Dose interruption or modification was reported in 3.7% (8/217) and symptomatic treatment including corticosteroids was reported in 5.1% (11/217) of patients.
CK elevation/ rhabdomyolysis.

Melanoma studies.

CK elevation and rhabdomyolysis occurred when encorafenib was used in combination with binimetinib in melanoma patients (see Section 4.8 Adverse Effects (Undesirable Effects) of binimetinib PI).
Renal dysfunction.

Melanoma studies.

In the pooled Combo 450 population, mild mostly Grade 1 asymptomatic blood serum creatinine elevation was reported in 6.2% (17/274) of patients. The incidence of Grade 3 or 4 elevation was 0.7% (2/274). Renal failure events including acute kidney injury and renal impairment were reported in 3.3% (9/274) of patients with Grade 3 or 4 events in 2.2% (6/274) of patients. Renal failure was generally reversible with dose interruption, rehydration and other general supportive measures.

Colorectal cancer studies.

Blood creatinine elevation was reported in 2.8% (6/216) of patients treated with encorafenib 300 mg in combination with cetuximab. All were mild except one event of Grade 4. Renal failure events were Grade 3 or 4 and reported as acute kidney injury in 1.9% (4/216) of patients and renal failure in 0.5% (1/216) of patients.
Liver laboratory abnormalities.

Melanoma studies.

The incidences of liver laboratory abnormalities reported in the pooled Combo 450 population are listed below:
Increased transaminases: 15.7% (43/274) overall - Grade 3-4: 5.5% (15/274).
Increased GGT: 14.6% (40/274) overall - Grade 3-4: 8.4% (23/274).
In the Combo 300 arm of the COLUMBUS study, the incidence of liver laboratory abnormalities was:
Increased transaminases: 13.2% (34/257) overall - Grade 3-4: 5.4% (14/257).
Increased GGT: 14.0% (36/257) overall - Grade 3-4: 4.7% (12/257).

Colorectal cancer studies.

The incidence of increased transaminases in patients treated with encorafenib 300 mg in combination with cetuximab was 8.8% (19/216) of patients, with Grade 3 in 1.4% (3/216) of patients.
Gastrointestinal disorders.

Melanoma studies.

In the pooled Combo 450 population, diarrhoea was observed in 38% (104/274) of patients and was Grade 3 or 4 in 3.3% (9/274) of patients. Diarrhoea led to dose discontinuation in 0.4% of patients and to dose interruption or dose modification in 4.4% of patients.
Constipation occurred in 24.1% (66/274) of patients and was Grade 1 or 2. Abdominal pain was reported in 27.4% (75/274) of patients and was Grade 3 in 2.6% (7/274) patients. Nausea occurred in 41.6% (114/274) with Grade 3 or 4 observed in 2.6% (7/274) of patients. Vomiting occurred in 28.1% (77/274) of patients with Grade 3 or 4 reported in 2.2% (6/274) of patients.

Colorectal cancer studies.

In patients treated with encorafenib 300 mg in combination with cetuximab, diarrhoea was observed in 38.4% (83/216) of patients and was Grade 3 in 2.8% (6/216) of patients. Diarrhoea led to treatment discontinuation in 0.5% (1/216) of patients and to dose interruption or dose modification in 3.7% (8/216) of patients.
Abdominal pain was reported in 36.6% (79/216) of patients and was Grade 3 in 5.1% (11/216) of patients. Nausea occurred in 38.0% (82/216) of patients with Grade 3 observed in 0.5% (1/216) of patients. Vomiting occurred in 27.3% (59/216) of patients with Grade 3 reported in 1.4% (3/216) of patients. Constipation occurred in 18.1% (39/216) of patients and was Grade 1 or 2.
Anaemia.

Melanoma studies.

In the pooled Combo 450 population, anaemia was reported in 19.7% (54/274) of patients; 4.7% (13/274) patients had a Grade 3 or 4. No patients discontinued treatment due to anaemia, 1.5% (4/274) required dose interruption or dose modification. In the Combo 300 population of the COLUMBUS study, anaemia was observed in 9.7% (25/257) of patients with Grade 3 or 4 reported in 2.7% (7/257) of patients.
Headache.

