BRAFTOVI 50mg capsules medication leaflet

Each hard capsule contains 50 mg of encorafenib.

Each hard capsule contains 75 mg of encorafenib.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

Orange opaque cap and flesh opaque body, printed with a stylised “A” on the cap and “LGX 50mg”on the body. The length of the capsule is approximately 22 mm.

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

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

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

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

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

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 tumoursexpressing BRAF V600E and V600K mutations, colorectal tumours expressing a BRAF V600Emutation or NSCLC expressing a BRAF V600E mutation. Encorafenib should not be used in patientswith wild type BRAF malignant melanoma, wild type BRAF colorectal cancer or wild-type BRAF

Melanoma and NSCLC

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

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

Melanoma and NSCLC

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

For information on the posology and recommended dose modifications of binimetinib, see section 4.2of 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 combinationwith binimetinib in melanoma or NSCLC indications

Dose level Encorafenib dosewhen used in combination with binimetinib

Starting dose Six 75 mg (450 mg) capsules once daily1st dose reduction Four 75 mg (300 mg) capsules once daily2nd dose reduction Three 75 mg (225 mg) capsules once daily

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

Subsequent tolerate 100 mg (two 50 mg capsules) once daily.modification

For NSCLC indication:

Encorafenib should be permanently discontinued if patient is unable totolerate 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. Ifbinimetinib is temporarily interrupted, encorafenib should be reduced to 300 mg once daily during thetime of binimetinib dose interruption (see section 4.2 of binimetinib SmPC) as encorafenib is notwell-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. Ifencorafenib 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 reactionsprimarily related to binimetinib) for the following: retinal pigment epithelial detachment (RPED),retinal vein occlusion (RVO), interstitial lung disease/pneumonitis, cardiac dysfunction, creatinephosphokinase (CK) elevation and rhabdomyolysis, and venous thromboembolism (VTE).

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

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

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

Dose reduction recommendations for encorafenib are presented in Table 2.

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

Dose level Encorafenib dosewhen used in combination with cetuximab

Starting dose Four 75 mg (300 mg) capsules once daily1st dose reduction Three 75 mg (225 mg) capsules once daily2nd 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 todiscontinue encorafenib permanently.

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

Severity of adverse reactiona Encorafenib

* Grade 2 Encorafenib should be maintained.

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

* Grade 3 Encorafenib should be withheld until improved to Grade 0 or1 and resumed at the same dose if first occurrence, or resumedat a reduced dose if recurrent Grade 3.

* Grade 4 Encorafenib should be permanently discontinued.

Severity of adverse reactiona Encorafenib

* Grade 2 Encorafenib should be maintained and supportive measuressuch as topical therapy should be instituted.

If not improved despite supportive therapy within 2 weeks,encorafenib should be withheld until improved to Grade 0 or1 and treatment should be resumed at same dose level or at areduced dose.

* Grade 3 Encorafenib should be withheld, supportive measures such astopical therapy should be instituted, and the patient should bereassessed weekly.

Encorafenib should be resumed at same dose level or at areduced 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, encorafenibshould be withheld and ophthalmic monitoring should berepeated within 2 weeks.

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

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

If not improved within 6 weeks, ophthalmic monitoringshould be repeated and encorafenib should be permanentlydiscontinued.

* Grade 4 Encorafenib should be permanently discontinued and a followup with ophthalmologic monitoring should be performed.

QTc Prolongation

* QTcF > 500 ms and Encorafenib should be withheld (see monitoring in sectionchange ≤ 60 ms from 4.4).pre-treatment value Encorafenib should be resumed at a reduced dose when QTcF≤500 ms.

Encorafenib should be discontinued if more than onerecurrence.

* QTcF>500 ms and Encorafenib should be permanently discontinued (seeincreased by >60 ms monitoring in section 4.4).from pre-treatmentvalues

* Grade 2 (aspartate Encorafenib should be maintained.

aminotransferase (AST) If no improvement within 4 weeks, encorafenib should beor alanine withheld until improved to Grade 0 or 1 or to pre-aminotransferase (ALT) treatment/baseline levels and then resumed at the same dose.>3x ≤5x upper limit ofnormal (ULN))

* First occurrence of Encorafenib should be withheld for up to 4 weeks.

Grade 3 (AST or ALT * If improved to Grade 0 or 1 or to baseline levels, it>5x ULN and blood should be resumed at a reduced dose.bilirubin >2x ULN) * If not improved, encorafenib should be permanentlydiscontinued

Severity of adverse reactiona Encorafenib

* First occurrence of Encorafenib should be withheld for up to 4 weeks

Grade 4 (AST or ALT * If improved to Grade 0 or 1 or to baseline levels, then it>20 ULN) should be resumed at a reduced dose level.

* If not improved, encorafenib should be permanentlydiscontinued.

Or, encorafenib should be permanently discontinued.

* Recurrent Grade 3 (AST It should be considered to permanently discontinueor ALT > 5x ULN and encorafenib.blood bilirubin > 2x

ULN)

* Recurrent Grade 4 (AST Encorafenib should be permanently discontinued.or ALT > 20 ULN)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 withbinimetinib or in combination with cetuximab for other adverse reactions

Severity of adverse reaction Encorafenib

* Recurrent or intolerable Encorafenib should be withheld for up to 4 weeks.

Grade 2 adverse reactions * If improved to Grade 0 or 1 or to baseline levels,

* First occurrence of Grade 3 It should be resumed at a reduced dose.

adverse reactions * If not improved, encorafenib should be permanentlydiscontinued

* First occurrence of any Encorafenib should be withheld for up to 4 weeks

Grade 4 adverse reaction * If improved to Grade 0 or 1 or to baseline levels, then itshould be resumed at a reduced dose level.

* If not improved, encorafenib should be permanentlydiscontinued.

Or, encorafenib should be permanently discontinued.

* Recurrent Grade 3 adverse Permanent discontinuation of encorafenib should bereactions considered.

* Recurrent Grade 4 adverse Encorafenib should be permanently discontinued.reactions

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

If a dose of encorafenib is missed, the patient should only take the missed dose if it is more than12 hours until the next scheduled dose.

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

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

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

Administration of encorafenib should be undertaken with caution at a dose of 300 mg once daily inpatients 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.

No dose adjustment is required for patients with mild or moderate renal impairment based on apopulation pharmacokinetics (PK) analysis. There are no clinical data with encorafenib in patientswith 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 4.4and 5.2).

The safety and efficacy of encorafenib have not yet been established in children and adolescents. Nodata are available.

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

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

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

Encorafenib is to be given in combination with binimetinib (for patients with BRAF V600 mutantunresectable or metastatic melanoma, and for patients with BRAF V600E mutant advanced

NSCLC), or in combination with cetuximab (for patients with BRAF V600E mutant metastaticcolorectal cancer). For additional information on warnings and precautions associated withbinimetinib or cetuximab treatment, see section 4.4 of binimetinib SmPC or cetuximab SmPC.

There are limited data for the use of the combination of encorafenib with binimetinib in patients whohave progressed on a prior BRAF inhibitor given for the treatment of unresectable or metastaticmelanoma with BRAF V600 mutation. These data show that the efficacy of the combination would belower in these patients.

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).

LVD defined as symptomatic or asymptomatic decreases in ejection fraction has been reported whenencorafenib is used in combination with binimetinib. It is recommended that left ventricular ejectionfraction (LVEF) is assessed by echocardiogram or multi-gated acquisition (MUGA) scan beforeinitiation 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 abaseline LVEF that is either below 50% or below the institutional lower limits of normal. Therefore, inthese patients, binimetinib should be used with caution and for any symptomatic left ventriculardysfunction, 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 weeksuntil recovery.

