4.1. Therapeutic indications

Melanoma

Encorafenib in combination with binimetinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

Colorectal cancer (CRC)

Encorafenib in combination with cetuximab is indicated for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation, who have received prior systemic therapy.

Non-small cell lung cancer (NSCLC)

Encorafenib in combination with binimetinib is indicated for the treatment of adult patients with advanced non-small cell lung cancer with a BRAF V600E mutation.

4.2. Posology and method of administration

Encorafenib treatment should be initiated and supervised under the responsibility of a physician experienced in the use of anticancer medicinal products.

BRAF mutation testing

Before taking encorafenib, patients must have confirmation of BRAF V600E mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose. If the CE-marked IVD is not available, an alternative validated test should be used.

The efficacy and safety of encorafenib have been established only in patients with melanoma tumours expressing BRAF V600E and V600K mutations, colorectal tumours expressing a BRAF V600E mutation or NSCLC expressing a BRAF V600E mutation. Encorafenib should not be used in patients with wild type BRAF malignant melanoma, wild type BRAF colorectal cancer or wild-type BRAF NSCLC.

Posology

Melanoma and NSCLC

The recommended dose of encorafenib is 450 mg (six 75 mg capsules) once daily, when used in combination with binimetinib.

Colorectal cancer

The recommended dose of encorafenib is 300 mg (four 75 mg capsules) once daily, when used in combination with cetuximab.

Dose modification

Melanoma and NSCLC

The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation of encorafenib (see Tables 1, 3 and 4).

For information on the posology and recommended dose modifications of binimetinib, see section 4.2 of binimetinib Summary of Product Characteristics (SmPC).

Dose reduction recommendations for encorafenib are presented in Table 1.

Table 1: Recommended dose modifications for encorafenib when used in combination with binimetinib in melanoma or NSCLC indications

Dose level

Encorafenib dose

when used in combination with binimetinib

Starting dose

Six 75 mg (450 mg) capsules once daily

1st dose reduction

Four 75 mg (300 mg) capsules once daily

2nd dose reduction

Three 75 mg (225 mg) capsules once daily

Subsequent modification

For melanoma indication:

There are limited data for dose reduction to 100 mg once daily.

Encorafenib should be permanently discontinued if patient is unable to tolerate 100 mg (two 50 mg capsules) once daily.

For NSCLC indication:

Encorafenib should be permanently discontinued if patient is unable to tolerate 225 mg (three 75 mg capsules) once daily.

Administration of encorafenib at a dose of 450 mg once daily as a single agent is not recommended. If binimetinib is temporarily interrupted, encorafenib should be reduced to 300 mg once daily during the time of binimetinib dose interruption (see section 4.2 of binimetinib SmPC) as encorafenib is not well‑tolerated at the dose of 450 mg as a single agent. If binimetinib is permanently discontinued, encorafenib should be discontinued.

If encorafenib is temporarily interrupted (see Tables 3 and 4), binimetinib should be interrupted. If encorafenib is permanently discontinued, then binimetinib should be discontinued.

If treatment-related toxicities occur, then encorafenib and binimetinib should be dose reduced, interrupted or discontinued. Dose modifications are necessary for binimetinib only (adverse reactions primarily related to binimetinib) for the following: retinal pigment epithelial detachment (RPED), retinal vein occlusion (RVO), interstitial lung disease/pneumonitis, cardiac dysfunction, creatine phosphokinase (CK) elevation and rhabdomyolysis, and venous thromboembolism (VTE).

If one of these toxicities occurs, see section 4.2 of binimetinib SmPC for dose modification instructions for binimetinib.

Colorectal cancer

The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation of encorafenib (see Tables 2, 3 and 4).

For information on the posology and recommended dose modifications of cetuximab, see section 4.2 of cetuximab SmPC.

Dose reduction recommendations for encorafenib are presented in Table 2.

Table 2: Recommended dose modifications for encorafenib when used in combination with cetuximab in CRC indication

Dose level

Encorafenib dose

when used in combination with cetuximab

Starting dose

Four 75 mg (300 mg) capsules once daily

1st dose reduction

Three 75 mg (225 mg) capsules once daily

2nd dose reduction

Two 75 mg (150 mg) capsules once daily

If encorafenib is permanently discontinued, cetuximab should be discontinued.

If cetuximab is permanently discontinued, encorafenib should be discontinued.

Melanoma, colorectal cancer and NSCLC

Dose modifications in case of adverse reactions are provided below and in Tables 3 and 4.

For new primary cutaneous malignancies: No dose modifications are required for encorafenib.

