MEKTOVI 15mg film-coated tablets medication leaflet

Mektovi 15 mg film-coated tablets

Mektovi 45 mg film-coated tablets

Mektovi 15 mg film-coated tablets

Each film-coated tablet contains 15 mg of binimetinib.

Each film-coated tablet contains 133.5 mg of lactose monohydrate.

Mektovi 45 mg film-coated tablets

Each film-coated tablet contains 45 mg of binimetinib.

Each film-coated tablet contains 234.9 mg of lactose monohydrate.

For the full list of excipients, see section 6.1

Film-coated tablet (tablet).

Mektovi 15 mg film-coated tablets

Yellow to dark yellow, unscored biconvex, ovaloid film-coated tablets approximately 12 mm in lengthand 5 mm in width, with the “A” logo debossed on one side of the tablet and “15” on the other side.

Mektovi 45 mg film-coated tablets

White to off-white, unscored biconvex, ovaloid film-coated tablets approximately 15 mm in lengthand 6 mm in width, with “45” debossed on one side.

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

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

Binimetinib treatment in combination with encorafenib should be initiated and supervised under theresponsibility of a physician experienced in the use of anticancer medicinal products.

Before taking binimetinib in combination with encorafenib, patients must have confirmation of

BRAF V600E mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with thecorresponding intended purpose. If the CE-marked IVD is not available, an alternative validated testshould be used.

The efficacy and safety of binimetinib in combination with encorafenib have been established only inpatients with melanoma tumours expressing BRAF V600E and V600K mutations, or NSCLCexpressing a BRAF V600E mutation. Binimetinib in combination with encorafenib should not be usedin patients with wild type BRAF malignant melanoma or wild type BRAF NSCLC.

The recommended dose of binimetinib is 45 mg (three 15 mg tablets or one 45 mg tablet) twice dailyapproximately 12 hours apart, corresponding to a total daily dose of 90 mg.

The management of adverse reactions may require dose reduction, temporary interruption or treatmentdiscontinuation (see below, Table 1 and Table 2).

For patients receiving 45 mg binimetinib twice daily, the recommended reduced dose of binimetinib is30 mg twice daily. Dose reduction below 30 mg twice daily is not recommended. Therapy should bediscontinued if the patient is not able to tolerate 30 mg orally twice daily.

If the adverse reaction that resulted in a dose reduction is under effective management, dosere-escalation to 45 mg twice daily may be considered. Dose re-escalation to 45 mg twice daily is notrecommended if the dose reduction is due to left ventricular dysfunction (LVD) or any Grade 4 toxicity.

Dose modifications recommendations in case of adverse reactions are presented below and in

Tables 1 and 2.

If treatment-related toxicities occur when binimetinib is used in combination with encorafenib, thenboth treatments should be simultaneously dose reduced, interrupted or discontinued. Exceptions wheredose reductions are necessary for encorafenib only (adverse reactions primarily related to encorafenib)are: palmar-plantar erythrodysaesthesia syndrome (PPES), uveitis including iritis and iridocyclitis and

QTc prolongation.

If one of these toxicities occurs, see section 4.2 of encorafenib Summary of Product Characteristics(SmPC) for dose modification instructions for encorafenib.

If binimetinib is temporarily interrupted, encorafenib should be reduced to 300 mg once daily duringthe time of binimetinib dose interruption (see Tables 1 and 2) as encorafenib is not well-tolerated atthe dose of 450 mg as a single agent. If binimetinib is permanently discontinued, encorafenib shouldbe discontinued.

If encorafenib is temporarily interrupted (see section 4.2 of encorafenib SmPC), binimetinib should beinterrupted. If encorafenib is permanently discontinued, then binimetinib should be discontinued.

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

Table 1: Recommended dose modifications for binimetinib (used in combination withencorafenib) for selected adverse reaction

Severity of adverse reactiona Binimetinib

* Grade2 Binimetinib should be maintained.

If rash worsens or does not improve within 2 weeks withtreatment, binimetinib should be withheld until improved to

Grade 0 or 1 and then resumed at the same dose if firstoccurrence or resumed at a reduced dose if recurrent Grade2.

* Grade 3 Binimetinib should be withheld until improved to Grade 0 or 1and resumed at the same dose if first occurrence or resumed ata reduced dose if recurrent Grade 3.

* Grade 4 Binimetinib should be permanently discontinued.

* Symptomatic retinal pigment Binimetinib should be withheld for up to 2 weeks andepithelial detachments (RPED) ophthalmic monitoring should be repeated including visual(Grade 2 or 3) acuity assessment.

* If improved to Grade 0 or 1, binimetinib should beresumed at same dose.

* If improved to Grade 2, binimetinib should be resumed ata lower dose.

* If not improved to Grade 2, binimetinib should bepermanently discontinued.

* Symptomatic RPED (Grade 4) Binimetinib should be permanently discontinued.associated with reduced visualacuity (Grade 4)

* Retinal vein occlusion (RVO) Binimetinib should be permanently discontinued.

