BRAFTOVI

Encorafenib treatment should be initiated and supervised under the responsibility of a physician experienced in the use of anticancer medicinal products. BRAF mutation testing Before taking encorafenib, patients must have confirmation of BRAF V600E mutation assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose.

If the CE-marked IVD is not available, an alternative validated test should be used. The efficacy and safety of encorafenib have been established only in patients with melanoma tumours expressing BRAF V600E and V600K mutations, colorectal tumours expressing a BRAF V600E mutation or NSCLC expressing a BRAF V600E mutation.

Encorafenib should not be used in patients with wild type BRAF malignant melanoma, wild type BRAF colorectal cancer or wild-type BRAF NSCLC. Posology Melanoma and NSCLC The recommended dose of encorafenib is 450 mg (six 75 mg capsules) once daily, when used in combination with binimetinib.

Colorectal cancer The recommended dose of encorafenib is 300 mg (four 75 mg capsules) once daily, when used in combination with cetuximab. Dose modification Melanoma and NSCLC The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation of encorafenib (see Tables 1, 3 and 4).

2 of binimetinib Summary of Product Characteristics (SmPC). Dose reduction recommendations for encorafenib are presented in Table 1.

Table 1:

Recommended dose modifications for encorafenib when used in combination with binimetinib in melanoma or NSCLC indications Dose level Encorafenib dose when used in combination with binimetinib Starting dose Six 75 mg (450 mg) capsules once daily 1st dose reduction Four 75 mg (300 mg) capsules once daily 2nd dose reduction Three 75 mg (225 mg) capsules once daily Subsequent modification For melanoma indication: There are limited data for dose reduction to 100 mg once daily.

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

For NSCLC indication:

Encorafenib should be permanently discontinued if patient is unable to tolerate 225 mg (three 75 mg capsules) once daily. Administration of encorafenib at a dose of 450 mg once daily as a single agent is not recommended. 2 of binimetinib SmPC) as encorafenib is not well-tolerated at the dose of 450 mg as a single agent.

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

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

2 of binimetinib SmPC for dose modification instructions for binimetinib. Colorectal cancer The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation of encorafenib (see Tables 2, 3 and 4).

2 of cetuximab SmPC. Dose reduction recommendations for encorafenib are presented in Table 2.

Table 2:

Recommended dose modifications for encorafenib when used in combination with cetuximab in CRC indication Dose level Encorafenib dose when used in combination with cetuximab Starting dose Four 75 mg (300 mg) capsules once daily 1st dose reduction Three 75 mg (225 mg) capsules once daily 2nd dose reduction Two 75 mg (150 mg) capsules once daily If encorafenib is permanently discontinued, cetuximab should be discontinued.

If cetuximab is permanently discontinued, encorafenib should be discontinued. Melanoma, colorectal cancer and NSCLC Dose modifications in case of adverse reactions are provided below and in Tables 3 and 4.

For new primary cutaneous malignancies:

No dose modifications are required for encorafenib. For new primary non-cutaneous RAS mutation-positive malignancies: it should be considered to discontinue encorafenib permanently.

Table 3:

Recommended dose modifications for encorafenib when used in combination with binimetinib or in combination with cetuximab for selected adverse reactions Severity of adverse reactiona Encorafenib Cutaneous reactions • Grade 2 Encorafenib should be maintained.

If rash worsens or does not improve within 2 weeks with treatment, encorafenib should be withheld until Grade 0 or 1 and then resumed at the same dose. • Grade 3 Encorafenib should be withheld until improved to Grade 0 or 1 and resumed at the same dose if first occurrence, or resumed at a reduced dose if recurrent Grade 3.

• Grade 4 Encorafenib should be permanently discontinued. Palmar-plantar erythrodysaesthesia syndrome (PPES) • Grade 2 Encorafenib should be maintained and supportive measures such as topical therapy should be instituted. If not improved despite supportive therapy within 2 weeks, encorafenib should be withheld until improved to Grade 0 or 1 and treatment should be resumed at same dose level or at a reduced dose.

• Grade 3 Encorafenib should be withheld, supportive measures such as topical therapy should be instituted, and the patient should be reassessed weekly. Encorafenib should be resumed at same dose level or at a reduced dose level when improved to Grade 0 […]

Summary of safety profile The safety of encorafenib (450 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) has been evaluated in the integrated safety population (ISP) of 372 patients including patients with BRAF V600 mutant unresectable or metastatic melanoma and BRAF V600E mutant advanced NSCLC (hereafter referred to as the Combo 450 ISP).