For new primary non-cutaneous RAS mutation-positive malignancies: it should be considered to discontinue encorafenib permanently.

Table 3: Recommended dose modifications for encorafenib when used in combination with binimetinib or in combination with cetuximab for selected adverse reactions

Severity of adverse reactiona

Encorafenib

Cutaneous reactions

• Grade 2

Encorafenib should be maintained.

If rash worsens or does not improve within 2 weeks with treatment, encorafenib should be withheld until Grade 0 or 1 and then resumed at the same dose.

• Grade 3

Encorafenib should be withheld until improved to Grade 0 or 1 and resumed at the same dose if first occurrence, or resumed at a reduced dose if recurrent Grade 3.

• Grade 4

Encorafenib should be permanently discontinued.

Palmar-plantar erythrodysaesthesia syndrome (PPES)

• Grade 2

Encorafenib should be maintained and supportive measures such as topical therapy should be instituted.

If not improved despite supportive therapy within 2 weeks, encorafenib should be withheld until improved to Grade 0 or 1 and treatment should be resumed at same dose level or at a reduced dose.

• Grade 3

Encorafenib should be withheld, supportive measures such as topical therapy should be instituted, and the patient should be reassessed weekly.

Encorafenib should be resumed at same dose level or at a reduced dose level when improved to Grade 0 or 1.

Uveitis including iritis and iridocyclitis

• Grade 1‑3

If Grade 1 or 2 uveitis does not respond to specific (e.g. topical) ocular therapy or for Grade 3 uveitis, encorafenib should be withheld and ophthalmic monitoring should be repeated within 2 weeks.

If uveitis is Grade 1 and it improves to Grade 0, then treatment should be resumed at the same dose.

If uveitis is Grade 2 or 3 and it improves to Grade 0 or 1, then treatment should be resumed at a reduced dose.

If not improved within 6 weeks, ophthalmic monitoring should be repeated and encorafenib should be permanently discontinued.

• Grade 4

Encorafenib should be permanently discontinued and a follow up with ophthalmologic monitoring should be performed.

QTc Prolongation

• QTcF > 500 ms and change ≤ 60 ms from pre-treatment value

Encorafenib should be withheld (see monitoring in section 4.4).

Encorafenib should be resumed at a reduced dose when QTcF ≤500 ms.

Encorafenib should be discontinued if more than one recurrence.

• QTcF>500 ms and increased by >60 ms from pre-treatment values

Encorafenib should be permanently discontinued (see monitoring in section 4.4).

Liver laboratory abnormalities

• Grade 2 (aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3x­ ≤5x upper limit of normal (ULN))

Encorafenib should be maintained.

If no improvement within 4 weeks, encorafenib should be withheld until improved to Grade 0 or 1 or to pre-treatment/baseline levels and then resumed at the same dose.

• First occurrence of Grade 3 (AST or ALT >5x ULN and blood bilirubin >2x ULN)

Encorafenib should be withheld for up to 4 weeks.

• If improved to Grade 0 or 1 or to baseline levels, it should be resumed at a reduced dose.

• If not improved, encorafenib should be permanently discontinued

• First occurrence of Grade 4 (AST or ALT >20 ULN)

Encorafenib should be withheld for up to 4 weeks

• If improved to Grade 0 or 1 or to baseline levels, then it should be resumed at a reduced dose level.

• If not improved, encorafenib should be permanently discontinued.

Or, encorafenib should be permanently discontinued.

• Recurrent Grade 3 (AST or ALT > 5x ULN and blood bilirubin > 2x ULN)

It should be considered to permanently discontinue encorafenib.

• Recurrent Grade 4 (AST or ALT > 20 ULN)

Encorafenib should be permanently discontinued.

a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03

Table 4: Recommended dose modifications for encorafenib when used in combination with binimetinib or in combination with cetuximab for other adverse reactions

Severity of adverse reaction

Encorafenib

• Recurrent or intolerable Grade 2 adverse reactions

• First occurrence of Grade 3 adverse reactions

Encorafenib should be withheld for up to 4 weeks.

• If improved to Grade 0 or 1 or to baseline levels,

It should be resumed at a reduced dose.

• If not improved, encorafenib should be permanently discontinued

• First occurrence of any Grade 4 adverse reaction

Encorafenib should be withheld for up to 4 weeks

• If improved to Grade 0 or 1 or to baseline levels, then it should be resumed at a reduced dose level.

• If not improved, encorafenib should be permanently discontinued.

Or, encorafenib should be permanently discontinued.

• Recurrent Grade 3 adverse reactions

Permanent discontinuation of encorafenib should be considered.