Melanoma studies.

In the pooled Combo 450 population, headache occurred in 21.5% (59/274) of patients, including Grade 3 in 1.5% (4/274) of patients. In the Combo 300 population of the COLUMBUS study, headache was reported in 12.1% (31/257) of patients and was Grade 3 in 0.4% (1/257) of patients.

Colorectal cancer studies.

In patients treated with encorafenib 300 mg in combination with cetuximab, headache occurred in 20.4% (44/216) of patients and was Grade 1 or 2.
Fatigue.

Melanoma studies.

In the pooled Combo 450 population, fatigue occurred in 43.8% (120/274) of patients including Grade 3 in 2.9% (8/274) of patients. In the Combo 300 population of the COLUMBUS study, fatigue was observed in 33.5% (86/257) of patients with 1.6% (4/257) Grade 3 or 4 events.

Colorectal cancer studies.

In patients treated with encorafenib 300 mg in combination with cetuximab, fatigue was reported in 56.9% (123/216) of patients including Grade 3 in 7.9% (17/216) of patients.

Special populations.

Elderly patients. The number of patients aged 75 years or older enrolled in clinical studies was not sufficient to enable meaningful assessment of differential safety in this population compared to younger patients, in any tumour type.

Melanoma studies.

In patients treated with Combo 450 (n=274), 194 patients (70.8%) were < 65 years, 65 patients (23.7%) were 65 to 74 years and 15 patients (5.5%) were aged > 75. No overall differences in safety or efficacy were observed between elderly patients (≥ 65) and younger patients. The proportions of patients experiencing AEs and SAEs were similar in patients aged < 65 years and those aged ≥ 65 years. The most common AEs reported with a higher incidence in patients aged ≥ 65 years compared to patients aged < 65 years included diarrhoea, pruritus, GGT and blood phosphatase alkaline elevation.

Colorectal cancer studies.

In patients treated with encorafenib 300 mg in combination with cetuximab (n=216), 134 patients (62%) were < 65 years old, 62 patients (28.7%) were 65-74 years old and 20 patients (9.3%) were aged ≥ 75. The most common AEs reported with a higher incidence in patients aged ≥ 65 years compared to patients aged < 65 years included, anaemia, asthenia, decreased appetite and dyspnoea.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

At doses of encorafenib between 600 to 800 mg once daily, renal dysfunction (grade 3 hypercreatinemia) was observed in 3 out of 14 patients. The highest administered dose occurred as a dosing error in one patient who took encorafenib at a dose of 600 mg twice daily for 1 day (total dose 1200 mg). AEs reported by this patient were Grade 1 events of nausea, vomiting and blurred vision; all were subsequently resolved.

Management of overdose.

There is no specific treatment for overdose with encorafenib. If overdose occurs, encorafenib treatment should be interrupted and renal function must be monitored as well as adverse reactions. Symptomatic treatment and supportive care should be provided as needed. Since encorafenib is moderately bound to plasma proteins, haemodialysis is likely to be ineffective in the treatment of overdose with encorafenib.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Pharmacotherapeutic group: antineoplastic agent, protein kinase inhibitor. ATC code: L01EC03.
Encorafenib is an ATP-competitive small molecule RAF kinase inhibitor. The IC50 of encorafenib against BRAF V600E, BRAF and CRAF enzymes was determined to be 0.35, 0.47 and 0.30 nanoM, respectively. The encorafenib dissociation half-life was > 30 hours and resulted in prolonged pERK inhibition. Encorafenib suppresses the RAF/MEK/ERK pathway in tumour cells expressing several mutated forms of BRAF kinase (V600E, V600D and V600K). However, it does not inhibit RAF/MEK/ERK signalling in cells expressing wild-type BRAF. Encorafenib also binds to other kinases in vitro including STK36, JNK1/2/3, LIMK1/2 and MEK4/5, at clinically achievable concentrations. Specifically, encorafenib inhibits in vitro and in vivo BRAF V600E, V600D and V600K mutation positive melanoma cell growth and BRAF V600E mutant colorectal cancer cell growth. In vivo, encorafenib has been evaluated for its ability to inhibit pERK and pMEK, and tumour growth in xenograft models in nude mice. Overall, encorafenib has demonstrated potent activity against RAF enzymes and possesses anti-proliferative activity in vitro and in vivo in BRAF mutant tumour xenograft models.

