European Medicines Agency Validates Pierre Fabre’s Application for Combination of BRAFTOVI® (encorafenib), MEKTOVI® (binimetinib) and cetuximab for the Treatment of BRAFV600E-Mutant Metastatic Colorectal Cancer

Pierre Fabre today announced that the European Medicines Agency (EMA) has validated for review the filing of Type II variation applications for BRAFTOVI ^® (encorafenib) + MEKTOVI ^® (binimetinib) in combination with cetuximab for the treatment of patients with BRAF^V600E -mutant metastatic colorectal cancer (mCRC). Validation of the applications confirms the submission is complete, and the EMA will now begin its review procedure.

“BRAF-mutant mCRC is a devastating cancer, for which there are currently limited treatment options that can prolong the lives of patients. The acceptance of our application by the EMA brings us one step closer to realising our commitment towards advancing care for patients living with difficult-to-treat cancers,” said Jean-Luc Lowinski, CEO of the Pierre Fabre Pharmaceuticals Division. “If approved, BRAFTOVI+MEKTOVI in combination with cetuximab has the potential to be the first chemotherapy-free, targeted regimen for patients with BRAF^V600E -mutant mCRC.”

The application is based on data from the pivotal Phase 3 BEACON CRC trial. The randomised, open-label, global study evaluates the efficacy and safety of BRAFTOVI+MEKTOVI in combination with cetuximab in patients with advanced BRAF^V600E -mutant mCRC whose disease has progressed after one or two prior lines of therapy. This is a first-of-its-kind study, as the trial is designed to test combined BRAF/MEK targeted therapies in individuals with BRAF-mutant mCRC.¹ Expanded interim results from this trial were previously presented during a late-breaking oral session at the 2019 European Society for Medical Oncology (ESMO) Congress and simultaneously published online in the New England Journal of Medicine in September 2019.

The results of the BEACON CRC trial showed significant improvements in overall survival (OS) and objective response rates (ORR) for BRAFTOVI+MEKTOVI in combination with cetuximab and BRAFTOVI in combination with cetuximab, compared with cetuximab plus irinotecan-containing regimens. Both combination regimens demonstrated a safety profile with no unexpected toxicities.²

Patients with BRAF-mutant CRC generally have a poor prognosis with current available treatments. Currently, there are no approved therapies in Europe specifically indicated for this high medical need population.^3–10 BRAF mutations are estimated to occur in approximately 8-12% of patients with mCRC, and V600E is the most common mutation.^11–19

About Colorectal Cancer
Worldwide, colorectal cancer is the third most common type of cancer in men and the second most common in women, with approximately 1.8 million new diagnoses in 2018. Globally in 2018, approximately 881,000 deaths were attributed to colorectal cancer.²⁰ Every year more than 450,000 people in Europe are diagnosed with colorectal cancer and approximately 230,000 will die of their disease.²¹ BRAF mutations are estimated to occur in approximately 8-12% of patients with mCRC and represent a poor prognosis for these patients.^11-18,22 The V600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAF^V600E mutation is more than two times higher than for those with wild-type BRAF.^19,21,23

About BEACON CRC
BEACON CRC is a randomised, open-label, global trial evaluating the efficacy and safety of BRAFTOVI^® (encorafenib) + MEKTOVI^® (binimetinib) in combination with cetuximab in patients with BRAF^V600E -mutant mCRC whose disease has progressed after one or two prior regimens. BEACON CRC is the first and only Phase 3 trial designed to test a BRAF/MEK combination targeted therapy in BRAF^V600E -mutant mCRC. Thirty patients were treated in the safety lead-in and received BRAFTOVI+MEKTOVI in combination with cetuximab (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and cetuximab per label). Of the 30 patients, 29 had a BRAF^V600 mutation. Microsatellite instability high, resulting from defective DNA mismatch repair, was detected in only one patient. As previously announced, BRAFTOVI+MEKTOVI in combination with cetuximab showed an acceptable safety profile that supported initiation of the randomised portion of the trial. The randomised portion of the BEACON CRC trial is designed to assess the efficacy of BRAFTOVI in combination with cetuximab with or without MEKTOVI compared with cetuximab and irinotecan-based therapy. 665 patients were randomised 1:1:1 to receive BRAFTOVI+MEKTOVI in combination with cetuximab, BRAFTOVI in combination with cetuximab or the control arm (irinotecan-based therapy and cetuximab). The study was amended to include an interim analysis of endpoints, including ORR. The primary OS endpoint is a comparison of BRAFTOVI+MEKTOVI in combination with cetuximab with the control arm. Secondary endpoints address efficacy of BRAFTOVI in combination with cetuximab compared with the control arm and compared with BRAFTOVI+MEKTOVI in combination with cetuximab. Other secondary endpoints include progression-free survival, duration of response, safety and tolerability. Health-related quality of life data will also be assessed. The trial is being conducted at over 200 investigational sites in North America, South America, Europe and the Asia-Pacific region. The BEACON CRC trial is being conducted with support from Pierre Fabre, Ono Pharmaceutical Co. Ltd., and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