1). The most common adverse reactions (>25%) occurring in patients treated with encorafenib administered with binimetinib were fatigue, nausea, diarrhoea, vomiting, abdominal pain, myopathy/muscular disorders, and arthralgia. The safety of encorafenib (300 mg orally once daily) in combination with binimetinib (45 mg orally twice daily) was evaluated in 257 patients with BRAF V600 mutant unresectable or metastatic melanoma (hereafter referred to as the Combo 300 population), based on the Phase III study (CMEK162B2301, Part 2).

The most common adverse reactions (>25%) occurring in patients treated with encorafenib 300 mg administered with binimetinib were fatigue, nausea and diarrhoea. The encorafenib single agent (300 mg orally once daily) safety profile is based on data from 217 patients with unresectable or metastatic BRAF V600-mutant melanoma (hereafter referred to as the pooled encorafenib 300 population).

The most common adverse drug reactions (ADRs) (>25%) reported with encorafenib 300 were hyperkeratosis, alopecia, PPES, fatigue, rash, arthralgia, dry skin, nausea, myalgia, headache, vomiting and pruritus. The safety of encorafenib (300 mg orally once daily) in combination with cetuximab (dosed as per its SmPC) was evaluated in 216 patients with BRAF V600E-mutant metastatic colorectal cancer, based on the phase III study ARRAY-818-302.

The most common ADRs (>25%) reported in this population were: fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletal pain, decreased appetite, rash and vomiting. 9 % in patients treated with encorafenib 300 mg in combination with cetuximab.

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

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

Table 5:

Adverse reactions Frequency Encorafenib single agent 300 mg (n = 217) Encorafenib 450 mg in combination with binimetinib (n = 372) Encorafenib 300 mg in combination with cetuximab (n = 216) Neoplasms benign, malignant and unspecified Very common Skin papilloma* Melanocytic naevus Melanocytic naevus Common cuSCC a New Primary cuSCCa Skin papilloma* cuSCCa Skin papilloma* Melanoma* New Primary Melanoma* Uncommon Basal cell carcinoma Basal cell carcinoma* Basal cell carcinoma* Blood and lymphatic system disorders Very common Anaemia Immune system disorders Common Hypersensitivityb Hypersensitivityb Hypersensitivityb Metabolism and nutrition disorders Very common Decreased appetite Decreased appetite Not known Tumour lysis syndrome Psychiatric disorders Very common Insomnia Insomnia Nervous system disorders Very common Headache* Neuropathy peripheral* Dysgeusia* Neuropathy peripheral* Dizziness* Headache* Neuropathy peripheral* Headache* Common Facial paresisc Dysgeusia* Dizziness* Dysgeusia Uncommon Facial paresisc Eye disorders Very common Visual impairment* RPED * Common Uveitis * Uncommon Uveitis* Cardiac disorders Common Supraventricular tachycardiad LVDh Supraventricular tachycardiad Vascular disorders Very common Haemorrhagei Hypertension * Haemorrhagei Common VTEj Gastrointestinal disorders Very common Nausea Vomiting* Constipation Nausea Vomiting* Constipation Abdominal pain* Diarrhoea* Nausea Vomiting* Constipation Abdominal pain* Diarrhoea* Common Colitis k Uncommon Pancreatitis* Pancreatitis* Pancreatitis* Skin and subcutaneous tissue disorders Very common PPES Hyperkeratosis* Rash* Dry skin* Pruritus* Alopecia* Erythema e Skin hyperpigmentation* Hyperkeratosis* Rash* Dry skin* Pruritus* Alopecia* Dermatitis acneiform* Rash* Dry skin* Pruritus* Common Dermatitis acneiform* Skin exfoliationf Photosensitivity* Dermatitis acneiform* PPES Erythema* Panniculitis* Photosensitivity* Skin hyperpigmentation PPES Hyperkeratosis* Alopecia Erythemae Uncommon Skin exfoliationf Musculoskeletal and connective tissue disorders Very common Arthralgia* Myalgiag Pain in extremity Back pain Arthralgia* Myopathy/Muscular disorderl Pain in extremity Back pain* Arthralgia/Musculoskeletal pain* Myopathy/Muscular disorder* Pain in extremity Back pain Common Arthritis * Uncommon Rhabdomyolysis Renal and urinary disorders Common Renal failure * Renal failure* Renal failure* General disorders and administration site conditions Very common Fatigue * Pyrexia* Fatigue* Pyrexia* Peripheral oedemam Fatigue* Pyrexia* Investigations Very common Gamma-glutamyl transferase (GGT) increased* Blood creatine phosphokinase increased Gamma-glutamyl transferase (GGT) increased* Transaminase increased* Common Transaminase increased* Blood creatinine increased* Lipase increased Blood alkaline phosphatase increased Blood creatinine increased* Amylase increased Lipase increased Blood creatinine increased* Transaminase increased* Uncommon Amylase increased Amylase increased Lipase increased *composite terms which included more than one preferred term a […]

Encorafenib is to be given in combination with binimetinib (for patients with BRAF V600 mutant unresectable or metastatic melanoma, and for patients with BRAF V600E mutant advanced NSCLC), or in combination with cetuximab (for patients with BRAF V600E mutant metastatic colorectal cancer).

4 of binimetinib SmPC or cetuximab SmPC. Encorafenib in combination with binimetinib in patients who have progressed on a BRAF inhibitor There are limited data for the use of the combination of encorafenib with binimetinib in patients who have progressed on a prior BRAF inhibitor given for the treatment of unresectable or metastatic melanoma with BRAF V600 mutation.

These data show that the efficacy of the combination would be lower in these patients. 1). Left ventricular dysfunction (LVD) LVD defined as symptomatic or asymptomatic decreases in ejection fraction has been reported when encorafenib is used in combination with binimetinib.

It is recommended that left ventricular ejection fraction (LVEF) is assessed by echocardiogram or multi-gated acquisition (MUGA) scan before initiation of encorafenib and binimetinib, one month after initiation, and then at approximately 3-month intervals or more frequently as clinically indicated, while on treatment.

2 of binimetinib SmPC. The safety of encorafenib in combination with binimetinib has not been established in patients with a baseline LVEF that is either below 50% or below the institutional lower limits of normal. Therefore, in these patients, binimetinib should be used with caution and for any symptomatic left ventricular dysfunction, Grade 3-4 LVEF decrease or for absolute decrease of LVEF from baseline of ≥ 10%, binimetinib and encorafenib should be discontinued and LVEF should be evaluated every 2 weeks until recovery.

8). The risk of haemorrhage may be increased with concomitant use of anticoagulant and antiplatelet therapy. 2) and as clinically indicated. Ocular toxicities Ocular toxicities including uveitis, iritis, and iridocyclitis can occur when encorafenib is administered.

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

2. 2 of binimetinib SmPC for guidance. QT prolongation QT Prolongation has been observed in patients treated with BRAF-inhibitors. A thorough QT study to evaluate the QT prolongation potential of encorafenib has not been conducted. Overall, results suggest that single agent encorafenib has the potential to cause mild increases in heart rate.

1). There are insufficient data to exclude a clinically significant exposure dependent QT prolongation. g. congestive heart failure, bradyarrhythmias) before treatment initiation and during treatment. It is recommended that an electrocardiogram (ECG) is assessed before initiation of encorafenib, one month after initiation, and then at approximately 3-month intervals or more frequently as clinically indicated, while on treatment.

2). 8). Cutaneous malignancies Cutaneous malignancies such as cutaneous squamous cell carcinoma (cuSCC) including kerathoacanthoma have been observed in patients treated with BRAF-inhibitors including encorafenib. 8). Dermatologic evaluations should be performed prior to initiation of therapy with encorafenib, every 2 months while on therapy and for up to 6 months following treatment discontinuation.

Suspicious skin lesions should be managed with dermatological excision and dermatopathologic evaluation. Patients should be instructed to immediately inform their physicians if new skin lesions develop. Encorafenib should be continued without any dose modification.

Non-cutaneous malignancies Based on its mechanism of action, encorafenib may promote malignancies associated with activation of RAS through mutation or other mechanisms. Patients receiving encorafenib should undergo a head and neck examination, chest/abdomen computerised tomography (CT) scan, anal […]

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