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 antiplatelettherapy. The occurrence of Grade ≥3 haemorrhagic events should be managed with dose interruptionor treatment discontinuation (see Table 4 in section 4.2) and as clinically indicated.

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 (seesection 4.8).

Patients should be assessed at each visit for symptoms of new or worsening visual disturbance. Ifsymptoms of new or worsening visual disturbances including diminished central vision, blurred visionor 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 has been observed in patients treated with BRAF-inhibitors. A thorough QT study toevaluate 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 heartrate. Across pooled combination studies of encorafenib and binimetinib at the recommended doses anda single-agent encorafenib study, results suggest that encorafenib has the potential to result in smallincreases 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, onemonth after initiation, and then at approximately 3-month intervals or more frequently as clinicallyindicated, while on treatment. The occurrence of QTc prolongation can be managed with dosereduction, interruption or discontinuation with correction of abnormal electrolytes and control of riskfactors (see section 4.2).

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 such as cutaneous squamous cell carcinoma (cuSCC) includingkerathoacanthoma have been observed in patients treated with BRAF-inhibitors including encorafenib.

New primary melanoma has been observed in patients treated with BRAF inhibitors includingencorafenib (see section 4.8).

Dermatologic evaluations should be performed prior to initiation of therapy with encorafenib, every2 months while on therapy and for up to 6 months following treatment discontinuation. Suspiciousskin 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.

Based on its mechanism of action, encorafenib may promote malignancies associated with activationof RAS through mutation or other mechanisms. Patients receiving encorafenib should undergo a headand neck examination, chest/abdomen computerised tomography (CT) scan, anal and pelvicexaminations (for women) and complete blood cell counts prior to initiation, during and at the end oftreatment as clinically appropriate. It should be considered to permanently discontinue encorafenib inpatients who develop RAS mutation-positive non-cutaneous malignancies. Benefits and risks shouldbe carefully considered before administering encorafenib to patients with a prior or concurrent cancerassociated with RAS mutation.

The occurrence of TLS, which may be fatal, has been associated with the use of encorafenib inassociation with binimetinib (see section 4.8). Risk factors for TLS include high tumour burden,preexisting chronic renal insufficiency, oliguria, dehydration, hypotension and acidic urine. Thesepatients should be monitored closely and treated promptly as clinically indicated, and prophylactichydration should be considered.

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

As encorafenib is primarily metabolised and eliminated via the liver, patients with mild to severehepatic impairment may have increased encorafenib exposure over the range of inter-subjectvariability exposure (see section 5.2).

In the absence of clinical data, encorafenib is not recommended in patients with moderate or severehepatic impairment.

Administration of encorafenib should be undertaken with caution at a dose of 300 mg once daily inpatients with mild hepatic impairment (see section 4.2).

Closer monitoring of encorafenib related toxicities in patients with mild hepatic impairment isrecommended, including clinical examination and liver function tests, with assessment of ECGs asclinically appropriate during treatment.

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. Creatinineelevation has been commonly reported with encorafenib as single agent or in combination withbinimetinib or cetuximab. Observed cases of renal failure including acute kidney injury and renalimpairment were generally associated with vomiting and dehydration. Other contributing factorsincluded diabetes and hypertension. Blood creatinine should be monitored as clinically indicated andcreatinine elevation managed with dose modification or discontinuation (see Table 4 in section 4.2).

Patients should ensure adequate fluid intake during treatment.

Concurrent use of strong CYP3A inhibitors during treatment with encorafenib should be avoided. Ifconcomitant use with a strong CYP3A inhibitor is necessary, patients should be carefully monitoredfor safety (see section 4.5).

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

Encorafenib is primarily metabolised by CYP3A4.

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

Model based predictions indicate that the effect of posaconazole after repeated administrations couldbe similar for AUC (3-fold increase) and slightly greater for Cmax (2.7-fold increase). Model-basedpredictions 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 beavoided (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.

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 ofencorafenib. 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 inductionpotential should be considered.

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 thecoadministration of narrow therapeutic index CYP3A4 substrates cannot be avoided, adjust the dose ofthese 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 thereforeadministered with caution.

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

In vivo, encorafenib is an inhibitor of OATP1B1, OATP1B3 and/or BCRP. Coadministration ofencorafenib 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 ofrenal transporters OAT1, OAT3, OCT2 (such as furosemide, penicillin) or agents that are substrates ofthe hepatic transporters OCT1 (such as, bosentan) or substrates of P-gp (e.g. posaconazole) may alsohave increased exposure.

Therefore, these agents, substrates of transporters should be co-administered with caution.

Women of childbearing potential must use effective contraception during treatment with encorafeniband for at least 1 month following the last dose. Encorafenib may decrease the efficacy of hormonalcontraceptives (see section 4.5). Therefore, female patients using hormonal contraception are advisedto use an additional or alternative method such as a barrier method (e.g. condom) during treatmentwith encorafenib and for at least 1 month following the last dose.

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

Encorafenib is not recommended during pregnancy and in women of childbearing potential not usingcontraception. If encorafenib is used during pregnancy or if the patient becomes pregnant while takingencorafenib, the patient should be informed of the potential hazard to the foetus.

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

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 theclinical relevance of this is unknown, male patients should be informed of the potential risk forimpaired spermatogenesis.

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

The safety of encorafenib (450 mg orally once daily) in combination with binimetinib (45 mg orallytwice daily) has been evaluated in the integrated safety population (ISP) of 372 patients includingpatients with BRAF V600 mutant unresectable or metastatic melanoma and BRAF V600E mutantadvanced NSCLC (hereafter referred to as the Combo 450 ISP). In Combo 450 ISP, 274 patientsreceived the combination for the treatment of BRAF V600 mutant unresectable or metastaticmelanoma (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 encorafenibadministered 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 orallytwice daily) was evaluated in 257 patients with BRAF V600 mutant unresectable or metastaticmelanoma (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 treatedwith 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 from217 patients with unresectable or metastatic BRAF V600-mutant melanoma (hereafter referred to asthe 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, basedon the phase III study ARRAY-818-302. The most common ADRs (>25%) reported in this populationwere: fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletalpain, decreased appetite, rash and vomiting.

The rate of all study drug discontinuation due to any adverse reaction was 1.9 % in patients treatedwith encorafenib 300 mg in combination with cetuximab.

Adverse reactions are listed below by MedDRA body system organ class and the following frequencyconvention: 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 theavailable data).