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 target 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 and others. The combination of BRAFTOVI+MEKTOVI is currently only approved for use in unresectable or metastatic melanoma with a BRAF^V600 mutation. The use of BRAFTOVI+MEKTOVI in combination with cetuximab for the treatment of patients with BRAF^V600E -mutant mCRC is investigational and not approved by the European Commission (EC).

On 20 September 2018, the EC granted marketing authorisation for the combination of BRAFTOVI and MEKTOVI for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF^V600 mutation, as confirmed by a validated test.^24,25 The EC decision is applicable to all 28 European Union member states plus Iceland, Liechtenstein and Norway. BRAFTOVI and MEKTOVI have also received regulatory approval in the United States (U.S.), Australia and Japan. On 27 June 2018, the combination of BRAFTOVI and MEKTOVI was approved by the FDA for the treatment of unresectable or metastatic melanoma with a BRAF^V600E or BRAF^V600K mutation, as detected by an FDA-approved test.^26,27 BRAFTOVI and MEKTOVI are not indicated for treatment of patients with wild-type BRAF melanoma. In Japan, the combination is approved for unresectable melanoma with a BRAF mutation. BRAFTOVI and MEKTOVI have received regulatory approvals in Australia and Switzerland for BRAFTOVI and MEKTOVI for the treatment of unresectable melanoma with a BRAF mutation submitted by Pierre Fabre.

Pfizer has exclusive rights to BRAFTOVI^® and MEKTOVI^® in the U.S. and Canada. Pfizer has granted Ono Pharmaceutical Co. Ltd. exclusive rights to commercialise both products in Japan and South Korea, Medison exclusive rights to commercialise both products in Israel and Pierre Fabre exclusive rights to commercialise both products in all other countries, including Europe, Latin America and Asia (excluding Japan and South Korea).

About Pierre Fabre
With a portfolio representing a continuum of activities spanning from prescription drugs and consumer healthcare products to dermo-cosmetics, Pierre Fabre is the 2^nd largest dermo-cosmetics laboratory in the world, the 2^nd largest private French pharmaceutical group and the market leader in France for products sold over the counter in pharmacies. Its portfolio includes several global brands and franchises among which Eau Thermale Avène, Klorane, Ducray, René Furterer, A-Derma, Galénic, Elancyl, Naturactive, Pierre Fabre Health Care, Pierre Fabre Oral Care, Pierre Fabre Dermatologie and Pierre Fabre Oncologie.

In 2018, Pierre Fabre generated 2.3 billion euros in revenues, of which 64% came from its international business and 61% from its dermo-cosmetics division. Pierre Fabre, which has always been headquartered in the South-West of France, counts about 11,000 employees worldwide, owns subsidiaries and offices in over 40 countries and enjoys distribution agreements in over 130 countries. In 2018, Pierre Fabre dedicated 187 million euros to R&D efforts, split between oncology, dermatology, consumer healthcare and dermo-cosmetics.

Pierre Fabre is 86%-owned by the Pierre Fabre Foundation, a government-recognised public-interest foundation, and secondarily by its own employees through an international employee stock ownership plan.

In 2019, Ecocert Environment assessed the Group’s corporate social and environmental responsibility approach according to the ISO 26000 standard on sustainable development and awarded it the ECOCERT 26000 “Excellence” level.

www.pierre-fabre.com
@PierreFabre

References
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[24] European Medicines Agency. BRAFTOVI^® (encorafenib) Summary of Product Characteristics. Available at: https://www.ema.europa.eu/documents/product-information/braftovi-epar-product-information_en.pdf. Accessed November 2019.
[25] European Medicines Agency. MEKTOVI^® (binimetinib) Summary of Product Characteristics. Available at: https://www.ema.europa.eu/documents/product-information/mektovi-epar-product-information_en.pdf. Accessed November 2019.
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Contact information

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