* Grade 2 Left ventricular LVEF should be evaluated every 2 weeks.ejection fraction (LVEF) * If asymptomatic:decrease or asymptomatic, Binimetinib should be withheld for up to 4 weeks.absolute decrease in LVEF of Binimetinib should be resumed at a reduced dose if all ofgreater than 10 % from baseline the following are present within 4 weeks:that is below lower limit of o LVEF is at or above the LLNnormal (LLN) o Absolute decrease from baseline is 10 % orless.

* If the LVEF does not recover within 4 weeks, binimetinibshould be permanently discontinued.

* Grade 3 or 4 LVEF decrease or Binimetinib should be permanently discontinued.symptomatic left ventricular LVEF should be evaluated every 2 weeks until recovery.dysfunction (LVD)

* Grade 3 (CK > 5 - 10x upper Binimetinib dose should be maintained and it should belimit of normal (ULN)) ensured that patient is adequately hydrated.asymptomatic

* Grade 4 (CK > 10x ULN) Binimetinib should be withheld until improved toasymptomatic Grade 0 or 1. It should be ensured that patient has adequatehydration.

Severity of adverse reactiona Binimetinib

* Grade 3 or grade 4 (CK > 5x Binimetinib should be withheld until improved to

ULN) with muscle symptoms or Grade 0 or 1.renal impairment * If resolved within 4 weeks, binimetinib should be resumedat a reduced dose, or

* Binimetinib should be permanently discontinued.

* Uncomplicated deep vein Binimetinib should be withheld.thrombosis (DVT) or * If improved to Grade 0 or 1, binimetinib should bepulmonary embolism (PE) ≤ resumed at a reduced dose, or

Grade 3 * If not improved, binimetinib should be permanentlydiscontinued.

* Grade 4 PE Binimetinib should be permanently discontinued.

* Grade 2 aspartate Binimetinib dose should be maintained.aminotransferase (AST) or If no improvement within 2 weeks, binimetinib should bealanine aminotransferase withheld until improved to Grade 0 or 1 or to baseline levels,(ALT) > 3x - ≤ 5x upper limit and then resumed at the same dose.of normal (ULN)

* First occurrence of Grade 3 Binimetinib should be withheld for up to 4 weeks.(AST or ALT > 5x ULN and * If improved to Grade 0 or 1 or baseline level, binimetinibblood bilirubin > 2x ULN) should be resumed at reduced dose, or

* If not improved, binimetinib should be permanentlydiscontinued.

* First occurrence of Grade 4 Binimetinib should be withheld for up to 4 weeks.(AST or ALT > 20 ULN) * If improved to Grade 0 or 1 or baseline levels, binimetinibshould be resumed at a reduced dose level, or

* If not improved, binimetinib should be permanentlydiscontinued.

Or, binimetinib should be permanently discontinued.

* Recurrent Grade 3 (AST or It should be considered to permanently discontinue

ALT > 5x ULN and blood binimetinib.bilirubin > 2x ULN)

* Recurrent Grade 4 (AST or Binimetinib should be permanently discontinued.

ALT > 20 ULN)

* Grade 2 Binimetinib should be withheld for up to 4 weeks.

* If improved to Grade 0 or 1, binimetinib should beresumed at reduced dose, or

* If not resolved within 4 weeks, binimetinib should bepermanently discontinued.

* Grade 3 or Grade 4 Binimetinib should be permanently discontinued.a National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)version 4.03

Table 2: Recommended dose modifications for binimetinib (used in combination withencorafenib) for other adverse reactions

Severity of adverse reaction Binimetinib

* Recurrent or intolerable Grade 2 Binimetinib should be withheld for up to 4 weeks.adverse reactions * If improved to Grade 0 or 1 or baseline level, binimetinib

* First occurrence of Grade 3 should be resumed at reduced dose, oradverse reactions * If not improved, binimetinib should be permanentlydiscontinued.

* First occurrence of Grade 4 Binimetinib should be withheld for up to 4 weeks.adverse reactions * If improved to Grade 0 or 1 or baseline levels,binimetinib should be resumed at a reduced dose level,or

* If not improved, binimetinib should be permanentlydiscontinued.

Or, binimetinib should be permanently discontinued.

* Recurrent Grade 3 adverse It should be considered to permanently discontinuereactions binimetinib.

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

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

If a dose of binimetinib is missed, it should not be taken if it is less than 6 hours until the next dose isdue.

In case of vomiting after administration of binimetinib, the patient should not re-take the dose andshould take the next scheduled dose.

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

No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh A).

As encorafenib is not recommended in patients with moderate (Child Pugh B) or severe hepaticimpairment (Child-Pugh C), administration of binimetinib is not recommended in these patients. (seesection 4.2 of encorafenib SmPC).

No dose adjustment is recommended for patients with renal impairment (see section 5.2).

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

.