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

Table 5: Adverse reactions

Frequency Encorafenib single Encorafenib 450 mg Encorafenib 300 mg inagent 300 mg in combination with combination with cetuximab (n(n = 217) binimetinib (n = 372) = 216)

Neoplasms benign, malignant and unspecified

*

Very common Skin papilloma Melanocytic naevus

Melanocytic naevuscuSCC a cuSCCa cuSCCa

Common New Primary Skin papilloma* Skin papilloma*

Melanoma* New Primary Melanoma*

*

Uncommon Basal cell carcinoma Basal cell carcinoma Basal cell carcinoma*

Very common Anaemia

Common Hypersensitivityb Hypersensitivityb Hypersensitivityb

Very common Decreased appetite Decreased appetite

Not known Tumour lysis syndrome

Very common Insomnia Insomnia

Headache* Neuropathy peripheral* Neuropathy peripheral*

* * *

Very common Neuropathy peripheral Dizziness Headache

Dysgeusia* Headache*

Common Facial paresisc Dysgeusia* Dizziness*

Dysgeusia

Uncommon Facial paresisc

Very common Visual impairment*

RPED *

Common Uveitis *

Uncommon Uveitis*

Common Supraventricular LVDh Supraventricular tachycardiadtachycardiad

Very common Haemorrhagei Haemorrhagei

Hypertension *

Common VTEj

Nausea Nausea Nausea

Vomiting* Vomiting* Vomiting*

Very common Constipation Constipation Constipation

Abdominal pain* Abdominal pain*

Diarrhoea* Diarrhoea*

Common Colitis k

Uncommon Pancreatitis* Pancreatitis* Pancreatitis*

PPES Hyperkeratosis* Dermatitis acneiform*

Hyperkeratosis* Rash* Rash*

Rash* Dry skin* Dry skin*

Dry skin* Pruritus* Pruritus*

Very common Pruritus* Alopecia*

Alopecia*

Erythema e

Skinhyperpigmentation*

Common Dermatitis acneiform* Dermatitis acneiform* Skin hyperpigmentation

Skin exfoliationf PPES PPES

Photosensitivity* Erythema* Hyperkeratosis*

Panniculitis* Alopecia

Photosensitivity* Erythemae

Uncommon Skin exfoliationf

Arthralgia* Arthralgia* Arthralgia/Musculoskeletal pain*

Myalgiag Myopathy/Muscular Myopathy/Muscular disorder*

Very common Pain in extremity disorderl Pain in extremity

Back pain Pain in extremity Back pain

Back pain*

Common Arthritis *

Uncommon Rhabdomyolysis

Common Renal failure * Renal failure* Renal failure*

Very common Fatigue * Fatigue* Fatigue*

Pyrexia* Pyrexia* Pyrexia*

Peripheral oedemam

Gamma-glutamyl Blood creatinetransferase (GGT) phosphokinaseincreased* increased

Very common Gamma-glutamyltransferase (GGT)increased*

Transaminaseincreased*

Common Transaminase Blood alkaline Blood creatinine increased*increased* phosphatase increased Transaminase increased*

Blood creatinine Blood creatinineincreased* increased*

Lipase increased Amylase increased

Lipase increased

Uncommon Amylase increased Amylase increased

Lipase increased

*composite terms which included more than one preferred terma includes keratoacanthoma, squamous cell carcinoma and squamous cell carcinoma of skinb includes, but not limited to, angioedema, drug hypersensitivity, hypersensitivity, hypersensitivityvasculitis and urticariac includes facial nerve disorder, facial paralysis, facial paresis, Bell's palsyd includes but not limited to extrasystoles and sinus tachycardiae includes erythema, generalised erythema, plantar erythemaf includes dermatitis exfoliative, skin exfoliation, exfoliative rashg includes myalgia, muscle fatigue, muscle injury, muscle spasm, muscle weaknessh includes left ventricular dysfunction, ejection fraction decreased, cardiac failure and ejection fractionabnormali includes haemorrhage at various sites including, but not limited to, cerebral haemorrhage, intracranialhaemorrhage, vaginal haemorrhage, heavy menstrual bleeding, intermenstrual bleeding,haematochezia, haemoptysis, haemothorax, gastrointestinal haemorrhage and haematuriaj 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 thrombosisk includes colitis, colitis ulcerative, enterocolitis and proctitisl includes myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositism includes, but not limited to, fluid retention, peripheral oedema, localised oedema, generalisedoedema and swelling

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

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 to22.8 months).

In the pooled encorafenib 300 population, cuSCC was reported in 7.4% (16/217) patients. For patientsin the Phase III study (CMEK162B2301) who developed cuSCC, the median time to onset of the firstevent of cuSCC (all grades) was 2.3 months (range 0.3 to 12.0 months).

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

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.

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

Melanoma and NSCLC

In the Combo 450 population, uveitis was reported in 3.5% (13/372) of patients, and was Grade 1 in0.5% (2/372), Grade 2 in 2.7% (10/372) and Grade 3 in 0.3% (1/372). Visual impairment, includingblurred vision and reduced visual acuity, occurred in 23.1% (86/372) of patients. Uveitis and visualimpairment 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) ofpatients with 0.4% (1/257) Grade 4 event.

LVD was reported when encorafenib is used in combination with binimetinib in melanoma and

NSCLC patients (see section 4.8 of binimetinib SmPC).

Melanoma and NSCLC

Haemorrhagic events were observed in 16.7% (62/372) of patients in the Combo 450 ISP. Most eventswere Grade 1 or 2: 13.2% (49/372), and 3.5% (13/372) were Grade ≥3. Few patients required doseinterruptions or dose reductions (2.4% or 9/372). Haemorrhagic events led to discontinuation oftreatment in 0.8% (3/372) of patients. The most frequent haemorrhagic events were haematuria in2.7% (10/372) of patients, haematochezia in 2.7% (10/372) and rectal haemorrhage in 2.2% (8/372) ofpatients. 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.

Haemorrhagic events were observed in 21.3% (46/216) of patients treated with encorafenib300 mg in combination with cetuximab; 1.4% (3/216) of patients were Grade 3 events and one fatalcase 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 in2.8% (6/216), rectal haemorrhage in 2.8% (6/216) of patients and haematuria in 2.8% (6/216) ofpatients.

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

VTE was reported when encorafenib is used in combination with binimetinib in melanoma and

NSCLC patients (see section 4.8 of binimetinib SmPC).

Melanoma and NSCLC

In the Combo 450 ISP, pancreatic enzyme elevation, mostly asymptomatic, was reported. Amylaseand 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.

In the population treated with encorafenib 300 mg in combination with cetuximab, pancreatitis grade 3with lipase and amylase increased events were reported in 1 patient (0.5%) and led to doseinterruption.

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. Mostevents were mild, with Grade 3 or 4 events reported in 4.6% (10/217) of patients. Rash led todiscontinuation in 0.5% (1/217) of patients and to dose interruption or dose modification in 7.4%(16/217) of patients.

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.

Melanoma and NSCLC

PPES was reported in 5.1% (19/372) of patients in the Combo 450 ISP. All the PPES adversereactions were either Grade 1 (2.7%) or Grade 2 (2.4%). Dose interruption or dose modificationoccurred 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 patientswith 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. Mostevents 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 todose interruption or dose modification in 23.0% (50/217) of patients.

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

Melanoma and NSCLC

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

In patients treated with encorafenib 300 mg in combination with cetuximab, dermatitis acneiformoccurred 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.

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. Doseinterruption 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.

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. Doseinterruption 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 in1.4% (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 discontinuationin 0.9% (2/217). Dose interruption or modification was reported in 3.7% (8/217) and symptomatictreatment including corticosteroids was reported in 5.1% (11/217) of patients.

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

Melanoma and NSCLC

In the Combo 450 ISP, mild, mostly Grade 1, asymptomatic blood creatinine elevation was noted in9.4% (35/372) of patients treated with the Combo 450. The incidence of Grade 3 or 4 elevation was0.8% (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 4events in 1.9% (7/372) of patients. Renal failure was generally reversible with dose interruption,rehydration and other general supportive measures.

Blood creatinine elevation was reported in 2.8% (6/216) of patients treated with encorafenib 300 mg incombination 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.