Combination with binimetinib.

In non-clinical studies, the combination of encorafenib and binimetinib demonstrated additive or synergistic anti-proliferative activity in vitro in numerous BRAF-mutant cell lines. In vivo, treatment with the combination resulted in greater anti-tumour activity with respect to tumour growth inhibition and better tumour responses (PR and SD) in BRAF V600E mutant human melanoma xenograft studies in mice than that which was achieved with either agent alone. Additionally, the combination of encorafenib and binimetinib prevented the emergence of treatment resistance in BRAF V600E mutant human melanoma xenografts in mice.

Combination with cetuximab.

One of the main mechanisms of resistance of BRAF-mutant mCRC to RAF inhibitors has been identified as the re-activation of EGFR with bypassing signal transduction via BRAF. Combinations of a BRAF inhibitor (e.g. encorafenib) with agents targeting EGFR (e.g. cetuximab) have been shown to improve anti-tumour efficacy in non-clinical models.

Cardiac electrophysiology.

Melanoma studies.

In a pooled safety analysis across melanoma studies, the incidence of new QTcF prolongation > 500 ms was 0.7% (2/268) in the Combo 450 population, and 2.5% (5/203) in the pooled encorafenib 300 mg population. QTcF prolongation of > 60 ms compared to pre-treatment values was observed in 4.9% (13/268) patients in the Combo 450 population, and in 3.4% (7/204) in the pooled encorafenib 300 mg population (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Special Precautions for Use).

Colorectal cancer studies.

In the encorafenib plus cetuximab arm of BEACON CRC, the incidence of new QTcF prolongation > 500 ms was 3.2% (7/216), and QTcF prolongation of > 60 ms (compared to pre-treatment values) was observed in 8.8% (19/216) of patients (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Clinical trials.