Mektovi is for oral use.

The tablets are to be swallowed whole with water. They may be taken with or without food.

For patients unable to swallow, Mektovi 15 mg tablets may be dispersed in a small glass(approximately 10 mL) of either water, orange juice or apple juice and taken immediately. The glassshould be rinsed with approximately 10 mL of water, orange juice or apple juice, and content drunkimmediately.

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

Binimetinib is to be given in combination with encorafenib. For additional information on warningsand precautions associated with encorafenib treatment, see section 4.4 of encorafenib SmPC.

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

There are limited efficacy data with the combination of binimetinib and encorafenib 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 can occur whenbinimetinib is administered.

It is recommended that LVEF is assessed by echocardiogram or multi-gated acquisition (MUGA) scanbefore initiation of binimetinib, 1 month after initiation, and then at approximately 3-month intervalsor more frequently as clinically indicated, while on treatment. The occurrence of LVEF decrease canbe managed with treatment interruption, dose reduction or with treatment discontinuation (seesection 4.2).

The safety of binimetinib in combination with encorafenib has not been established in patients with abaseline LVEF that is either below 50 % or below the institutional LLN. Therefore, in these patients,binimetinib should be used with caution and for any symptomatic left ventricular dysfunction,

Grade 3-4 LVEF, or absolute decrease of LVEF from baseline of ≥ 10 %, binimetinib should bediscontinued and LVEF should be evaluated every 2 weeks until recovery.

Haemorrhages, including major haemorrhagic events, can occur when binimetinib is administered (seesection 4.8). The risk of haemorrhage may be increased with concomitant use of anticoagulant andantiplatelet therapy. The occurrence of Grade ≥ 3 haemorrhagic events should be managed with doseinterruption, reduction or treatment discontinuation (see Table 2 in section 4.2) and as clinicallyindicated.

Ocular toxicities including RPED and RVO can occur when binimetinib is administered. Uveitisincluding iridocyclitis and iritis have been reported in patients treated with binimetinib in combinationwith encorafenib (see section 4.8).

Binimetinib is not recommended in patients with a history of RVO. The safety of binimetinib has notbeen established in patients with predisposing factors for RVO including uncontrolled glaucoma,ocular hypertension, uncontrolled diabetes mellitus or a history of hyperviscosity orhypercoagulability syndromes. Therefore, binimetinib should be used with caution in these patients.

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

The occurrence of symptomatic RPED can be managed with treatment interruption, dose reduction orwith treatment discontinuation (see Table 1 in section 4.2).

Binimetinib should be permanently discontinued with the occurrence of RVO (see Table 1 insection 4.2).

If during treatment patient develops uveitis, see section 4.2 of encorafenib SmPC for guidance.

Asymptomatic CK elevations are seen in patients treated with binimetinib (see section 4.8), and,rhabdomyolysis was uncommonly reported. Special attention should be paid to patients withneuromuscular conditions associated with CK elevation and rhabdomyolysis.

CK and creatinine levels should be monitored monthly during the first 6 months of treatment and asclinically indicated. The patient should be advised to maintain an adequate fluid intake duringtreatment. Depending on the severity of symptoms, degree of CK elevation or creatinine elevation,dose reduction, dose interruption or permanent discontinuation of binimetinib may be required (see

Table 1 in section 4.2).

Hypertension, or worsening of pre-existing hypertension, can occur with the use of binimetinib. Bloodpressure should be measured at baseline and monitored during treatment, with control of hypertensionby standard therapy as appropriate. In case of severe hypertension, temporary interruption ofbinimetinib is recommended until hypertension is controlled (see Table 2 in section 4.2).

VTE can occur when binimetinib is administered (see section 4.8). Binimetinib should be used withcaution in patients who are at risk for, or who have a history of VTE.

If during treatment patient develops VTE or pulmonary embolism, it should be managed with doseinterruption, reduction or treatment discontinuation (see Table 1 in section 4.2).

Pneumonitis/ILD can occur with binimetinib. Treatment with binimetinib should be withheld inpatients with suspected pneumonitis or ILD, including patients presenting new or progressivepulmonary symptoms or findings such as cough, dyspnoea, hypoxia, reticular opacities or pulmonaryinfiltrates (see Table 1 in section 4.2). Binimetinib should be permanently discontinued in patientsdiagnosed with treatment related pneumonitis or ILD.

New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with

BRAF inhibitors and can occur when binimetinib is administered in combination with encorafenib(see section 4.8).

Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) includingkerathoacanthoma has been observed in patients treated with binimetinib when used in combinationwith encorafenib.

Dermatologic evaluations should be performed prior to initiation of therapy with binimetinib incombination with encorafenib, every 2 months while on therapy and for up to 6 months followingdiscontinuation of the combination. Suspicious skin lesions should be managed with dermatologicalexcision and dermatopathologic evaluation. Patients should be instructed to immediately inform theirphysicians if new skin lesions develop. Binimetinib and encorafenib should be continued without anydose modifications.