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 laboratoryabnormalities 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

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

Melanoma and NSCLC

In the Combo 450 ISP, diarrhoea was observed in 41.7% (155/372) of patients and was Grade 3-4 in3.8% (14/372) patients. Diarrhoea led to treatment discontinuation in 0.8% of patients and to doseinterruption 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 wasreported in 28.5% (106/372) of patients and was Grade 3 in 2.2% (8/372) patients. Nausea occurred in46.0% (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) ofpatients and was Grade 3 in 1.6% (4/257) of patients. Vomiting occurred in 15.2% (39/257) of patientswith Grade 3 reported in 0.4% (1/257) of patients. Diarrhoea occurred in 28.4% (73/257) of patientswith Grade 3 reported in 1.6% (4/257) of patients.

In patients treated with encorafenib 300 mg in combination with cetuximab, diarrhoea was observed in38.4% (83/216) of patients and was Grade 3 in 2.8% (6/216) of patients. Diarrhoea led to treatmentdiscontinuation 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) ofpatients. Nausea occurred in 38.0% (82/216) of patients with Grade 3 observed in 0.5% (1/216) ofpatients. Vomiting occurred in 27.3% (59/216) of patients with Grade 3 reported in 1.4 % (3/216) ofpatients. Constipation occurred in 18.1% (39/216) of patients and was Grade 1 or 2.

Gastrointestinal disorders were typically managed with standard therapy.

Melanoma and NSCLC

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

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

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) ofpatients and was Grade 3 in 0.4% (1/257) of patients.

In patients treated with encorafenib 300 mg in combination with cetuximab, headache occurred in20.4% (44/216) of patients and was Grade 1 or 2.

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) ofpatients with 1.6% (4/257) Grade 3-4 events.

In patients treated with encorafenib 300 mg in combination with cetuximab, fatigue was reported in56.9% (123/216) of patients including Grade 3 in 7.9% (17/216) of patients.

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 overalldifferences in safety or efficacy were observed between elderly patients (≥ 65) and younger patientsexcept 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%) orleading 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 ≥ 75years compared to patients aged < 75 years included fatigue, nausea, diarrhoea, vomiting and anaemia.

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%) wereaged ≥ 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, andhaemorrhage.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

At doses of encorafenib between 600 to 800 mg once daily, renal dysfunction (Grade 3hypercreatinaemia) was observed in 3 out of 14 patients. The highest administered dose occurred as adosing error in one patient who took encorafenib at a dose of 600 mg twice daily for 1 day (total dose1200 mg). Adverse reactions reported by this patient were Grade 1 events of nausea, vomiting andblurred vision; all subsequently resolved.

There is no specific treatment for overdose.

Since encorafenib is moderately bound to plasma proteins, haemodialysis is likely to be ineffective inthe treatment of overdose with encorafenib. There is no known antidote for encorafenib. In the eventof an overdose, encorafenib treatment should be interrupted and renal function must be monitored aswell as adverse reactions. Symptomatic treatment and supportive care should be provided as needed.

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EC03

Encorafenib is a potent and highly selective ATP-competitive small molecule RAF kinase inhibitor.

The half maximal inhibitory concentration (IC50) of encorafenib against BRAF V600E, BRAF and

CRAF enzymes was determined to be 0.35, 0.47 and 0.30 nM, respectively. The encorafenibdissociation half-life was >30 hours and resulted in prolonged pERK inhibition. Encorafenibsuppresses the RAF/MEK/ERK pathway in tumour cells expressing several mutated forms of BRAFkinase (V600E, D and K). Specifically, encorafenib inhibits in vitro and in vivo BRAF V600E, D and

K mutant melanoma cell growth and BRAF V600E mutant colorectal cancer cell growth. Encorafenibdoes not inhibit RAF/MEK/ERK signalling in cells expressing wild-type BRAF.

Encorafenib and binimetinib (a MEK inhibitor, see section 5.1 of binimetinib SmPC) both inhibit the

MAPK pathway, resulting in higher anti-tumour activity, compared to treatment with either drugalone.

One of the main mechanisms of resistance of BRAF-mutant CRC to RAF inhibitors has beenidentified as the re-activation of EGFR with bypassing signal transduction via BRAF. Combinations ofa BRAF inhibitor, e.g. encorafenib and agents targeting EGFR, e.g. cetuximab have shown to improveanti-tumour efficacy in non-clinical models.

The safety and efficacy of encorafenib in combination with binimetinib were evaluated in a 2-part

Phase III, randomised (1:1:1) active-controlled, open-label, multicentre study in patients withunresectable or metastatic BRAF V600 E or K mutant melanoma (Study CMEK162B2301), asdetected using a BRAF assay. Patients had histologically confirmed cutaneous or unknown primarymelanoma but those with uveal or mucosal melanoma were excluded. Patients were permitted toreceive prior adjuvant therapy and one prior line of immunotherapy for unresectable locally advancedor metastatic disease. Prior treatment with BRAF/ MEK inhibitors was not allowed.

Study CMEK162B2301, part 1

In Part 1, patients in the study were randomised to receive encorafenib 450 mg orally daily andbinimetinib 45 mg orally twice daily (Combo 450, n = 192), encorafenib 300 mg orally daily(Enco 300, n = 194), or vemurafenib 960 mg orally twice daily (hereafter referred to as Vem, n = 191).

Treatment continued until disease progression or unacceptable toxicity. Randomisation was stratifiedby American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, vs IVM1c) and

Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) and prior immunotherapyfor unresectable or metastatic disease (yes vs no).

The primary efficacy outcome measure was progression-free survival (PFS) of Combo 450 comparedwith vemurafenib as assessed by a blinded independent review committee (BIRC). PFS as assessed byinvestigators (investigator assessment) was a supportive analysis. An additional secondary endpointincluded 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 responserate (ORR), duration of response (DoR) and disease control rate (DCR) as assessed by BIRC and byinvestigator assessment.

The median age of patients was 56 years (range 20-89), 58% were male, 90% were Caucasian, and72% 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 lactatedehydrogenase (LDH), and 45% of patients had at least 3 organs with tumour involvement at baselineand 3.5% had brain metastases. 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 Combo450 arm; 5 patients in vemurafenib arm; 11 patients in Enco 300 arm) and 5 patients in the adjuvantsetting (2 patients in Combo 450 arm; 2 patients in vemurafenib arm; 1 patient in Enco 300 arm).

The median duration of exposure was 11.7 months in patients treated with Combo 450, 7.1 months inpatients treated with Enco 300 and 6.2 months in patients treated with vemurafenib. The medianrelative dose intensity (RDI) for Combo 450 was 100% for encorafenib and 99.6% for binimetinib; themedian RDI was 86.2% for Enco 300 and 94.5% for vemurafenib.

Part 1 of Study CMEK162B2301 demonstrated a statistically significant improvement in PFS in thepatients treated with Combo 450 compared with patients treated with vemurafenib. Table 6summarises the PFS and other efficacy results based on central review of the data by a blindedindependent radiology committee.

The efficacy results based on investigator assessment were consistent with the independent centralassessment. Unstratified subgroup analyses demonstrated point estimates in favour of Combo 450,including LDH at baseline, ECOG performance status and AJCC stage.