• Recurrent Grade 4 adverse reactions

Encorafenib should be permanently discontinued.

Duration of treatment

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

Missed doses

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

In case of vomiting after administration of encorafenib, the patient should not take an additional dose and should take the next scheduled dose.

Special populations

Elderly patients

No dose adjustment is required for patients aged 65 years and older (see section 5.2).

Hepatic impairment

Patients with mild to severe hepatic impairment may have increased encorafenib exposure (see section 5.2).

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 need for dose adjustment cannot be determined. Encorafenib should be used with caution in patients with severe renal impairment (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of encorafenib have not yet been established in children and adolescents. No data are available.

Method of administration

Braftovi is for oral use. The capsules are to be swallowed whole with water. They may be taken with or without food. The concomitant administration of encorafenib with grapefruit juice should be avoided (see sections 4.4 and 4.5).

For patients unable to swallow, Braftovi capsules may be opened and the content dispersed in a small quantity (approximately 20 mL) of apple sauce and taken immediately.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Encorafenib is to be given in combination with binimetinib (for patients with BRAF V600 mutant unresectable or metastatic melanoma, and for patients with BRAF V600E mutant advanced NSCLC), or in combination with cetuximab (for patients with BRAF V600E mutant metastatic colorectal cancer). For additional information on warnings and precautions associated with binimetinib or cetuximab treatment, see section 4.4 of binimetinib SmPC or cetuximab SmPC.

Encorafenib in combination with binimetinib in patients who have progressed on a BRAF inhibitor

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

Encorafenib in combination with binimetinib in patients with brain metastases

There are limited efficacy data with the combination of encorafenib and binimetinib in patients with a BRAF V600 mutant melanoma or BRAF V600E mutant NSCLC which have metastasised to the brain (see section 5.1).

Left ventricular dysfunction (LVD)

LVD defined as symptomatic or asymptomatic decreases in ejection fraction has been reported when encorafenib is used in combination with binimetinib. It is recommended that left ventricular ejection fraction (LVEF) is assessed by echocardiogram or multi-gated acquisition (MUGA) scan before initiation of encorafenib and binimetinib, one month after initiation, and then at approximately 3‑month intervals or more frequently as clinically indicated, while on treatment. If during treatment LVD occurs, see section 4.2 of binimetinib SmPC.

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 limits of normal. Therefore, in these patients, binimetinib should be used with caution and for any symptomatic left ventricular dysfunction, Grade 3‑4 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.

Haemorrhage

Haemorrhages, including major haemorrhagic events, can occur with encorafenib (see section 4.8). The risk of haemorrhage may be increased with concomitant use of anticoagulant and antiplatelet therapy. The occurrence of Grade ≥3 haemorrhagic events should be managed with dose interruption or treatment discontinuation (see Table 4 in section 4.2) and as clinically indicated.

Ocular toxicities

Ocular toxicities including uveitis, iritis, and iridocyclitis can occur when encorafenib is administered. RPED has also been reported in patients treated with encorafenib in combination with binimetinib (see section 4.8).

Patients should be assessed at each visit for symptoms of new or worsening visual disturbance. If symptoms of new or worsening visual disturbances including diminished central vision, blurred vision or loss of vision are identified, a prompt ophthalmologic examination is recommended.

If uveitis including iridocyclitis and iritis occurs during treatment, see section 4.2.

If during treatment patient develops RPED or RVO, see section 4.2 of binimetinib SmPC for guidance.

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.

Overall, results suggest that single agent encorafenib has the potential to cause mild increases in heart rate. Across pooled combination studies of encorafenib and binimetinib at the recommended doses and a single-agent encorafenib study, results suggest that encorafenib has the potential to result in small increases in QTc interval (see section 5.1).

There are insufficient data to exclude a clinically significant exposure dependent QT prolongation.

Due to the potential risk for QT prolongation, it is recommended that serum electrolytes abnormalities, including magnesium and potassium, are corrected and risk factors for QT prolongation controlled (e.g. congestive heart failure, bradyarrhythmias) before treatment initiation and during treatment.

It is recommended that an electrocardiogram (ECG) is assessed 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, interruption or discontinuation with correction of abnormal electrolytes and control of risk factors (see section 4.2).

New primary malignancies

New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur when encorafenib is administered (see section 4.8).

Cutaneous malignancies

Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma 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).

Dermatologic 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 with dermatological excision and dermatopathologic 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 malignanciesBased 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 complete blood cell counts prior to initiation, during and at the end of treatment as clinically appropriate. It should be considered to permanently discontinue 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.