COLUMBUS - BRAF V600 mutant unresectable or metastatic melanoma. The safety and efficacy of encorafenib in combination with binimetinib were evaluated in the COLUMBUS study: a Phase III, randomised (1:1:1) active-controlled, open-label, multicentre trial in patients with unresectable or metastatic BRAF V600 E or K mutant melanoma (also known as CMEK162B2301). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the bioMerieux THxID BRAF assay. Patients were permitted to receive prior adjuvant therapy and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior treatment with BRAF/ MEK inhibitors was not allowed.
In Part 1 of the study, patients were randomised to receive encorafenib 450 mg orally once daily and binimetinib 45 mg orally twice daily (Combo 450, N=192), encorafenib 300 mg orally once daily (Enco 300, N=194), or vemurafenib 960 mg orally twice daily (Vem, N=191). In Part 2, patients were randomised to receive encorafenib 300 mg orally once daily and binimetinib 45 mg orally twice daily (Combo 300, N=258) or encorafenib 300 mg orally once daily (n=86). Safety data from Part 2 are reflected in Section 4.8 Adverse Effects (Undesirable Effects). Treatment continued until disease progression or unacceptable toxicity. Randomisation was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1) and prior immunotherapy for unresectable or metastatic disease (yes versus no).
The primary efficacy outcome measure was progression-free survival (PFS) of Combo 450 compared with vemurafenib as assessed by a blinded independent review committee (BIRC). PFS as assessed by investigators (investigator assessment) was a supportive analysis. The key secondary endpoint included PFS of Combo 450 compared with Enco 300. Other secondary efficacy comparisons between Combo 450 and either vemurafenib or Enco 300 included overall survival (OS), objective response rate (ORR), duration of response (DoR) and disease control rate (DCR) as assessed by BIRC and by investigator assessment.
The median age for patients was 56 years (range 20 to 89), 58% were male, 90% were Caucasian, and 72% of patients had baseline ECOG performance status of 0.
Most patients had metastatic disease (95%) and were Stage IVM1c (64%); 27% of patients had elevated baseline serum LDH, and 45% of patients had ≥ 3 organs with tumour involvement at baseline and 3.5% had brain metastases.
A total of 27 patients (5%) had received prior checkpoint inhibitors (anti-PD1/PDL1 or ipilimumab) (8 patients in Combo 450 arm, 4%; 7 patients in vemurafenib arm, 4%; 12 patients in Enco 300 arm (6%) including 22 patients in the metastatic setting (6 patients in Combo 450 arm; 5 patients in vemurafenib arm; 11 patients in Enco 300 arm) and 5 patients in the adjuvant setting (2 patients in Combo 450 arm; 2 patients in vemurafenib arm; 1 patient in Enco 300 arm). Most patients were BRAF V600E mutant (88.6%), while the remainder were V600K mutant (10.9%).
The median duration of exposure was 11.7 months in patients treated with Combo 450, 7.1 months in patients treated with Enco 300 and 6.2 months in patients treated with vemurafenib. The median relative dose intensity (RDI) for Combo 450 was 99.6% for binimetinib and 100% for encorafenib; the median RDI was 86.2% for Enco 300 and 94.5% for vemurafenib.
The COLUMBUS study demonstrated a statistically significant improvement in PFS in patients treated with Combo 450 compared with patients treated with vemurafenib. Patients treated with Combo 450 also had improved ORR, DCR, and DoR compared with patients treated with vemurafenib. Table 8 and Figure 1 summarise the PFS and other efficacy results based on central review of the data by the BIRC.
The efficacy results based on investigator assessment were consistent with the independent central assessment. The PFS analysis per investigator assessment showed an improvement of PFS in patients treated with Combo 450 compared with patients treated with vemurafenib (14.8 vs 7.3 months, respectively), HR 0.49 (95% CI 0.37, 0.64) (p < 0.001 one sided).
The ORR analysis per investigator assessment showed an improvement of ORR in patients treated with Combo 450 compared with patients treated with vemurafenib: (75% (95% CI 68.3, 81.0) vs 49.2% (95% CI 41.9 56.5), respectively (p < 0.001 one sided). In the Combo 450 arm, CR was 16.1%, PR 58.9% and SD 18.2%.
At a cut-off date of 7 November 2017, an update of the PFS analyses was performed. The PFS analysis per independent central review showed an improvement of PFS in patients treated with Combo 450 compared with patients treated with vemurafenib (14.9 vs 7.3 months, respectively), HR 0.51 (95% CI: 0.39, 0.67) (p < 0.001 one sided) and also compared with patients treated with encorafenib (14.9 vs 9.6 months, respectively), HR 0.77 (95% CI: 0.59, 1.0) (p = 0.0249 one sided). The analysis per central review showed that encorafenib improved PFS vs. vemurafenib (9.6 vs 7.3 months, respectively), HR 0.68 (95% CI: 0.52, 0.88) (p = 0.0019 one sided). The PFS results per investigator review showed consistent results.
An interim OS analysis of Part 1 of the COLUMBUS study, performed at the cut-off date of 7 November 2017 demonstrated a statistically significant improvement in OS for Combo 450 compared with vemurafenib (HR 0.61, 95% CI 0.47, 0.79). See Table 9 and Figure 2.
A similar proportion of patients in each treatment arm received subsequent treatment with checkpoint inhibitors, mainly pembrolizumab, nivolumab and ipilimumab (34.4% Combo 450 arm, 36.1% Enco 300 arm, 39.8% vemurafenib arm).

Subgroup analyses of PFS.