Based on its mechanism of action, encorafenib may promote malignancies associated with activationof RAS through mutation or other mechanisms. Patients receiving binimetinib in combination withencorafenib 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 toinitiation, during and at the end of treatment as clinically appropriate.

Permanent discontinuation of binimetinib and encorafenib should be considered in patients whodevelops RAS mutation-positive non-cutaneous malignancies. Benefits and risks should be carefullyconsidered before administering binimetinib in combination with encorafenib to patients with a prioror concurrent cancer associated with RAS mutation.

The occurrence of TLS, which may be fatal, has been associated with the use of binimetinib inassociation with encorafenib (see section 4.8). Risk factors for TLS include high tumour burden, pre-existing 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 can occur with binimetinib (seesection 4.8). Liver laboratory values should be monitored before initiation of binimetinib andencorafenib and at least monthly during the 6 first months of treatment, and then as clinicallyindicated. Liver laboratory abnormalities should be managed with dose interruption, reduction ortreatment discontinuation (see Table 1 in section 4.2).

Liver metabolism mainly via glucuronidation is the primary route of elimination of binimetinib (seesection 5.2). As encorafenib is not recommended in patients with moderate (Child Pugh B) and severehepatic impairment (Child Pugh C), administration of binimetinib is not recommended in these patients(see sections 4.2 and 5.2).

Mektovi contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicinal product.

Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. The extent of druginteractions mediated by UGT1A1 is unlikely to be clinically relevant (see section 5.2); however, asthis has not been evaluated in a formal clinical study, UGT1A1 inducers (such as rifampicin andphenobarbital) and inhibitors (such as indinavir, atazanavir, sorafenib) should be co-administered withcaution.

While encorafenib is a relatively potent reversible inhibitor of UGT1A1, no differences in binimetinibexposure have been observed clinically when binimetinib is co-administered with encorafenib (seesection 5.2).

Inducers of CYP1A2 enzymes (such as carbamazepine and rifampicin) and inducers of Pgp transport(such as Saint John's wort or phenytoin) may decrease binimetinib exposure, which could result in adecrease of efficacy.

Binimetinib is a potential inducer of CYP1A2, and caution should be taken when it is used withsensitive substrates (such as duloxetine or theophylline).

Binimetinib is a weak inhibitor of OAT3, and caution should be taken when it is used with sensitivesubstrates (such as pravastatin or ciprofloxacin).

Women of childbearing potential must use effective contraception during treatment with binimetiniband for at least 1 month following the last dose.

There are no data from the use of binimetinb in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). Binimetinib is not recommended during pregnancy and inwomen of childbearing potential not using contraception. If binimetinib is used during pregnancy, or ifthe patient becomes pregnant while taking binimetinib, the patient should be informed of the potentialhazard to the foetus.

It is unknown whether binimetinib or its metabolite are excreted in human milk. A risk to the breastfednewborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feedingor to discontinue Mektovi therapy taking into account the benefit of breast-feeding for the child andthe benefit of therapy for the mother.

There are no data on the effect on fertility in humans for binimetinib.

Binimetinib has minor influence on the ability to drive or use machines. Visual disturbances have beenreported in patients treated with binimetinib during clinical studies. Patients should be advised not todrive or use machines if they experience visual disturbances or any other adverse reaction that mayaffect their ability to drive and use machines (see sections 4.4 and 4.8).

The safety of binimetinib (45 mg orally twice daily) in combination with encorafenib (450 mg orallyonce 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 Combo 450 ISP). In Combo 450 ISP, 274 patients receivedthe 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 received the combination for the treatment of BRAF V600E mutant advanced NSCLC(in one non-randomized Phase II study (ARRAY-818-202)) (see section 5.1).

The most common adverse reactions (> 25 %) occurring in patients treated with binimetinibadministered with encorafenib 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.

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) and not known (cannot be estimated from the availabledata).

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

Table 3: Adverse reactions occurring in patients receiving binimetinib in combination withencorafenib at the recommended dose (n = 372)

System Organ Class Adverse reaction Frequency (All grades)a

Neoplasms benign, Cutaneous squamous cell carcinoma Common

*malignant and unspecified Skin papilloma Common

Basal cell carcinoma* Uncommon

Blood and lymphatic Anaemia Very commonsystem disorders

Immune system disorders Hypersensitivityb Common

Metabolism and nutrition Tumour lysis syndrome Not knowndisorders

Neuropathy peripheral* Very common

Nervous system disorders Dizziness* Very common

Headache* Very common

Dysgeusia Common

Facial paresisc Uncommon

Visual impairment* Very common

Eye disorders RPED* Very common

Uveitis* Common

Cardiac disorders Left ventricular dysfunctiond Common

Haemorrhagee Very common

Vascular disorders Hypertension* Very common

Venous thromboembolismf Common

Abdominal pain* Very common

Diarrhoea* Very common

Vomiting* Very common

Gastrointestinal disorders Nausea Very common

Constipation Very common

Colitisg Common

Pancreatitis* Uncommon

Hyperkeratosis * Very common

Rash * Very common

Dry skin* Very common

Pruritus* Very common

*

Skin and subcutaneous Alopecia Very commontissue disorders Photosensitivity* Common