Tumour lysis syndrome (TLS)

The occurrence of TLS, which may be fatal, has been associated with the use of encorafenib in association with binimetinib (see section 4.8). Risk factors for TLS include high tumour burden, pre-existing chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. These patients should be monitored closely and treated promptly as clinically indicated, and prophylactic hydration should be considered.

Liver laboratory abnormalities

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

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).

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).

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 sections 4.2 and 5.2).

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 Table 4 in section 4.2). Patients should ensure adequate fluid intake during treatment.

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).

Caution should be exercised if a moderate CYP3A inhibitor is co-administered with encorafenib.

4.5. Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on encorafenib

Encorafenib is primarily metabolised by CYP3A4.

CYP3A4 inhibitors

Co-administration of moderate (diltiazem) and strong (posaconazole) CYP3A4 inhibitors with single doses of encorafenib in healthy volunteers resulted in a 2 and 3-fold increase in the area under the concentration-time curve (AUC), respectively and in 44.6% and 68.3% increase in maximum encorafenib concentration (Cmax) respectively.

Model ­based predictions indicate that the effect of posaconazole after repeated administrations could be similar for AUC (3­-fold increase) and slightly greater for Cmax (2.7­-fold increase). Model-based predictions for ketoconazole suggest an increase of approx. 5-fold for encorafenib AUC and 3­ to 4-fold for encorafenib Cmax after administration of encorafenib 450 and 300 mg QD, respectively.

Therefore, concomitant administration of encorafenib with strong CYP3A4 inhibitors should be avoided (due to increased encorafenib exposure and potential increase in toxicity, see section 5.2). Examples of strong CYP3A4 inhibitors include, but are not limited to, ritonavir, itraconazole, clarithromycin, telithromycin, posaconazole and grapefruit juice. If concomitant use of a strong CYP3A inhibitor is unavoidable, patients should be carefully monitored for safety.

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. When encorafenib is co-administered with a moderate CYP3A inhibitor, patients should be carefully monitored for safety.

CYP3A4 inducers

Co-administration of encorafenib with a strong CYP3A4 inducer was not assessed in a clinical study; 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 potential should be considered.

Effects of encorafenib on other medicinal products

CYP substrates

Encorafenib is a strong inducer of CYP3A4. Concomitant use with agents that are substrates of CYP3A4 (e.g., hormonal contraceptives) may result in loss of efficacy of these agents. If the coadministration of narrow therapeutic index CYP3A4 substrates cannot be avoided, adjust the dose of these substrates in accordance with their approved SmPC.

Encorafenib is an inhibitor of UGT1A1. Concomitant agents that are substrates of UGT1A1 (e.g. raltegravir, atorvastatin, dolutegravir) may have increased exposure and should be therefore administered with caution.

Effect of encorafenib on binimetinib

While encorafenib is a relatively potent reversible inhibitor of UGT1A1, no differences in binimetinib exposure have been observed clinically when binimetinib was co-administered with encorafenib.

Transporter substrates

In vivo, encorafenib is an inhibitor of OATP1B1, OATP1B3 and/or BCRP. Coadministration of encorafenib with OATP1B1, OATP1B3 or BCRP substrates (such as rosuvastatin, atorvastatin, methotrexate) can result in increased concentrations (see section 5.2).

In vitro, encorafenib potentially inhibits a number of other transporters. Agents that are substrates of renal transporters OAT1, OAT3, OCT2 (such as furosemide, penicillin) or agents that are substrates of the hepatic transporters OCT1 (such as bosentan) or substrates of P-gp (e.g. posaconazole) may also have increased exposure. Therefore, these agents should be co‑administered with caution.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential / Contraception in females

Women of childbearing potential must use effective contraception during treatment with encorafenib and for at least 1 month following the last dose. Encorafenib may decrease the efficacy of hormonal contraceptives (see section 4.5). 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.

Pregnancy

There are no data from the use of encorafenib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).

Encorafenib is not recommended during pregnancy and in women of childbearing potential not using contraception. 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.

Breast-feeding

It is unknown whether encorafenib or its metabolites are excreted in human milk. A risk to the breastfed newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue encorafenib therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother.

Fertility

There are no data on the effects of encorafenib on fertility in humans. Based on findings in animals, the use of encorafenib may impact fertility in males of reproductive potential (see section 5.3). As the clinical relevance of this is unknown, male patients should be informed of the potential risk for impaired spermatogenesis.

4.7. Effects on ability to drive and use machines

Encorafenib has minor influence on the ability to drive or use machines. Visual disturbances have been reported in some patients treated with encorafenib during clinical studies. Patients should be advised not to drive or use machines if they experience visual disturbances or any other adverse reactions that may affect their ability to drive and use machines (see sections 4.4 and 4.8).