All subgroup analyses of PFS per BIRC including gender, age (< 65/ ≥ 65), region (North America, Europe, Australia, other), number of organs involved at baseline (1, 2, 3, > 3), LDH at baseline (< ULN/ ≥ ULN), ECOG performance status (0/1), AJCC Stage (IIIB, IIIC, IVM1a, IVM1b/IVM1c), and prior adjuvant therapy (Yes/No) demonstrated point estimates in favour of the Combo 450 arm, except for the presence of brain metastases at baseline, a subgroup that only included 12 patients. Most of the HRs in the Combo 450 arm relative to the vemurafenib arm were within the range of the HR observed in the overall population.

Quality of life (QoL) (cut-off date: 19 May 2016).

The Functional Assessment of Cancer Therapy-Melanoma (FACT-M), the European Organisation for Research and Treatment of Cancer's core quality of life questionnaire (EORTC QLQ-C30) and the EuroQoL-5 Dimension-5 Level examination (EQ-5D-5L) were used to explore patient-reported outcomes (PRO) measures of health-related Quality of Life, functioning, melanoma symptoms, and treatment-related side effects. The data showed favourable outcomes for the Combo 450 arm over the vemurafenib arm. The median time to definitive 10% deterioration in the FACT-M score was not reached in the Combo 450 arm and was 22.1 months (95% CI 15.2, NE) in the vemurafenib arm with a HR for the difference of 0.46 (95% CI 0.29, 0.72). The median time to definitive 10% deterioration in the EORTC QLQ-C30 global health status score was delayed by more than 7 months in the Combo 450 arm compared to the vemurafenib arm: 23.9 months (95% CI 20.4, NE) vs. 16.6 months (95% CI 11.9, NE) with a HR for the difference of 0.55 (95% CI 0.37, 0.80). As these were exploratory endpoints, they must be interpreted with caution in the context of an open-label study design.
Patients receiving Combo 450 reported no change or a slight improvement in the mean change from baseline EQ-5D-5L index score at all visits, whilst patients receiving vemurafenib or encorafenib reported decreases at all visits (p-values < 0.001).
BEACON CRC - BRAF V600E mutant metastatic colorectal cancer (mCRC). Encorafenib in combination with cetuximab was evaluated in BEACON CRC: a randomised, active-controlled, open-label, multicentre trial (also known as ARRAY 818-302). Eligible patients were required to have metastatic colorectal cancer harbouring a BRAF V600E mutation (as detected using the Qiagen thera-screen BRAF V600E RGQ polymerase chain reaction (PCR) Kit) that had progressed after 1 or 2 prior regimens. Other key eligibility criteria included absence of prior treatment with a RAF, MEK, or EGFR inhibitor, eligibility to receive cetuximab per local labelling with respect to tumour RAS status, and ECOG performance status (PS) 0-1. Randomisation was stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), prior use of irinotecan (yes versus no), and cetuximab product used (US-licensed versus EU-approved).
A total of 665 patients were randomised (1:1:1) to one of the following treatment arms:
Encorafenib 300 mg orally once daily in combination with cetuximab (encorafenib plus cetuximab arm) [n=220].
Encorafenib 300 mg orally once daily in combination with binimetinib and cetuximab [n=224].
Irinotecan with cetuximab or irinotecan/5-fluorouracil/folinic acid (FOLFIRI) with cetuximab (control arm) [n=221].
Cetuximab was dosed as per its approved European label (SmPC). Patients in the control arm received cetuximab with either irinotecan 180 mg/m2 intravenously on Days 1 and 15 of each 28-day cycle or FOLFIRI intravenously (irinotecan 180 mg/m2 on Days 1 and 15; folinic acid 400 mg/m2 on Days 1 and 15; then fluorouracil 400 mg/m2 bolus on Days 1 and 15 followed by fluorouracil 2400 mg/m2/day by continuous infusion over 2 days). Treatment continued until disease progression or unacceptable toxicity.
The primary efficacy outcomes were overall survival (OS) and Overall Response Rate (ORR). Additional efficacy outcome measures included progression-free survival (PFS), and duration of response (DoR) as assessed by blinded independent central review (BICR). OS and PFS were assessed in all randomised patients. ORR and DoR were assessed in the first 330 patients randomised (plus any additional patients randomised on the same day as the 330th randomised patient).
A total of 220 patients were randomized to the Braftovi/cetuximab arm and 221 to the control arm.
The median age of patients randomised to the encorafenib plus cetuximab or the control arm was 61 years (range 27-91), 47% were male, 80% were white and 15% were Asian. Half had a baseline ECOG performance status of 0, 66% had received one prior line of systemic therapy and 34% had received two; 93% had previously received oxaliplatin and 52% had previously received irinotecan. Half of patients had at least 3 organs with tumour involvement at baseline.
The median duration of exposure was 3.2 months in the encorafenib plus cetuximab arm, and 1.4 months in the control arm. In the encorafenib plus cetuximab arm, the median relative dose intensity (RDI) was 98% for encorafenib and 94% for cetuximab. In the control arm, the median RDI was 85% for cetuximab, 76% for irinotecan and (in the subset of patients who received them) 75% for Folinic acid and 74% for 5-FU.
Encorafenib 300 mg in combination with cetuximab demonstrated a statistically significant improvement in OS, ORR and PFS compared to the control arm. Efficacy results are summarised in Table 10, Figure 3 and Figure 4.
The efficacy results based on investigator assessment were consistent with the independent central assessment.