Dermatitis acneiform* Common

Palmar-plantar erythrodysaesthesia Commonsyndrome (PPES)

Erythema* Common

Panniculitis* Common

Arthralgia* Very common

Musculoskeletal and Myopathy/Muscular disorderh Very commonconnective tissue disorders Back pain* Very common

Pain in extremity Very common

Rhabdomyolysis Uncommon

Renal and urinary Renal failure* Commondisorders

General disorders and Pyrexia* Very commonadministration site Peripheral oedema i Very commonconditions Fatigue* Very common

Blood creatine phosphokinase Very Commonincreased

Transaminase increased* Very Common

Gamma-glutamyl transferase Very Common

Investigations increased*

Blood creatinine increased* Common

Blood alkaline phosphatase increased Common

Amylase increased Common

Lipase increased Common

*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 left ventricular dysfunction, ejection fraction decreased, cardiac failure and ejection fractionabnormale 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 haematuriaf 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 thrombosisg includes colitis, colitis ulcerative, enterocolitis and proctitish includes myalgia, muscular weakness, muscle spasm, muscle injury, myopathy, myositisi includes, but not limited to, fluid retention, peripheral oedema, localised oedema, generalised oedemaand 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).

CuSCC was reported when binimetinib was used in combination with encorafenib (see section 4.8 ofencorafenib SmPC).

In the Combo 450 ISP, RPED was reported in 22.3% (83/372) of patients. RPED was Grade 1(asymptomatic) in 15.6% (58/372) of patients, Grade 2 in 5.1% (19/372) of patients and Grade 3 in1.6 % (6/372) of patients. Most events were reported as retinopathy, retinal detachment, subretinalfluid, macular oedema, and central serous chorioretinopathy and led to dose interruptions or dosemodifications in 3.8% (14/372) of patients. The median time to onset of the first event of RPED (allgrades) was 1.4 month (range 0.0 to 17.5 months).

Visual impairment, including vision blurred and reduced visual acuity, occurred in 23.1% (86/372) ofpatients. Visual impairment was generally reversible.

Uveitis was also reported when binimetinib was used in combination with encorafenib (see section 4.8of encorafenib SmPC).

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.

In the Combo 450 ISP, LVD was reported in 9.4 % (35/372) of patients. Grade 3 events occurred in1.3 % (5/372) of patients. LVD led to treatment discontinuation in 0.8% (3/372) of patients and led todose interruptions or dose reductions in 6.2 % (23/372) of patients.

The median time to first occurrence of LVD (any grade) was 5.2 months (range 0.0 to 25.7 months) inpatients who developed an LVEF below 50 %. The mean LVEF value dropped by 5.3 % in the

Combo 450 ISP, from a mean of 63.3 % at baseline to 58.0 %. LVD was generally reversiblefollowing dose reduction or dose interruption.

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 requiring 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)of patients. Fatal gastric ulcer haemorrhage with multiple organ failure as a concurrent cause of death,occurred in one patient. Cerebral haemorrhage/intracranial haemorrhage occurred in 1.6% (6/372) ofpatients 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.

New onset elevated blood pressure or worsening of pre-existing hypertension were reported in 11.0 %(41/372) of patients treated with the Combo 450 ISP. Hypertension events were reported as Grade 3 in5.1 % (19/372) of patients, including hypertensive crisis (0.3 % (1/372). Hypertension led to doseinterruption or adjustment in 2.2 % (8/372) of patients. Hypertensive adverse reactions requiredadditional therapy in 7.5 % (28/372) of patients.

In the Combo 450 ISP, VTE occurred in 4.8% (18/372) of patients, including 1.9% (7/372) of patientswho developed pulmonary embolism. VTE was reported as Grade 1 or 2 in 4.0 % (15/372) of patientsand Grade 3 or 4 in 0.8 % (3/372) of patients. VTE led to dose interruptions or dose modifications in1.1% (4/372) patients and to additional therapy in 4.6% (17/372) of patients.

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

Dermatologic reactions may occur when binimetinib is used in combination with encorafenib.

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 treatment discontinuation in 0.8%(3/372) of patients and to dose interruption or dose modification in 2.4% (9/372) of patients.

In the Combo 450 ISP, dermatitis acneiform occurred in 4.0% (15/372) of patients. Dermatitisacneiform was reported as Grade 1 or 2 in 3.8% (14/372) of patients and Grade 3 in 0.3% (1/372) ofpatients. No event led to treatment discontinuation. Dose modification was reported in 0.5 % (2/372)of patients.