4.8. Undesirable effects

Summary of safety profile

The safety of encorafenib (450 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) has been evaluated in the integrated safety population (ISP) of 372 patients including patients with BRAF V600 mutant unresectable or metastatic melanoma and BRAF V600E mutant advanced NSCLC (hereafter referred to as the Combo 450 ISP). In Combo 450 ISP, 274 patients received the combination for the treatment of BRAF V600 mutant unresectable or metastatic melanoma (in two Phase II studies (CMEK162X2110 and CLGX818X2109) and one Phase III study (CMEK162B2301, Part 1)), and 98 patients received the combination for the treatment of BRAF V600E mutant advanced NSCLC (in one Phase II study (ARRAY-818-202)) (see section 5.1).

The most common adverse reactions (≥25%) occurring in patients treated with encorafenib administered with binimetinib were fatigue, nausea, diarrhoea, vomiting, abdominal pain, myopathy/muscular disorders, and arthralgia.

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), based on the Phase III study (CMEK162B2301, Part 2). The most common adverse reactions (≥25%) occurring in patients treated with encorafenib 300 mg administered with binimetinib were fatigue, nausea and diarrhoea.

The encorafenib single agent (300 mg orally once daily) safety profile is based on data from 217 patients with unresectable or metastatic BRAF V600-mutant melanoma (hereafter referred to as the pooled encorafenib 300 population). The most common adverse drug reactions (ADRs) (≥25%) reported with encorafenib 300 were hyperkeratosis, alopecia, PPES, fatigue, rash, arthralgia, dry skin, nausea, myalgia, headache, vomiting and pruritus.

The safety of encorafenib (300 mg orally once daily) in combination with cetuximab (dosed as per its SmPC) was evaluated in 216 patients with BRAF V600E-mutant metastatic colorectal cancer, based on the phase III study ARRAY-818-302. 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.

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.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA body system organ class and the following frequency convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 5: Adverse reactions

Frequency

Encorafenib single agent 300 mg (n = 217)

Encorafenib 450 mg in combination with binimetinib (n = 372)

Encorafenib 300 mg in combination with cetuximab (n = 216)