5.2 Pharmacokinetic Properties

The pharmacokinetics of encorafenib were studied in adult healthy subjects and patients with solid tumours, including advanced and unresectable or metastatic cutaneous melanoma harbouring a BRAF-V600E or BRAF-V600K mutation, and in patients with metastatic colorectal cancer with a BRAF V600E mutation. The pharmacokinetics of encorafenib have been shown to be approximatively dose linear after single and multiples doses. After repeat once-daily dosing, steady-state conditions were reached within 15 days. The accumulation ratio of approximately 0.5 is likely due to auto-induction of CYP3A4. The intersubject variability (CV%) of AUC ranged from 12.3% to 68.9%.

Absorption.

After oral administration, encorafenib is rapidly absorbed with a median Tmax of 1.5 to 2 hours. Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, at least 86% of the encorafenib dose was absorbed. Administration of a single 100 mg dose of encorafenib with a high-fat, high-calorie meal decreased the maximum encorafenib concentration (Cmax) by 36%, while the area under the concentration-time curve (AUC) was unchanged. A drug interaction study in healthy subjects indicated the extent of encorafenib exposure was not altered in the presence of a gastric pH-altering agent (rabeprazole).

Distribution.

Encorafenib is moderately (86.1%) bound to human plasma proteins in vitro. Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, the mean (SD) blood-to-plasma concentration ratio is 0.58 (0.02) and the mean (CV%) apparent volume of distribution (Vz/F) of encorafenib is 226 L (32.7%).

Metabolism.

Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, metabolism was found to be the major clearance pathway for encorafenib (approximately 88% of the recovered radioactive dose). The predominant biotransformation reaction of encorafenib was N-dealkylation. Other major metabolic pathways involved hydroxylation, carbamate hydrolysis, indirect glucuronidation and glucose conjugate formation.

Excretion.

Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, radioactivity was eliminated equally in both the faeces and urine (mean of 47.2%). In urine, 1.8% of the radioactivity was excreted as encorafenib. The mean (CV%) apparent clearance (CL/F) of encorafenib was 27.9 L/h (9.15%). The median (range) encorafenib terminal half-life (T1/2) was 6.32 h (3.74 to 8.09 h).

Special populations.

Hepatic impairment.

Results from a dedicated clinical trial indicate a 25% higher encorafenib exposure in patients with mild hepatic impairment (Child-Pugh Class A) compared with subjects with normal liver function. This translates into a 55% increase of the unbound encorafenib exposure.
The pharmacokinetics of encorafenib has not been evaluated clinically in patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. As encorafenib is primarily metabolised and eliminated via the liver, based on PBPK modelling patients with moderate to severe hepatic impairment may have greater increases in exposure than patients with mild hepatic impairment. No dosing recommendation can be made in patients with moderate or severe hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Special Precautions for Use).