Table 6: Study CMEK162B2301, Part 1: Progression-free survival and confirmed overallresponse results (independent central review)

Encorafenib + Encorafenib Vemurafenibbinimetinib N=194 N=191

N=192 (Enco300) (Vem)(Combo 450)

Cut-off date: 19 May 2016

PFS (primary analysis)

Number of events (%) 98 (51.0) 96 (49.5) 106 (55.5)

Median, months 14.9 9.6 7.3(95% CI) (11.0, 18.5) (7.5,14.8) (5.6, 8.2)

HRa (95% CI) (vs Vem) 0.54 (0.41, 0.71)p-value (stratified log-rank)b <0.0001

HRa (95% CI) (vs Vem) 0.68 (0.52, 0.90)

Nominal p-value 0.007

HRa (95% CI) (vs Enco 300) 0.75 (0.56,1.00)p-value (stratified log-rank)b 0.051

Confirmed overall responses

Overall response rate, n (%) 121 (63.0) 98 (50.5) 77 (40.3)(95% CI) (55.8, 69.9) (43.3, 57.8) (33.3, 47.6)

CR, n (%) 15 (7.8) 10 (5.2) 11 (5.8)

PR, n (%) 106 (55.2) 88 (45.4) 66 (34.6)

SD, n (%) 46 (24.0) 53 (27.3) 73 (38.2)

DCR, n (%) 177 (92.2) 163 (84.0) 156 (81.7)(95% CI) (87.4, 95.6) (78.1, 88.9) (75.4, 86.9)

Duration of response

Median, months 16.6 14.9 12.3(95% CI) (12.2, 20.4) (11.1, NE) (6.9, 16.9)

CI=Confidence interval; CR=Complete Response; DCR=Disease Control Rate (CR+PR+SD+Non-CR/Non-PD;

Non-CR/Non-PD applies only to patients without a target lesion who did not achieve CR or have PD);

HR=hazard ratio; NE=Not estimable; PFS=progression-free survival; PR=Partial response; SD=stable disease.

Vem=vemurafenib.a Hazard ratio based on a stratified Cox proportional hazard modelb Log-rank p-value (2-sided)

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-reportedoutcomes (PRO) measures of health-related Quality of Life, functioning, melanoma symptoms, andtreatment-related adverse reactions. A definitive 10% deterioration in FACT-M and in EORTC QLQ-

C30 was significantly delayed in patients treated with Combo 450 relative to other treatments. Themedian time to definitive 10% deterioration in the FACT-M score was not reached in the Combo 450arm and was 22.1 months (95% CI: 15.2, NE) in the vemurafenib arm with a HR for the difference of0.46 (95% CI: 0.29, 0.72). An analysis of time to definitive 10% deterioration in EORTC QLQ-C30score provided with similar results.

Patients receiving Combo 450 reported no change or a slight improvement in the mean change frombaseline EQ-5D-5L index score at all visits, whilst patients receiving vemurafenib or encorafenibreported decreases at all visits (with statistical significant differences). An evaluation of change overtime in score yielded the same trend for EORTC QLQ-C30 and at all visit for FACT-M.

Study CMEK162B2301, part 2

Part 2 of Study CMEK162B2301 was designed to assess the contribution of binimetinib to theencorafenib and binimetinib combination.

The PFS for encorafenib 300 mg orally daily used in combination with binimetinib 45 mg orally twicedaily (Combo 300, n = 258) was compared to the PFS for Enco 300 (n = 280, including 194 patientsfrom Part 1 and 86 patients from Part 2). Enrolment in Part 2 started after all Part 1 patients wererandomised.

Final efficacy analysis of Study CMEK162B2301, parts 1 and 2 (cut-off date: 31 March 2023)

The final efficacy analysis was consistent with the results of the interim analysis and showed a benefitin OS for Combo 450 over vemurafenib (HR 0.67 [95% CI:0.53,0.84] with median OS of 33.6 monthsvs 16.9 months). The PFS and ORR (per BIRC) results also confirmed a numerical benefit in favour of

Combo 450, with a 7.6 months longer median PFS in the Combo 450 arm as compared to vemurafenibarm, see all detailed final efficacy results in Table 7 and Figures 1 and 2 below.

Moreover, Part 2 final analysis showed a numerical difference in OS for Combo 300 (Part 2) over

Enco 300 monotherapy (Parts 1+2) (HR 0.89 [95% CI:0.72,1.09] with median OS of 27.1 months[95% CI:21.6-33.3] vs 22.7 months [95% CI: 19.3-29.3]). The median PFS remained longer in the

Combo 300 (Part 2) arm than in the Enco 300 (Parts 1+2) group with median PFS estimates of12.9 months (95% CI: 10.9, 14.9) and 9.2 months (95% CI: 7.4, 11.1), respectively. The confirmed

ORR (per BIRC) was 67.8% (95% CI: 61.8, 73.5) and 51.4% (95% CI 45.4, 57.4) in the Combo 300(Part 2) and Enco 300 (Parts 1 + 2) arms, respectively. Similar results were observed per Investigatorassessment.

Table 7: Study CMEK162B2301 : Final results on PFS, OS and confirmed ORR (cut-off date:31 March 2023)

Encorafenib + Encorafenib Vemurafenibbinimetinib N=194 N=191

N=192 (Enco 300)(Combo 450) (Vem)

Final analysis, cut-off date: 31 March 2023

PFS (by BIRC)

Number of events 123 119 121(%) (64.1) (61.3) (63.4)

Median a, months 14.9 9.6 7.3(95% CI) (11.0, 20.2) (7.4, 14.8) (5.6, 7.9)

HRc (95% CI) (vs Vem) 0.51 (0.39, 0.66) 0.68 (0.53, 0.88)

Log-rank p-value (1-sided)* <0.0001 0.0017

HRc (95% CI) (vs Enco 300) 0.77 (0.60, 0.99)

Log-rank p-value (1-sided)* 0.0214

OS

Number of events 139 125 147(%) (72.4) (64.4) (77.0)

Median a, months 33.6 23.5 16.9(95% CI) (24.4, 39.2) (19.6, 33.6) (14.0, 24.5)

Survival probability bat 1 year %(95%CI) 75.5 (68.8, 81.0) 74.6 (67.6, 80.3) 63.1 (55.7, 69.7)at 2 years % (95% CI) 57.7 (50.3, 64.3) 49.1 (41.5, 56.2) 43.2 (35.9, 50.2)at 3 years % (95% CI) 46.5 (39.3, 53.4) 40.9 (33.6, 48.1) 31.4 (24.8, 38.2)at 5 years % (95% CI) 34.7 (28.0, 41.5) 34.9 (27.9, 42.0) 21.4 (15.7, 27.8)at 9 years % (95% CI) 26.0 (19.8, 32.5) 27.8 (21.1, 34.8) 18.2 (12.8, 24.3)

HRc (95% CI) (vs Vem) 0.67 (0.53, 0.84) 0.74 (0.58, 0.94)

Log-rank p-value (1-sided)* 0.0003 0.0063

HRc (95% CI) (vs Enco 300) 0.93 (0.73, 1.19)

Log-rank p-value (1-sided)* 0.2821

Confirmed Best Overall Response (per BIRC)

Confirmed ORR d, n (%) 123 (64.1) 100 (51.5) 78 (40.8)(95% CI) (56.8, 70.8) (44.3, 58.8) (33.8, 48.2)

CR, n (%) 29 (15.1) 17 (8.8) 16 (8.4)

PR, n (%) 94 (49.0) 83 (42.8) 62 (32.5)

SD, n (%) 44 (22.9) 52 (26.8) 71 (37.2)

DCR d, n (%) 177 (92.2) 163 (84.0) 155 (81.2)(95% CI) (87.4, 95.6) (78.1, 88.9) (74.8, 86.4)

Duration of Response (per BIRC)

Median, months 18.6 15.5 12.3(95% CI) (12.7, 27.6) (11.1, 29.5) (6.9, 14.5)

CI=Confidence Interval; CR=Complete Response; PR=Partial response; SD=stable disease;

DCR=Disease Control Rate (CR+PR+SD+Non-CR/Non-PD); HR=hazard ratio; ORR=objectiveresponse rate (CR+PR); PR and CR are confirmed by repeat assessments performed not less than 4weeks after the criteria for response is first met.a Median (time to event) and its 95% CIs are generated by KM estimation with Brookmeyer &

Crowley methodb Survival probability (obtained from the KM survival estimates, Greenwood formula used for CIs)c Both Log-rank test and Cox PH model are stratified by IVRS AJCC stage and ECOG Performancestatusd estimated 95% CI are obtained using the exact Clopper-Pearson method

*nominal p-value

Figure 1 Study CMEK162B2301: Kaplan-Meier plot of PFS by BIRC (cut-off date:31 March 2023)

Combo 45010 Encorafenib 300mg0 Vemurafenib0 10 20 30 40 50 60 70 80 90 100 110

Time (months)

Combo 450 Encorafenib 300mg Vemurafenib

Median(months) 14.9 9.6 7.3

Number of patients at risk

Combo 450 192 92 63 44 33 29 27 23 21 18 6 0

Encorafenib 300mg 194 71 43 31 24 18 14 13 9 8 4 0

Vemurafenib 191 45 22 16 10 7 6 4 3 2 1 0

Figure 2 Study CMEK162B2301: Kaplan-Meier plot of OS (cut-off date: 31 March 2023)

Combo 45010 Encorafenib 300mg0 Vemurafenib0 10 20 30 40 50 60 70 80 90 100 110

Time (months)

Combo 450 Encorafenib 300mg Vemurafenib

Median(months) 33.6 23.5 16.9

Number of patients at risk

Combo 450 192 157 117 96 79 73 63 57 50 46 26 0

Encorafenib 300mg 194 140 98 79 67 59 55 52 49 43 21 0

Vemurafenib 191 131 84 62 48 44 34 31 28 27 16 0

EEvveenntt--ffrreeee PPrroobbaabbiilliittyy ((%%)) EEvveenntt--ffrreeee PPrroobbaabbiilliittyy ((%%))

BRAF V600E Mutant metastatic colorectal cancer - Study ARRAY-818-302

Encorafenib in combination with cetuximab was evaluated in a randomised, active-controlled, open-label, multicentre trial (ARRAY 818-302 BEACON CRC). Eligible patients were required to have

BRAF V600E mutant metastatic colorectal cancer that had progressed after 1 or 2 prior regimens.

Enrolled patients were eligible to receive cetuximab per locally approved label with regards to tumour

RAS status. Prior use of RAF inhibitors, MEK inhibitors or EGFR inhibitors was prohibited.

Randomisation was stratified by Eastern Cooperative Oncology Group (ECOG) performance status,prior use of irinotecan and cetuximab source.

A total of 665 patients were randomised (1:1:1) to receive encorafenib 300 mg orally daily incombination with cetuximab dosed as per its approved SmPC (n=220), or encorafenib 300 mg orallydaily in combination with binimetinib 45 mg orally twice daily and cetuximab dosed as per itsapproved SmPC (n=224) or Control (irinotecan with cetuximab or irinotecan/5-fluorouracil/folinicacid (FOLFIRI) with cetuximab, n= 221). Treatment continued until disease progression orunacceptable toxicity.

The efficacy outcome measures were overall survival (OS) and overall response rate (ORR) asassessed by a blinded independent central review committee (BIRC), comparing encorafenib 300 mgin combination with cetuximab versus Control. Other efficacy measures are summarised in Table 8below.

The median age of patients was 61 years (range 26-91), 47 % were male and 83% were white. 51% ofpatients had baseline ECOG performance status of 0, and 51% received prior irinotecan. 46.8% ofpatients had at least 3 organs with tumour involvement at baseline.

The median duration of exposure was 3.2 months in patients treated with encorafenib 300 mg incombination with cetuximab, and 1.4 months in patients treated with irinotecan/cetuximab or

FOLFIRI/cetuximab (Control arm). In patients treated with the combination of encorafenib 300 mgand cetuximab, the median relative dose intensity (RDI) was 98% for encorafenib and 93.5% forcetuximab. In the control arm, the median RDI was 85.4% for cetuximab, 75.7% for irinotecan and inthe subset of patients who received Folinic acid and 5-FU, the median RDI was 75.2% and 75%respectively.

Encorafenib 300 mg in combination with cetuximab demonstrated a statistically significantimprovement in OS, ORR and PFS compared to Control. Efficacy results are summarised in Table 8and Figures 3 and 4.

The efficacy results based on investigator assessment were consistent with the independent centralassessment.

Table 8: Study ARRAY-818-302: Efficacy Results

Encorafenib with cetuximab Irinotecan with cetuximab or

FOLFIRI with cetuximab (Control)

Cut-off date: 11 February 2019 (Primary analysis)

OS

Number of patientsa 220 221

Number of events (%) 93 (42.3) 114 (51.6)

Median, months (95% 8.4 (7.5-11.0) 5.4 (4.8, 6.6)

CI)

HR (95% CI)b,c (vs 0.60 (0.41-0.88)

Control)p-valueb,c 0.0002

Median duration of 7.6 7.2follow-up, months(95% CI) (6.4, 9.20) (6.1, 8.1)

ORR (per BIRC)

Number of patientse 113 107

ORR n (%) 23 (20.4) 2 (1.9)(95% CI)f (13.4, 29.0) (0.2, 6.6)

P-valueb,d,g <0.0001

CR, n (%) 6 (5.3) 0

PR, n (%) 17 (15.0) 2 (1.9)

SD, n (%) 57 (50.4) 26 (24.3)

DCR, n (%) 84 (74.3) 33 (30.8)(95% CI)f (65.3, 82.1) (22.3, 40.5)

PFS (per BIRC)

Number of patientsa 220 221

Number of events (%) 133 (60.5) 128 (57.9)

Median PFS, months 4.2 (3.7, 5.4) 1.5 (1.5, 1.7)(95% CI)

HR (95% CI)b,c 0.40 (0.30, 0.55

P-valueb,d < 0.0001

Updated analysis, cut-off date: 15 August 2019

OS

Number of patientsa 220 221

Number of events (%) 128 (58.2) 157 (71.0)

Median, months (95% 9.3 (8.0, 11.3) 5.9 (5.1, 7.1)

CI)

HR (95% CI)b (vs 0.61 (0.48, 0.77)

Control)p-valueb,d,h < 0.0001

Median duration of 12.3 12.9follow-up, months(95% CI) (11.1, 14.1) (10.9, 14.6)

ORR (per BIRC)

Number of patientsa 220 221

ORR n (%) 43 (19.5) 4 (1.8)(95% CI)f (14.5, 25.4) (0.5, pct. 4.6)p-valueb,d,g,h <0.0001

CR, n (%) 7 (3.2) 0

PR, n (%) 36 (16.4) 4 (1.8)

SD, n (%) 117 (53.2) 59 (26.7)

DCR, n (%) 167 (75.9) 69 (31.2)(95% CI)f (69.7, 81.4) (25.2, 37.8)

PFS (per BIRC)

Number of patientsa 220 221

Number of events (%) 167 (75.9) 147 (66.5)

Median PFS, months 4.3 1.5(95% CI) (4.1, 5.5) (1.5, 1.9)

HR (95% CI)b 0.44 (0.35, 0.55)

P-valueb,d, h < 0.0001

CI = Confidence interval; CR = Complete response; HR = Hazard ratio; ORR = Overall response rate; OS =

Overall survival; PR = Partial response; SD = Stable disease, DCR: Disease control rate (CR+PR+SD+Non-