Neoplasms benign, malignant and unspecified

Very common

Skin papilloma*

Melanocytic naevus

Melanocytic naevus

Common

cuSCC a

New Primary Melanoma*

cuSCCa

Skin papilloma*

cuSCCa

Skin papilloma*

New Primary Melanoma*

Uncommon

Basal cell carcinoma

Basal cell carcinoma*

Basal cell carcinoma*

Blood and lymphatic system disorders

Very common

Anaemia

Immune system disorders

Common

Hypersensitivityb

Hypersensitivityb

Hypersensitivityb

Metabolism and nutrition disorders

Very common

Decreased appetite

Decreased appetite

Not known

Tumour lysis syndrome

Psychiatric disorders

Very common

Insomnia

Insomnia

Nervous system disorders

Very common

Headache*

Neuropathy peripheral*

Dysgeusia*

Neuropathy peripheral*

Dizziness*

Headache*

Neuropathy peripheral*

Headache*

Common

Facial paresisc

Dysgeusia*

Dizziness*

Dysgeusia

Uncommon

Facial paresisc

Eye disorders

Very common

Visual impairment*

RPED *

Common

Uveitis *

Uncommon

Uveitis*

Cardiac disorders

Common

Supraventricular tachycardiad

LVDh

Supraventricular tachycardiad

Vascular disorders

Very common

Haemorrhagei

Hypertension *

Haemorrhagei

Common

VTEj

Gastrointestinal disorders

Very common

Nausea

Vomiting*

Constipation

Nausea

Vomiting*

Constipation

Abdominal pain*

Diarrhoea*

Nausea

Vomiting*

Constipation

Abdominal pain*

Diarrhoea*

Common

Colitis k

Uncommon

Pancreatitis*

Pancreatitis*

Pancreatitis*

Skin and subcutaneous tissue disorders

Very common

PPES

Hyperkeratosis*

Rash*

Dry skin*

Pruritus*

Alopecia*

Erythema e

Skin hyperpigmentation*

Hyperkeratosis*

Rash*

Dry skin*

Pruritus*

Alopecia*

Dermatitis acneiform*

Rash*

Dry skin*

Pruritus*

Common

Dermatitis acneiform*

Skin exfoliationf

Photosensitivity*

Dermatitis acneiform*

PPES

Erythema*

Panniculitis*

Photosensitivity*

Skin hyperpigmentation

PPES

Hyperkeratosis*

Alopecia

Erythemae

Uncommon

Skin exfoliationf

Musculoskeletal and connective tissue disorders

Very common

Arthralgia*

Myalgiag

Pain in extremity

Back pain

Arthralgia*

Myopathy/Muscular disorderl

Pain in extremity

Back pain*

Arthralgia/Musculoskeletal pain*

Myopathy/Muscular disorder*

Pain in extremity

Back pain

Common

Arthritis *

Uncommon

Rhabdomyolysis

Renal and urinary disorders

Common

Renal failure *

Renal failure*

Renal failure*

General disorders and administration site conditions

Very common

Fatigue *

Pyrexia*

Fatigue*

Pyrexia*

Peripheral oedemam

Fatigue*

Pyrexia*

Investigations

Very common

Gamma-glutamyl transferase (GGT) increased*

Blood creatine phosphokinase increased

Gamma-glutamyl transferase (GGT) increased*

Transaminase increased*

Common

Transaminase increased*

Blood creatinine increased*

Lipase increased

Blood alkaline phosphatase increased

Blood creatinine increased*

Amylase increased

Lipase increased

Blood creatinine increased*

Transaminase increased*

Uncommon

Amylase increased

Amylase increased

Lipase increased

*composite terms which included more than one preferred term

a includes keratoacanthoma, squamous cell carcinoma and squamous cell carcinoma of skin

b includes, but not limited to, angioedema, drug hypersensitivity, hypersensitivity, hypersensitivity vasculitis and urticaria

c includes facial nerve disorder, facial paralysis, facial paresis, Bell's palsy

d includes but not limited to extrasystoles and sinus tachycardia

e includes erythema, generalised erythema, plantar erythema

f includes dermatitis exfoliative, skin exfoliation, exfoliative rash

g includes myalgia, muscle fatigue, muscle injury, muscle spasm, muscle weakness

h includes left ventricular dysfunction, ejection fraction decreased, cardiac failure and ejection fraction abnormal

i includes haemorrhage at various sites including, but not limited to, cerebral haemorrhage, intracranial haemorrhage, vaginal haemorrhage, heavy menstrual bleeding, intermenstrual bleeding, haematochezia, haemoptysis, haemothorax, gastrointestinal haemorrhage and haematuria

j includes, but not limited to, pulmonary embolism, deep vein thrombosis, embolism, thrombophlebitis, thrombophlebitis superficial, thrombosis, phlebitis, superior vena cava syndrome, mesenteric vein thrombosis and vena cava thrombosis

k includes colitis, colitis ulcerative, enterocolitis and proctitis

l includes myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositis

m includes, but not limited to, fluid retention, peripheral oedema, localised oedema, generalised oedema and swelling

When encorafenib was used at a dose of 300 mg once daily in combination with binimetinib 45 mg twice daily (Combo 300) in study CMEK162B2301-Part 2, the frequency category was lower compared to the pooled Combo 450 population for the following adverse reactions: anaemia, peripheral neuropathy, haemorrhage, hypertension, pruritus (common); and colitis, increased amylase and increased lipase (uncommon).

Description of selected adverse reactions

Cutaneous malignancies

Cutaneous squamous cell carcinoma

Melanoma and NSCLC

In the Combo 450 ISP, cuSCC including keratoacanthomas was observed in 3.0% (11/372) of patients. The median time to onset of the first event of cuSCC (all grades) was 6.5 months (range 1.0 to 22.8 months).

In the pooled encorafenib 300 population, cuSCC was reported in 7.4% (16/217) patients. For patients in the Phase III study (CMEK162B2301) 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

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

In the pooled encorafenib 300 population, new primary melanoma events occurred in 4.1% of patients (9 /217) and was 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

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 and NSCLC

In the Combo 450 ISP, uveitis was reported in 3.5% (13/372) of patients, and was Grade 1 in 0.5% (2/372), Grade 2 in 2.7% (10/372) and Grade 3 in 0.3% (1/372). Visual impairment, including blurred vision and reduced visual acuity, occurred in 23.1% (86/372) of patients. Uveitis and visual impairment were generally reversible.

RPED occurred in 22.3% (83/372) of patients, most of them had Grade 1-2 and 1.6% (6/372) had Grade 3 events.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, RPED was observed in 12.5% (32/257) of patients with 0.4% (1/257) Grade 4 event.

Left ventricular dysfunction

LVD was reported when encorafenib is used in combination with binimetinib in melanoma and NCSLC patients (see section 4.8 of binimetinib SmPC).

Haemorrhage

Melanoma and NCSLC

Haemorrhagic events were observed in 16.7% (62/372) of patients in the Combo 450 ISP. Most events were Grade 1 or 2: 13.2% (49/372), and 3.5% (13/372) were Grade ≥3. Few patients required dose interruptions or dose reductions (2.4% or 9/372). Haemorrhagic events led to discontinuation of treatment in 0.8% (3/372) of patients. The most frequent haemorrhagic events were haematuria in 2.7% (10/372) of patients, haematochezia in 2.7% (10/372) and rectal haemorrhage in 2.2% (8/372) of patients. Fatal gastric ulcer haemorrhage, with multiple organ failure as a concurrent cause of death, occurred in one patient. Cerebral haemorrhage/intracranial haemorrhage was reported in 1.6% (6/372) of patients, with fatal outcome in 4 patients.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, haemorrhagic events were observed in 6.6% (17/257) of patients and were Grade 3-4 in 1.6% (4/257) of patients.

Colorectal cancer

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

Hypertension was reported when encorafenib was used in combination with binimetinib in melanoma and NSCLC patients (see section 4.8 of binimetinib SmPC).

Venous thromboembolism

VTE was reported when encorafenib is used in combination with binimetinib in melanoma and NSCLC patients (see section 4.8 of binimetinib SmPC).

Pancreatitis

Melanoma and NSCLC

In the Combo 450 ISP, pancreatic enzyme elevation, mostly asymptomatic, was reported. Amylase and lipase elevations were reported in 4.0% (15/372) and 7.8% (29/372) of patients, respectively. Pancreatitis was reported in 0.8% (3/372) of patients. All 3 patients experienced Grade 3 events. Pancreatitis led to dose interruption in 0.3 % (1/372) of patients.

Colorectal cancer

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%) and led to dose interruption.

Dermatologic reactions

Rash

Melanoma and NSCLC

In the Combo 450 ISP, rash occurred in 20.4% (76/372) of patients. Most events were mild, with Grade 3 or 4 events reported in 1.1% (4/372) of patients. Rash led to discontinuation in 0.8% (3/372) patients and to dose interruption or dose modification in 2.4% (9/372) of patients.

In the pooled encorafenib 300 population, rash was reported in 43.3% (94/217) of patients. Most events were mild, with Grade 3 or 4 events reported in 4.6% (10/217) of patients. 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

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 (PPES)

Melanoma and NSCLC

PPES was reported in 5.1% (19/372) of patients in the Combo 450 ISP. All the PPES adverse reactions were either Grade 1 (2.7%) or Grade 2 (2.4%). Dose interruption or dose modification occurred in 1.1% (4/372) of patients.

In the Combo 300 arm in Part 2 of the pivotal study, PPES was observed in 3.9% (10/257) of patients with Grade 3 reported in 0.4% (1/257) of patients.

In the pooled encorafenib 300 population, PPES was reported in 51.6% (112/217) of patients. Most events were mild-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

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 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 and NSCLC

Dermatitis acneiform was reported when encorafenib is used in combination with binimetinib (see section 4.8 of binimetinib SmPC).

Colorectal cancer

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 and NSCLC

In the Combo 450 ISP, photosensitivity was observed in 4.3% (16/372) of patients. Most events were Grade 1-2, with Grade 3 reported in 0.3% (1/372) of patients and no event led to discontinuation. Dose interruption or dose modification was reported in 0.3% (1/372) 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 and NSCLC

In the Combo 450 ISP, facial paresis occurred in 0.8% (3/372) of patients including Grade 3 in 0.3% (1/372) of patients. The events were reversible, and no event led to treatment discontinuation. Dose interruption or modification was reported in 0.3% (1/372) of patients.

In the pooled encorafenib 300 population, facial paresis was observed in 7.4% (16/217) of patients. Most events were mild-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 and rhabdomyolysis

CK elevation and rhabdomyolysis occurred when encorafenib is used in combination with binimetinib in melanoma and NSCLC patients (see section 4.8 of binimetinib SmPC).

Renal dysfunction

Melanoma and NSCLC

In the Combo 450 ISP, mild, mostly Grade 1, asymptomatic blood creatinine elevation was noted in 9.4% (35/372) of patients treated with the Combo 450. The incidence of Grade 3 or 4 elevation was 0.8% (3/372). Renal failure events, including acute kidney injury, renal failure and renal impairment, were reported in 3.5% (13/372) patients treated with encorafenib and binimetinib with Grade 3 or 4 events in 1.9% (7/372) of patients. Renal failure was generally reversible with dose interruption, rehydration and other general supportive measures.

Colorectal cancer

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 abnormality

Melanoma and NSCLC

The incidences of liver laboratory abnormalities reported in the Combo 450 ISP are listed below:

• Increased transaminases: 16.4% (61/372) overall – 6.5% (24/372) Grade 3

• Increased GGT: 11.3% (42/372) overall – 6.7% (25/372) Grade 3-4

In Study CMEK162B2301-Part 2, in the Combo 300 arm, the incidence of liver laboratory abnormalities was:

• Increased transaminases: 13.2% (34/257) overall – 5.4% (14/257) Grade 3-4

• Increased GGT: 14.0% (36/257) overall – 4.7% (12/257) Grade 3-4

Colorectal cancer

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 and NSCLC

In the Combo 450 ISP, diarrhoea was observed in 41.7% (155/372) of patients and was Grade 3-4 in 3.8% (14/372) patients. Diarrhoea led to treatment discontinuation in 0.8% of patients and to dose interruption or dose modification in 8.1% of patients.

Constipation occurred in 24.7% (92/372) of patients and was Grade 1 or 2. Abdominal pain was reported in 28.5% (106/372) of patients and was Grade 3 in 2.2% (8/372) patients. Nausea occurred in 46.0% (171/372) with Grade 3 observed in 3.0% (11/372) of patients. Vomiting occurred in 31.2% (116/372) of patients with Grade 3 reported in 1.9% (7/372) of patients.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, nausea was observed in 27.2% (70/257) of patients and was Grade 3 in 1.6% (4/257) of patients. Vomiting occurred in 15.2% (39/257) of patients with Grade 3 reported in 0.4% (1/257) of patients. Diarrhoea occurred in 28.4% (73/257) of patients with Grade 3 reported in 1.6% (4/257) of patients.

Colorectal cancer

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.

Gastrointestinal disorders were typically managed with standard therapy.

Anaemia

Melanoma and NSCLC

In the Combo 450 ISP, anaemia was reported in 23.1% (86/372) of patients; 7.0% (26/372) patients had a Grade 3 or 4. No patients discontinued treatment due to anaemia, 3.2% (12/372) required dose interruption or dose modification.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, anaemia was observed in 9.7% (25/257) of patients with Grade 3-4 reported in 2.7% (7/257) patients.

Headache

Melanoma and NSCLC

In the Combo 450 ISP, headache occurred in 18.8% (70/372) of patients, including Grade 3 in 1.1% (4/372) of patients.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, headache was reported in 12.1% (31/257) of patients and was Grade 3 in 0.4% (1/257) of patients.

Colorectal cancer

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 and NSCLC

In the Combo 450 ISP, fatigue occurred in 48.1% (179/372) of patients including Grade 3 or 4 in 4.3% (16/372) of patients.

In Study CMEK162B2301-Part 2, in the Combo 300 arm, fatigue was observed in 33.5% (86/257) of patients with 1.6% (4/257) Grade 3-4 events.

Colorectal cancer

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

Melanoma and NSCLC

In patients treated with Combo 450 ISP (n = 372), 230 patients (61.8%) were <65 years old, 107 patients (28.8%) were 65 -74 years old and 35 patients (9.4%) were aged > 75. No overall differences in safety or efficacy were observed between elderly patients (≥ 65) and younger patients except diarrhoea and pruritus that were more frequently reported in elderly patients.

In the age subgroup of patients aged ≥ 75 years, Grade ≥3 adverse reactions (62.9% vs 47.5%), adverse reactions (all grades) requiring dose modification of any study drug (60.0% vs 48.1%) or leading to treatment discontinuation (25.7% vs 7.4%) were more frequently reported than in patients <75 years. The most common adverse reactions reported with a higher incidence in patients aged ≥ 75 years compared to patients aged < 75 years included fatigue, nausea, diarrhoea, vomiting and anaemia.

Colorectal cancer

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 adverse reactions reported with a higher incidence in patients aged ≥ 65 years compared to patients aged < 65 years included fatigue, decreased appetite, and haemorrhage.

In the colorectal cancer population, due to a very small number of patients treated in the age subgroup of patients aged ≥ 75 years, differences in the incidence of adverse reactions compared to patients aged < 75 years could not be assessed.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

At doses of encorafenib between 600 to 800 mg once daily, renal dysfunction (Grade 3 hypercreatinaemia) 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). Adverse reactions reported by this patient were Grade 1 events of nausea, vomiting and blurred vision; all subsequently resolved.

Management

There is no specific treatment for overdose.

Since encorafenib is moderately bound to plasma proteins, haemodialysis is likely to be ineffective in the treatment of overdose with encorafenib. There is no known antidote for encorafenib. In the event of an overdose, 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.