PPES can occur when binimetinib is used in combination with encorafenib (see section 4.8 ofencorafenib SmPC).

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.

Facial paresis was reported when binimetinib was used in combination with encorafenib (seesection 4.8 of encorafenib SmPC).

In the Combo 450 ISP, mostly mild asymptomatic blood CK elevation was reported in 23.9% (89/372)of patients. The incidence of Grade 3 or 4 adverse reactions was 5.1 % (19/372). The median time toonset of the first event was 2.8 months (range: 0.5 to 26 months).

Rhabdomyolysis was reported in 0.3% (1/372) of patients treated with encorafenib in combinationwith binimetinib. In this patient, rhabdomyolysis was observed with concomitant symptomatic

Grade 4 CK elevation.

Blood creatinine elevation and renal failure occurred when binimetinib was used in combination withencorafenib (see section 4.8 of encorafenib SmPC).

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 incidences of liver laboratoryabnormalities are listed below:

* 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

In the Combo 450 ISP, diarrhoea was observed in 41.7% (155/372) of patients and was Grade 3 or 4 in3.8% (14/372) of patients. Diarrhoea led to dose discontinuation in 0.8% of patients and to doseinterruption or dose modification in 8.1 % of patients. Constipation occurred in 24.7% (92/372) ofpatients 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 in3.0% (11/372) of patients. Vomiting occurred in 31.2% (116/372) of patients with Grade 3 reported in1.9% (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.

Gastrointestinal disorders were typically managed with standard therapy.

In the Combo 450 ISP, anaemia was reported in 23.1 % (86/372) of patients; 7.0% (26/372) of patientshad 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.

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 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 Combo 450 ISP (n = 372), 230 patients (61.8 %) were < 65 years old, 107patients (28.8 %) were 65 -74 years old and 35 patients (9.4 %) were aged > 75. No overall differencesin safety or efficacy were observed between elderly patients (≥ 65) and younger patients exceptdiarrhoea 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.

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.

The highest dose of binimetinib evaluated as single agent in clinical studies was 80 mg administeredorally twice daily and was associated with ocular (chorioretinopathy) and skin toxicities (dermatitisacneiform).

There is no specific treatment of overdose. If overdose occurs, the patient should be treated supportivelywith appropriate monitoring as necessary.

Since binimetinib is highly bound to plasma proteins, haemodialysis is likely to be ineffective in thetreatment of overdose with binimetinib.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EE03

Binimetinib is an ATP-uncompetitive, reversible inhibitor of the kinase activity of mitogen-activatedextracellular signal regulated kinase 1 (MEK1) and MEK2. In cell free system, binimetinib inhibits

MEK1 and MEK2 with the half maximal inhibitory concentration (IC50)’s in the 12-46 nM. MEKproteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, whichpromotes cellular proliferation. In melanoma and other cancers, this pathway is often activated bymutated forms of BRAF which activates MEK. Binimetinib inhibits activation of MEK by BRAF andinhibits MEK kinase activity. Binimetinib inhibits growth of BRAF V600 mutant melanoma cell linesand demonstrates anti-tumour effects in BRAF V600 mutant melanoma animal models.

Binimetinib and encorafenib (a BRAF inhibitor, see section 5.1 of encorafenib SmPC) both inhibit the

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

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

Phase III, randomised (1:1:1) active-controlled, open-label, multicenter 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 binimetinib 45 mg orally twice daily plusencorafenib 450 mg orally daily (Combo 450, n = 192), encorafenib 300 mg orally daily (hereafterreferred to as 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. Randomisationwas stratified by 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 priorimmunotherapy for 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 encorafenib 300 mg and 6.2 months in patients treated with vemurafenib. Themedian relative dose intensity (RDI) for Combo 450 was 99.6 % for binimetinib and 100 % forencorafenib the median 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 4summarises 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 4: Study CMEK162B2301, Part 1: Progression-free survival and confirmed overallresponse results (independent central review)

Encorafenib + Encorafenib Vemurafenibbinimetinibn = 192 n = 194 n = 191(Combo 450) (Enco 300) (Vem)

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 CRor have PD); HR = hazard ratio; NE = not estimable; PFS = progression-free survival; PR = partialresponse; 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 reaction. 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.

The median time to definitive 10 % deterioration in the FACT-M score was not reached in the

Combo 450 arm and was 22.1 months (95 % CI: 15.2, NE) in the vemurafenib arm with a HR for thedifference of 0.46 (95 % CI: 0.29, 0.72). An analysis of time to definitive 10 % deterioration in

EORTC QLQ-C30 score 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 5 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 5: 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 (per BIRC)

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

Mediana, 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 a, 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 advanced Non-small cell lung cancer - Study ARRAY-818-202

The safety and efficacy of binimetinib in combination with encorafenib 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 binimetinib 45 mg orally twice daily andencorafenib 450 mg orally once 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 presented below.

Of the 98 patients enrolled in this study, 59 (60.2%) were treatment naïve. The median age of patientswas 70 years (47-86), 53% were female, 88% were white and 30% had never smoked. 74% had abaseline ECOG performance status of 1 (67.8 % of participants had a baseline PS 1 in the treatmentnaïve population and 82.1% in the previously treated population). All patients had metastatic diseaseof 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 95.4% for binimetinib and 99.2% for encorafenib.

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 6.

Table 6: Study ARRAY-818-202: Efficacy Results

Binimetinib with Encorafenib

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 progressionand death are 23.1 months in treatment naïve patients (14.8; NE) and 12.0 months (6.3; NE) in previously treatedpatients.

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 was 1.1 %(4/363) in the Combo 450 ISP (n = 372), and 2.5 % (5/203) in the encorafenib single agent group ofpatients 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 section 5.1 of encorafenib SmPC).

The European Medicines Agency has waived the obligation to submit the results of studies withbinimetinib in all subsets of the paediatric population in lung cancer (see section 4.2 for informationon paediatric use).

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

After repeat twice-daily dosing concomitantly with encorafenib, steady-state conditions forbinimetinib were reached within 15 days with no major accumulation. The mean (CV %) Cmax,ss was654 ng/mL (34.7 %) and mean AUCss was 2.35 ug.h/mL (28.0 %) in combination with encorafenib asestimated by population PK modelling in patients with unresectable or metastatic BRAF V600 mutantmelanoma. Binimetinib pharmacokinetics have been shown to be approximately dose-linear.

After oral administration, binimetinib is rapidly absorbed with a median Tmax of 1.5 hours. Following asingle oral dose of 45 mg [14C] binimetinib in healthy subjects, at least 50 % of the binimetinib dosewas absorbed. Administration of a single 45 mg dose of binimetinib with a high-fat, high-calorie mealdecreased the maximum binimetinib concentration (Cmax) by 17 %, while the area under theconcentration-time curve (AUC) was unchanged. A drug interaction study in healthy subjectsindicated that the extent of binimetinib exposure is not altered in the presence of a gastric pH-alteringagent (rabeprazole).

Binimetinib is 97.2 % bound to human plasma proteins in vitro. Binimetinib is more distributed inplasma than blood. In humans, the blood-to-plasma ratio is 0.718. Following a single oral dose of45 mg [14C] binimetinib in healthy subjects, the apparent volume of distribution (Vz/F) of binimetinibis 374 L.

Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, the primarybiotransformation pathways of binimetinib observed in humans include glucuronidation,

N-dealkylation, amide hydrolysis, and loss of ethane-diol from the side chain. The maximumcontribution of direct glucuronidation to the clearance of binimetinib was estimated to have been61.2 %. Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, approximately60 % of the circulating radioactivity AUC in plasma was attributable to binimetinib. In vitro, CYP1A2and CYP2C19 catalyse the formation of the active metabolite, which represents less than 20 % of thebinimetinib exposure clinically.

Following a single oral dose of 45 mg [14C] binimetinib in healthy subjects, a mean of 62.3 % of theradioactivity was eliminated in the feces while 31.4 % was eliminated in the urine. In urine, 6.5 % ofthe radioactivity was excreted as binimetinib. The mean (CV %) apparent clearance (CL/F) ofbinimetinib was 28.2 L/h (17.5 %). The median (range) binimetinib terminal half-life (T1/2) was 8.66 h(8.10 to 13.6 h).

Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. In clinical studysub-analysis, however, there was no apparent relationship observed between binimetinib exposure and

UGT1A1 mutation status. In addition, simulations to investigate the effect of 400 mg atazanavir(UGT1A1 inhibitor) on the exposure of 45 mg binimetinib predicted similar binimetinib Cmax in thepresence or absence of atazanavir. Therefore, the extent of drug interactions mediated by UGT1A1 isminimal, and unlikely clinically relevant; however, as this has not been evaluated in a formal clinicalstudy, UGT1A1 inducers or inhibitors should be administered with caution.

In vitro, CYP1A2 and CYP2C19 catalyse the formation of the active metabolite, AR00426032 (M3)by oxidative N-desmethylation.

Binimetinib is a weak reversible inhibitor of CYP1A2 and CYP2C9.

In vitro experiments indicate that binimetinib is a substrate of P-glycoprotein (P-gp) and breast cancerresistance protein (BCRP). Inhibition of P-gp or BCRP is unlikely to result in a clinically importantincrease in binimetinib concentrations as binimetinib exhibits moderate to high passive permeability.

Binimetinib is a weak inhibitor of OAT3. No clinicallly significant drug-drug interactions caused bybinimetinib on other transporters is expected.

Binimetinib is metabolised by UGTs and CYP1A2 and is a substrate for Pgp. Specific inducers ofthese enzymes have not been studied and may result in a loss of efficacy.

Based on a population pharmacokinetic analysis, age or body weight do not have a clinically importanteffect on the systemic exposure of binimetinib in adults.

No clinical data are available in the paediatric population. The safety profile in the paediatricpopulation 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 45 mg BID with the same dose reduction: 30 mg

BID.

* Weighing less than 40 kg: 30 mg BID, based on the simulations at lower doses, no dosereduction is proposed,

Children under 12 years should not be treated with binimetinib.

Based on a population pharmacokinetic (PK) analysis, the PK of binimetinib were similar in males ascompared with females.

There are insufficient data to evaluate potential differences in the exposure of binimetinib by race orethnicity.

As binimetinib is primarily metabolised and eliminated via the liver, patients with moderate to severehepatic impairment may have increased exposure. Results from a dedicated clinical study withbinimetinib only indicate similar exposures in patients with mild impairment (Child-Pugh Class A)and subjects with normal liver function. A two-fold increase in total binimetinib exposure (AUC) wasobserved in patients with moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepaticimpairment (see section 4.2). This increase expends to three fold in both moderate and severe hepaticimpairment when considering unbound binimetinib exposure (see section 4.2).

Binimetinib has not been evaluated in patients with Gilbert’s disease. The main route of hepatictransformation of binimetinib being glucoronidation, the decision for treatement should be made bythe treating physician taking into account the individual benefit-risk.

Binimetinib undergoes minimal renal elimination. Results from a dedicated clinical study showed thatpatients with severe renal impairment (eGFR ≤ 29 mL/min/1.73 m2), had a 29 % increase in exposure(AUCinf), a 21 % increase in Cmax, and a 22 % decrease in CL/F compared to matching healthysubjects. These differences were within the variability observed for these parameters in both cohorts ofthis study (25 % - 49 %) and the variability previously observed in patient clinical studies, hence thesedifferences are unlikely to be clinically relevant.

The effects of renal impairment on the pharmacokinetics of binimetinib in combination withencorafenib have not been evaluated clinically.

Repeated oral administration of binimetinib in rats for up to 6 months was associated with soft tissuemineralisation, gastric mucosal lesions and reversible minimal to mild clinical pathology changes at 7to 12.5 times human therapeutic exposures. In a gastric irritation study in rats, an increased incidenceof superficial mucosal lesions and of hemorrhagic ulcers were observed. In cynomolgus monkeys, oraladministration of binimetinib was associated with gastro-intestinal intolerance, moderate clinicalpathology changes, bone marrow hypercellularity and microscopic findings of gastrointestinalinflammation, reversible at the lowest doses which were below human therapeutic exposures.

Carcinogenic potential of binimetinib was not evaluated. Standard genotixicity studies withbinimetinib were negative.

The potential embryo-foetal effects of binimetinib were evaluated in rats and rabbits. In rats, lowergestational body weight gain and fetal body weights and a decreased number of ossified fetalsternebrae were noted. No effects were noted at 14-times the human therapeutic exposure .

In rabbits, mortality, maternal physical signs of toxicity, lower gestational body weight and abortionwere noted. The number of viable foetuses and foetal body weights were reduced andpost-implantation loss and resorptions were increased. An increased litter incidence of foetalventricular septal defects and pulmonary trunk alterations was noted at the highest doses. No effectswere observed at 3times the human therapeutic exposure.

Fertility studies were not conducted with binimetinib. In repeat-dose toxicity studies, no concern interms of fertility was raised from pathological examination of reproductive organs in rats andmonkeys.

Binimetinib has phototoxic potential in vitro.

A minimal risk for photosensitisation was shown in vivo at an oral dose providing 3.8-fold higherexposure than that achieved with the recommended dose in humans. These data indicate that there isminimal risk for phototoxicity with binimetinib at therapeutic doses in patients.

Lactose monohydrate

Cellulose microcrystalline (E460i)

Silica colloidal anhydrous (E551)

Croscarmellose sodium (E468)

Magnesium stearate (E470b)

Mektovi 15 mg film-coated tablets

Poly(vinyl alcohol) (E1203)

Macrogol 3350 (E1521)

Titanium dioxide (E171)

Talc (E533b)

Iron oxide yellow (E172)

Iron oxide black (E172)

Mektovi 45 mg film-coated tablets

Poly(vinyl alcohol) (E1203)

Macrogol 4000 (E1521)

Calcium carbonate (E170)

Talc (E533b)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Mektovi 15 mg film-coated tablets

PVC/PVDC/Alu blister containing 12 tablets. Each pack contains either 84 or 168 tablets.

Not all pack sizes may be marketed.

Mektovi 45 mg film-coated tablets

PVC/PVDC/Alu blister containing 14 tablets. Each pack contains either 28 or 56 tablets.

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

Mektovi 15 mg film-coated tablets

EU/1/18/1315/001 84 film-coated tablets

EU/1/18/1315/002 168 film-coated tablets

Mektovi 45 mg film-coated tablets

EU/1/18/1315/003 28 film-coated tablets

EU/1/18/1315/004 56 film-coated tablets

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.