CR/Non-PD; Non-CR/Non-PD applies only to patients with a non-measurable disease who did not achieve CRor have PD)a Randomised Phase 3, Full Analysis Setb Stratified by ECOG PS, source of cetuximab, and prior irinotecan use at randomizationc Repeated CI derived using Lan DeMets O’Brien-Fleming boundaries associated with the observedinformation fraction at the interim analysisd 1-sidede Among the first 331 randomised patientsf Clopper-Pearson’s methodg Cochran Mantel-Haenszel testh Nominal p-value

Figure 3: Study ARRAY-818-302: Kaplan-Meier plot of Overall Survival (cut-offdate: 11 February 2019)

Figure 4: Study ARRAY-818-302: Kaplan-Meier plot of Overall Survival (cut-offdate: 15 August 2019)

BRAF V600E Mutant advanced Non-small cell lung cancer - Study ARRAY-818-202

The safety and efficacy of encorafenib in combination with binimetinib were studied in a Phase II,open-label, multicentre, non-comparative study (Study ARRAY-818-202, PHAROS). Patients wererequired to have histologically-confirmed metastatic NSCLC with a BRAF V600E mutation, ECOGperformance status of 0 or 1, and measurable disease. Patients had received 0 or 1 prior line ofsystemic therapy in the metastatic setting. Prior use of BRAF inhibitors or MEK inhibitors wasprohibited.

Patients were enrolled based on the determination of a BRAF V600E mutation in tumour tissue orblood (e.g., ctDNA genetic testing) by a local laboratory assay. Central confirmation of the

BRAF V600E mutation status (i.e. any short variant with protein effect V600E) was performed onarchival or fresh tumour tissue collected at enrolment and utilized the FoundationOne CDx - F1CDx(tissue) assay.

The analytical sensitivity was assessed through the Limit of Detection (LoD) study for F1CDx usingthe hit rate method (defined as the lowest level with ≥ 95% detection) by evaluating variant allelefrequency (VAF) for short variants. For F1CDx, the median LoD for substitution was determined to be3.2% VAF.

A total of 98 patients were enrolled and treated with encorafenib 450 mg orally once daily andbinimetinib 45 mg orally twice daily. Treatment continued until disease progression or unacceptabletoxicity.

The primary efficacy outcome measure was objective response rate (ORR) and was according to

RECIST v1.1 as evaluated by an Independent Radiology Review (IRR). Secondary endpoints includedduration of response (DoR), disease control rate (DCR), PFS and OS. Results of the primary analysiswith 18.2 months for treatment naïve and 12.8 months previously treated patients are presentedbelow.

Of the 98 patients enrolled in this study, 59 (60.2%) patients were treatment naïve. The median age ofpatients was 70 years (47-86), 53% were female, 88% were white and 30% had never smoked. 74%had a baseline ECOG performance status of 1 (67.8 % of participants had a baseline PS 1 in thetreatment naïve population and 82.1 % in the previously treated population). All patients hadmetastatic disease of which 8% had brain metastases at baseline and 97% had adenocarcinoma.

At the time of the primary analysis, the median duration of exposure was 15.1 months in treatmentnaïve patients and 5.4 months in previously treated patients. In the overall population, the medianrelative dose intensity (RDI) was 99.2% for encorafenib and 95.4% for binimetinib.

At the time of the primary analysis, the primary endpoint of IRR-assessed ORR in the treatment naïvepopulation was 74.6% (95% CI: 61.6, 85.0), including 9 (15.3%) CRs and 35 (59.3%) PRs.

The ORR by IRR in the previously treated population was 46.2% (95% CI: 30.1, 62.8), including 4(10.3%) CRs and 14 (35.9%) PRs.

Results updated with an additional 10-month follow-up (median duration of exposure of 16.3 months intreatment naïve patients and 5.5 months in previously treated patients) are provided in Table 9.

Table 9: Study ARRAY-818-202: Efficacy Results

Encorafenib with Binimetinib

Treatment Naïve Previously Treated(N=59) (N=39)

ORR per IRR

ORR, % (95% CI) 75% (62, 85) 46% (30, 63)

CR, % 15% 10%

PR, % 59% 36%

DoR per IRR N=44 N=18

Median DoR, months (95% CI) 40.0 (23.1, NE)* 16.7 (7.4, NE)*% with DoR ≥12 months 64% 44%

* Results from a sensitivity analysis considering new anti-cancer therapy as an event in addition to progression and deathare 23.1 months in treatment naïve patients (14.8; NE) and 12.0 months (6.3; NE) in previously treated patients.

N = number of patients; ORR = Objective Response Rate; CI = Confidence Interval; CR = Complete Response; PR =

Partial Response; DoR = Duration of Response; IRR= Independent Radiology Review; NE = not estimable

In the safety analysis of pooled studies, the incidence of new QTcF prolongation >500 ms was1.1% (4/363) in the Combo 450 ISP (n = 372), and 2.5% (5/203) in the encorafenib single agent groupof patients with melanoma. QTcF prolongation of >60 ms compared to pre-treatment values wasobserved in 6.0% (22/364) patients in the Combo 450 ISP, and in 3.4% (7/204) in the encorafenibsingle agent group (see sections 4.2 and 4.4).

In the safety analysis of the Phase 3 (ARRAY-818-302) safety set in colorectal indication, theincidence of new QTcF prolongation >500 ms was 3.2% (7/216) and QTcF prolongation of >60 mscompared to pre-treatment values was observed in 8.8% (19/216) of patients of the encorafenib +cetuximab arm (see sections 4.2 and 4.4).

The European Medicines Agency has waived the obligation to submit the results of studies withencorafenib in all subsets of the paediatric population in colorectal carcinoma and lung cancer (seesection 4.2 for information on paediatric use).

The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumours.

The pharmacokinetics of encorafenib have been shown to be approximatively dose linear after singleand multiples doses. After repeat once-daily dosing, steady-state conditions were reached within 15days. The accumulation ratio of approximately 0.5 is likely due to auto-induction of CYP3A4. Theinter-subject variability (CV%) of AUC is ranged from 12.3% to 68.9%.

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 theencorafenib dose was absorbed. Administration of a single 100 mg dose of encorafenib with ahigh-fat, high-calorie meal decreased the Cmax by 36%, while the AUC was unchanged. A druginteraction study in healthy subjects indicated the extent of encorafenib exposure was not altered in thepresence of a gastric pH-altering agent (rabeprazole).

Encorafenib is moderately (86.1%) bound to human plasma proteins in vitro. Following a single oraldose of 100 mg [14C] encorafenib in healthy subjects, the mean (SD) blood-to-plasma concentrationratio is 0.58 (0.02) and the mean (CV%) apparent volume of distribution (Vz/F) of encorafenib is226 L (32.7%).

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

Following a single oral dose of 100 mg [14C] encorafenib in healthy subjects, radioactivity waseliminated equally in both the faeces and urine (mean of 47.2%). In urine, 1.8% of the radioactivitywas 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).

No drug drug interaction was evidenced between encorafenib and cetuximab.

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

The effect of co-administering a strong CYP3A4 inducer on encorafenib exposure has not beenstudied in a dedicated trial. Repeat dose administration of encorafenib 450 mg once daily andbinimetinib 45 mg twice daily in melanoma patients with modafinil, a moderate CYP3A4 inducer,decreased encorafenib steady-state AUC by 24% and Cmax by 20%, compared to encorafenib alone.

In vitro experiments indicate encorafenib is a relatively potent reversible inhibitor of UGT1A1,

CYP2B6, CYP2C9 and CYP3A4/5, as well as a time-dependent inhibitor of CYP3A4. Encorafenibinduced CYP1A2, CYP2B6, CYP2C9 and CYP3A4 in human primary hepatocytes.

Repeat dose administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily inmelanoma patients with a single dose of CYP probe substrate cocktail reduced midazolam 2 mg(CYP3A4 substrate) AUC by 82% and Cmax by 74 %. It decreased omeprazole 20 mg (CYP2C19substrate) AUC by 17 % and did not change Cmax and increased caffeine 50 mg (CYP1A2 substrate)

AUC by 27 % and Cmax by 13 %. It decreased the ratio of losartan metabolite E3174 to losartan(CYP2C9 substrate) concentrations in urine by 28% and did not change the ratio of dextromethorphanmetabolite (dextrorphan) to dextromethorphan (CYP2D6 substrate) concentrations in urine. Theseresults indicate strong induction of CYP3A4, mild inhibition of CYP1A2 and no impact onpharmacokinetics of CYP2C19 substrates. From the urinary data, the inhibitory potency on CYP2C9and CYP2D6 cannot be finally concluded. No data are available for CYP2D6 poor metabolisers.

A single dose of encorafenib 450 mg and binimetinib 45 mg reduced bupropion 75 mg (CYP2B6substrate) AUC and Cmax by ≤ 25%. Repeated administration of encorafenib 450 mg daily andbinimetinib 45 mg twice daily reduced bupropion AUC and Cmax by ≤ 26 % and increased the AUCof the active metabolite hydroxybupropion by 49% indicating mild induction.

For co-administration with UGT1A1 substrates that undergo gut extraction, a minor to moderateinteraction is expected. While binimetinib is a UGT1A1 substrate, it does not undergo gut extractionand therefore no DDI with encorafenib is expected. Additionally, no differences in exposure have beenobserved clinically when binimetinib is co-administered with encorafenib.

Encorafenib was found to be a substrate of the P-glycoprotein (P-gp) transporters. Inhibition of P-gp isunlikely to result in a clinically important increase in encorafenib concentrations as encorafenibexhibits high intrinsic permeability. The involvement of several uptake transporter families (OCT1,

OATP1B1, OATP1B3 and OATPB1) was investigated in vitro using relevant transporter inhibitors.

The data suggest that hepatic uptake transporters are not involved in encorafenib distribution intoprimary human hepatocytes.

Repeated administration of encorafenib 450 mg once daily and binimetinib 45 mg twice daily with asingle 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, OATP1B3 and/or

BCRP transporters.

In vitro, encorafenib inhibited the hepatic transporter OCT1, but is unlikely to be an effective inhibitorclinically. Based on in vitro studies, there is potential for encorafenib to inhibit renal transporters

OCT2, OAT1, OAT3 at clinical concentrations. In addition, encorafenib may inhibit P-gp in the gut atthe expected clinical concentrations.

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

No clinical data are available in the paediatric population. The safety profile in the pediatricpopulation is unknown. In adolescents with BRAF V600-mutant metastatic melanoma aged 12 to <18years, population pharmacokinetic simulations show that the following doses and dose reductions forthe management of adverse reactions result in plasma exposure similar to that achieved in adults:

* Weighing 40 kg and more: the adult dose 450 mg QD with the same dose reductions: 300 and225 mg QD.

* Weighing between 30 and <40 kg: 300 mg QD, dose reduction to 225 mg QD and then 150mg QD,

* Weighing less than 30 kg: 225 mg QD, dose reduction to 150 mg QD.

Children under 12 years should not be treated with encorafenib.

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

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

There are no clinically relevant differences in encorafenib PK between Asians and non Asians. Thereare insufficient data to evaluate potential differences in the exposure of encorafenib in other races orethnicity.

Results from a dedicated clinical study indicate a 25% higher total encorafenib exposures in patientswith mild hepatic impairment (Child-Pugh Class A) compared with subjects with normal liverfunction. 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 primarilymetabolised and eliminated via the liver, based on PBPK modelling, patients with moderate to severehepatic impairment may have greater increases in exposure than patients with mild hepaticimpairment. No dosing recommendation can be made in patients with moderate or severe hepaticimpairment (see sections 4.2 and 4.4).

Encorafenib undergoes minimal renal elimination. No formal clinical study has been conducted toevaluate the effect of renal impairment on the pharmacokinetics of encorafenib.

In a population pharmacokinetic analysis, no clear trend in encorafenib CL/F was observed in patientswith mild (eGFR 60 to 90 mL/min/1.73 m2) or moderate (eGFR 30 to 59 mL/min/1.73 m2) renalimpairment compared with subjects with normal renal function (eGFR ≥90 mL/min/1.73 m2). A smalldecrease in CL/F (≤5%) was predicted for patients with mild and moderate renal impairment, which isunlikely to be clinically relevant. The pharmacokinetics of encorafenib have not been studied inpatients with severe renal impairment.

In the 4-week and 13-week rat toxicity studies, clinical signs, reduced body weight reducedepididymides and prostate weights and microscopic findings in testes, epididymides, stomach and skinwere noted. Partial reversibility of these findings was noted after a 4-week recovery period. No

NOAEL could be established for the 4-week study. The NOAEL determined in the 13-week study wasmore than 10-times human therapeutic exposures.

In the 4-week and 13-week monkey toxicity study, isolated/sporadic episodes of emesis and diarrhoeaas well as ophthalmic lesions were observed at slightly above human therapeutic exposures.

Ophthalmic lesions were partially reversible and consisted of a separation or detachment in the retinabetween the outer rods and cones layer and retinal pigmented epithelium at the central macula at thefovea. This observation was similar to that described in humans as central serous-likechorioretinopathy or central serous retinopathy.

Encorafenib was not genotoxic.

Fertility studies were not conducted with encorafenib. In the 13-week rat toxicology studies,encorafenib treatment at 6 mg/kg/d (dose level more than 5 times the human exposure at thetherapeutic dose) resulted in decreased testes and epididymis weights with tubular degeneration andoligospermia. In the 13-week study, partial reversibility was noted at the highest dose level(60 mg/kg/d).

The embryo-foetal development study in rats indicated that encorafenib induced foetal toxicity withlower foetal weights and delays in skeletal development.

The embryo-foetal development study in rabbits indicated that encorafenib induced foetal toxicity withlower foetal weights and transitory changes in skeletal development. Dilatation of the aortic arc wasobserved in some foetuses.

Encorafenib was phototoxic in an in vitro 3T3 Neutral Red Uptake Test. Encorafenib was not asensitiser in the in vivo mouse sensitization assay. Collectively, these data indicate that encorafenibhas a risk of phototoxic potential and minimal risk for sensitization at therapeutic doses in patients.

Copovidone (E1208)

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Iron oxide black (E172)

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Not applicable.

3 years.

Store below 30°C.

Store in the original package in order to protect from moisture.

Each pack contains either 28x1 or 112x1 hard capsules in polyamide/aluminium/PVC/aluminium/

PET/paper perforated unit dose blisters.

Not all pack sizes may be marketed.

Each pack contains either 42x1 or 168x1 hard capsules in polyamide/aluminium/PVC/aluminium/

PET/paper perforated unit dose blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

PIERRE FABRE MEDICAMENT

Les Cauquillous81500 Lavaur

France

EU/1/18/1314/001 28x1 hard capsules

EU/1/18/1314/003 112x1 hard capsules

EU/1/18/1314/002 42x1 hard capsules

EU/1/18/1314/004 168x1 hard capsules

Date of first authorisation: 20 September 2018

Date of latest renewal: 23 June 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.