Renal impairment.

Encorafenib undergoes minimal renal elimination. No formal clinical study has been conducted to evaluate the effect of renal impairment on the pharmacokinetics of encorafenib.
In a population PK analysis, no clear trend in encorafenib CL/F was observed in patients with mild (eGFR 60 to 90 mL/min/1.73 m2) or moderate (eGFR 30 to 59 mL/min/1.73 m2) renal impairment compared with subjects with normal renal function (eGFR ≥ 90 mL/min/1.73 m2). A small decrease in CL/F (≤ 5%) was predicted for patients with mild and moderate renal impairment, which is unlikely to be clinically relevant. The pharmacokinetics of encorafenib have not been studied in patients with severe renal impairment.

Age.

Based on a population pharmacokinetic analysis, age was found to be a significant covariate on encorafenib volume of distribution, but with high variability. Given the small magnitude of these changes and high variability, these are unlikely to be clinically meaningful, and no dose adjustments are needed for elderly patients.

The elderly.

Based on results from a population PK analysis of encorafenib in combination with binimetinib, the pharmacokinetics of encorafenib are similar in elderly patients as compared to younger patients.

Children and adolescents (< 18 years).

The pharmacokinetics of encorafenib have not been established in patients below the age of 18 years.

Body weight.

Based on a population pharmacokinetic analysis, body weight was found to be a significant model covariate on clearance and volume of distribution. However, given the small magnitude of change in clearance and the high variability in the predicted volume of distribution in the model, weight is unlikely to have a clinically relevant influence on the exposition of encorafenib.

Gender.

Based on a population pharmacokinetic analysis, gender was not found to be a significant model covariate on clearance or volume of distribution. As a result, no major changes in encorafenib exposure are expected based upon gender.

Race.

There have been no clinically relevant differences in encorafenib PK observed specifically in the Asian population. There are insufficient data to evaluate potential differences in the exposure of encorafenib on the basis of race or ethnicity.

5.3 Preclinical Safety Data

Genotoxicity.

Based on the results of in vitro bacterial reverse mutation assays, an in vitro human peripheral blood lymphocyte chromosomal aberration assay and an in vivo rat bone marrow micronucleus test, encorafenib is not genotoxic.

Carcinogenicity.

The carcinogenic potential of encorafenib was not evaluated.

6 Pharmaceutical Particulars

6.1 List of Excipients

Braftovi capsules are capsules for oral administration. Each capsule contains 50 or 75 mg encorafenib. The capsules also contain the excipients: copovidone, poloxamer, microcrystalline cellulose, succinic acid, crospovidone, colloidal anhydrous silica and magnesium stearate; the capsule shell contains the excipients: gelatin, titanium dioxide, iron oxide red, iron oxide yellow and iron oxide black; and the printing ink contains the excipients: shellac, iron oxide black, propylene glycol.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.
Store in original container.

6.5 Nature and Contents of Container

Braftovi 50 mg capsules.

Polyamide/aluminium/PVC/ aluminium/PET/paper perforated unit dose blisters containing 4 capsules.
Each pack contains 28 capsules.

Braftovi 75 mg capsules.

Polyamide/aluminium/PVC/ aluminium/PET/paper perforated unit dose blister containing 6 capsules.
Each pack contains 42 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

Chemical Abstracts Service (CAS) registry number: 1269440-17-6.
Chemical name: Methyl N-[(1S)-2-[[4-[3-[5-chloro-2-fluoro-3-[(methylsulfonyl)amino]phenyl]-1-(1- methylethyl)-1H-pyrazol-4-yl]-2-pyrimidinyl]amino]-1-methylethyl]carbamate.
Encorafenib is a white to almost white powder with the molecular formula C22H27ClFN7O4S and a molecular weight of 540.0. It is slightly soluble in aqueous media at pH 1, very slightly soluble at pH 2 (0.01 to 0.1%), and insoluble at pH 3 and above. Its dissociation constants (pKa) are 4.49 and 7.21. Encorafenib is not hygroscopic.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes