PIERRE-FABRE

Pierre Fabre today announced that the European Commission (EC) has granted marketing authorisation for the combination of BRAFTOVI^® (encorafenib) and MEKTOVI^® (binimetinib) for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF ^V600 mutation, as detected by a validated test.^1,2 The EC decision is applicable to all 28 European Union (EU) member states plus Liechtenstein, Iceland and Norway.

"We are extremely pleased that European patients with advanced BRAF -mutant melanoma will now have the combination of BRAFTOVI and MEKTOVI as a new treatment option”, said Frédéric Duchesne, President & CEO of the Pierre Fabre Pharmaceuticals Division. “All of us at Pierre Fabre are driven to make a real difference for patients. Bringing more than 30 years of oncology experience and our heritage in dermatology to our partnership with Array BioPharma, we have been able to harness our expertise in order to help men and women living with this devastating disease. Today’s news inspires us to continue pursuing new innovations that will benefit patients”.

The EC decision, which follows the positive opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) in July, is based on results from the Phase 3 COLUMBUS trial.³ This trial demonstrated that the combination of BRAFTOVI 450 mg once daily and MEKTOVI 45 mg twice daily significantly improved median progression-free survival (PFS), compared with vemurafenib alone 960 mg twice daily (14.9 months versus 7.3 months, respectively: hazard ratio [HR] 0.54, 95% confidence interval [CI], 0.41–0.71; two-sided p<0.0001).^{3 Data published in The Lancet Oncology 4 in September 2018 demonstrated that treatment with BRAFTOVI and MEKTOVI achieved a median overall survival (OS) of 33.6 months, compared with 16.9 months for patients treated with vemurafenib as a monotherapy (HR 0.61, 95% CI, 0.47–0.79; p<0.0001) in the planned analysis of os columbus>4 . The most common adverse reactions (≥25%) occurring in patients treated with BRAFTOVI administered with MEKTOVI at the recommended dose (n=274 based on two Phase II trials and COLUMBUS) were fatigue, nausea, diarrhoea, vomiting, retinal detachment, abdominal pain, arthralgia, increased blood creatine kinase and myalgia.1,2 In the COLUMBUS trial, adverse events leading to discontinuation that were suspected to be related to the study treatment occurred in 6% of patients.3,4}

“The European Commission’s approval is an important advance in improving the prognosis of patients with advanced BRAF -mutant melanoma”, said Professor Reinhard Dummer, University of Zürich, Vice-Chairman of the Department of Dermatology in the University Hospital of Zürich, Switzerland, and investigator of the COLUMBUS study. “Physicians and patients will now have BRAFTOVI and MEKTOVI as an effective and well-tolerated treatment combination option, which has been shown to delay disease progression and potentially prolong patients’ lives”.

Important safety information and recommendations for the use of BRAFTOVI and MEKTOVI are detailed in the Summary of Product Characteristics (SmPC), published in the European public assessment report (EPAR) and available in all official EU languages.
See full SmPC at: http://www.ema.europa.eu .

On 27 June 2018, Pierre Fabre’s partner Array BioPharma, which has exclusive rights for these medicines in the United States (US), announced that the combination of BRAFTOVI and MEKTOVI was approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma with a BRAF ^V600E or BRAF ^V600K mutation, as detected by an FDA-approved test.^5,6 BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma.

About BRAF -mutant Metastatic Melanoma
Melanoma develops when unrepaired DNA damage to skin cells triggers mutations that may lead them to multiply and form malignant tumours. Metastatic melanoma is the most serious and life-threatening type of skin cancer and is associated with low survival rates.^7,8 There are a variety of gene mutations that can lead to metastatic melanoma. The most common genetic mutation in metastatic melanoma is BRAF . There are more than 100,000 new cases of melanoma diagnosed in Europe each year,⁹ approximately half of which have BRAF  mutations, a key target in the treatment of metastatic melanoma.^10–11

About BRAFTOVI (encorafenib) and MEKTOVI (binimetinib)
BRAFTOVI (encorafenib) is an oral small-molecule BRAF kinase inhibitor and MEKTOVI (binimetinib) is an oral small-molecule MEK inhibitor that targets key enzymes in the MAPK signalling pathway (RAS-RAF-MEK-ERK). Inappropriate activation of proteins in this pathway has been shown to occur in many cancers, including melanoma, colorectal cancer, non-small-cell lung cancer, thyroid and others.

Pierre Fabre has exclusive rights to develop and commercialise BRAFTOVI and MEKTOVI worldwide, except in the US and Canada, where Array BioPharma retains exclusive rights; Israel, where Medison has exclusive rights; and in Japan and South Korea, where Ono Pharmaceutical has exclusive rights to commercialise both products.

BRAFTOVI + MEKTOVI Abbreviated EU Prescribing Information
▼These medicinal products are subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of SmPC for how to report adverse reactions.

Name of the medicinal products: BRAFTOVI (encorafenib) 75 mg hard capsules and 50 mg hard capsules. MEKTOVI (binimetinib) 15 mg film-coated tablets.

Clinical particulars:
Therapeutic indications: Encorafenib in combination with binimetinib is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF ^V600 mutation.

Posology and method of administration: Encorafenib treatment in combination with binimetinib should be initiated and supervised under the responsibility of a physician experienced in the use of anticancer medicinal products. Posology: The recommended dose of encorafenib is 450 mg (six 75 mg capsules) once daily, when used in combination with binimetinib. The recommended dose of binimetinib is 45 mg (three 15 mg tablets) twice daily corresponding to a total daily dose of 90 mg approximately 12 hours apart. Dose modification: The management of adverse reactions may require dose reduction, temporary interruption or treatment discontinuation (for complete information, please refer to SmPC 4.2 section). Method of administration: For oral use. The capsules of encorafenib are to be swallowed whole with water. They may be taken with or without food. The concomitant administration of encorafenib with grapefruit juice should be avoided. The tablets of binimitinib are to be swallowed whole with water. They may be taken with or without food.

Contraindications: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 of the BRAFTOVI and MEKTOVI SmPc.

Special warnings and precautions for use: Encorafenib and binimetinib have to be given in combination. Before taking encorafenib in combination with binimetinib, patients must have BRAF^V600 mutation confirmed by a validated test. For complete information on the following special warnings and precautions for use: Patients who have progressed on a BRAF inhibitor, patients with brain metastases. Left ventricular dysfunction, Haemorrhage, ocular toxicities. QT Prolongation, New primary malignancies, Cutaneous and non-cutaneous malignancies, Liver laboratory abnormalities, Hepatic impairment, Renal impairment, CK elevation and rhabdomyolysis, Hypertension, Venous thromboembolism (VTE), Pneumonitis/Interstitial lung disease, Lactose intolerance, please refer to BRAFTOVI and MEKTOVI SmPC 4.4 section.

Interaction with other medicinal products and other forms of interaction: Encorafenib is primarily metabolised by CYP3A4. Therefore, concomitant administration of encorafenib with strong CYP3A4 inhibitors should be avoided. Agents that are CYP3A4 substrates (inhibitor and inducer) should be co-administered with caution. Binimetinib is primarily metabolised through UGT1A1 mediated glucuronidation. Therefore, inducers and inhibitors of UGT1A1 should be co-administered with caution. For complete information, please refer to SmPC, 4.5 section.

Undesirable effects: Summary of safety profile: At the recommended dose (n=274) in patients with metastatic melanoma, the most common adverse reactions (≥ 25%) occurring in patients treated with encorafenib administered with binimetinib were fatigue, nausea, diarrhea, vomiting, retinal detachment, abdominal pain, arthralgia, blood CK increased and myalgia. For complete information, please refer to BRAFTOVI and MEKTOVI SmPC 4.8 section.

For complete information please refer to the full SmPC which can be found at: http://www.ema.europa.eu .

About COLUMBUS
The COLUMBUS trial (NCT01909453) is a two-part, international, randomised, open-label, Phase 3 trial evaluating the efficacy and safety of BRAFTOVI (encorafenib) in combination with MEKTOVI (binimetinib) compared with vemurafenib and encorafenib monotherapy in 921 patients with locally advanced, unresectable or metastatic melanoma with BRAF ^V600 mutation.¹² The primary endpoint of the trial was median progression-free survival (PFS); all secondary efficacy analyses, including the prospectively planned analysis overall survival (OS), are descriptive in nature. More than 200 sites across North America, Europe, South America, Africa, Asia and Australia participated in the COLUMBUS trial.

The EC decision is based on results from the Phase 3 COLUMBUS trial, which demonstrated that the combination improved median PFS, compared with vemurafenib alone (14.9 months versus 7.3 months, respectively: HR 0.54, 95% CI, 0.41–0.71; p<0.001).^{1–3 As presented at ASCO in June 2018, treatment with BRAFTOVI and MEKTOVI achieved a median OS of 33.6 months, compared with 16.9 months for patients treated with vemurafenib as a monotherapy (HR 0.61, 95% CI, 0.47–0.79; p<0.0001) in the planned analysis of os columbus>1–2,4 Adverse events leading to discontinuation that were suspected to be related to the study treatment occurred in 6% of patients.3,4 The most common Grade 3–4 adverse events, seen in more than 5% of patients, were: increased gamma-glutamyltransferase (9%), increased creatine phosphokinase (7%) and hypertension (6%).3,4}

About Pierre Fabre

To find out more Pierre Fabre, please go to www.pierre-fabre.com

References
[1] European Medicines Agency. BRAFTOVI^® (encorafenib) Summary of Product Characteristics.. Available at: http://www.ema.europa.eu . Publication pending (September 2018).
[2] European Medicines Agency. MEKTOVI^® (binimetinib) Summary of Product Characteristics. Available at: http://www.ema.europa.eu . Publication pending (September 2018).
[3] Dummer R, et al. Lancet Oncol 2018;19:603–615.
[4] Dummer R, et al. Lancet Oncol 2018. Available at: https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30497-2/fulltext Accessed September 2018.
[5] Array BioPharma. BRAFTOVI^® US Prescribing Information 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf . Accessed September 2018.
[6] Array BioPharma. MEKTOVI^® US Prescribing Information 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf . Accessed September 2018.
[7] American Cancer Society. Melanoma Skin Cancer. Available at: https://www.cancer.org/cancer/melanoma-skin-cancer.html . Accessed September 2018.
[8] National Cancer Institute. Survival by Stage. Available at: https://seer.cancer.gov/statfacts/html/melan.html . Accessed September 2018.
[9] Melanoma Patient Network Europe. Melanoma – The Facts. Available at: http://www.melanomapatientnetworkeu.org/melanoma.html . Accessed September 2018.
[10] Klein O, et al. Eur J Cancer 2013;49:1073–1079.
[11] American Cancer Society. What Causes Melanoma Skin Cancer? 2016. Available at: https://www.cancer.org/cancer/melanoma-skin-cancer/causes-risks-prevention/what-causes.html. Accessed September 2018 .
[12] Clinical Trials.gov. Study Comparing Combination of LGX818 Plus MEK162 Versus Vemurafenib and LGX818 Monotherapy in BRAF Mutant Melanoma (COLUMBUS). Available at: https://clinicaltrials.gov/ct2/show/NCT01909453 . Accessed September 2018.

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Contact:

Pierre Fabre Valérie Roucoules, (33) 1 49 10 83 84 valerie.roucoules@pierre-fabre.com