Press release

Pierre Fabre receives European approval for BRAFTOVI® (encorafenib)

3 June 2020

Pierre Fabre receives European approval for BRAFTOVI® (encorafenib) in combination with cetuximab for the treatment of adult patients with BRAFV600E-mutant metastatic colorectal cancer 

 

  • European approval is based on the Phase 3 BEACON CRC trial that demonstrated a significant improvement in overall survival of patients treated with BRAFTOVI in combination with cetuximab
  • BRAFTOVI in combination with cetuximab is the first and only targeted regimen approved in Europe specifically for patients with BRAFV600E-mutant metastatic colorectal cancer

Pierre Fabre today announced that the European Commission (EC) has approved BRAFTOVI® (encorafenib) in combination with cetuximab (marketed as Erbitux®) for the treatment of adult patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) who have received prior systemic therapy.1 This approval is based on data from the Phase 3 BEACON CRC trial.1,2 The EC decision is applicable to all 27 EU member states plus Iceland, Liechtenstein, Norway and the United Kingdom.3

This approval is truly great news and much needed for patients with BRAFV600E-mutant mCRC and for physicians treating this devastating cancer, as until now, there has been no EC-approved therapies specifically indicated for this high-medical-need population. The new encorafenib and cetuximab combination regimen will now change the way we treat these patients, with the possibility of delaying disease progression and prolonging their lives.

Josep Tabernero

MD, PhD, BEACON CRC trial lead investigator and director of the Vall d’Hebron Institute of Oncology in Barcelona

The EC decision, which follows the positive opinion by the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) on 30 April 2020, is based on available results from the pivotal Phase 3 BEACON CRC trial,2 the first and only randomised Phase 3 trial designed to test a BRAF combination targeted therapy in BRAFV600E-mutant mCRC. The data showed that BRAFTOVI in combination with cetuximab significantly improved overall survival (OS) in patients with BRAFV600E-mutant mCRC (median 9.3 months vs 5.9 months; hazard ratio: 0.61; 95% confidence interval: 0.48–0.77; p<0.0001) and reduced the risk of death by 39%, compared with the cetuximab plus irinotecan-containing regimen (control) arm. Furthermore, the data also reported an improved objective response rate (ORR; 20% vs 2%; p<0.0001; per assessment by blinded independent central review [BICR]), compared with the control arm. BRAFTOVI plus cetuximab demonstrated a well-tolerated safety profile with no unexpected toxicities in the trial. The most common adverse drug reactions (>25%), observed in the BEACON CRC trial, were fatigue, nausea, diarrhoea, dermatitis acneiform, abdominal pain, arthralgia/musculoskeletal pain, decreased appetite, rash and vomiting.1

We are extremely pleased that patients will now have access, for the very first time, to a targeted therapy specifically for BRAFV600E-mutant mCRC. Today’s approval is a testament to our long-term commitment to advancing care for patients living with difficult-to-treat cancers and to delivering precision medicine. We will now work tirelessly to bring this new treatment option to patients in Europe, as quickly as possible.

Jean-Luc Lowinski

CEO of Pierre Fabre Medical Care Business Unit

BRAF mutations are estimated to occur in approximately 8–12% of patients with mCRC, and V600E is the most common mutation.4–12 Patients with mCRC who have BRAFV600E-mutant tumours generally have a poor prognosis representing a high unmet medical need.13 Currently, there are no other approved targeted treatments in Europe specifically indicated for this patient population.14,15 

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

On 8 April 2020, Pierre Fabre’s partner Pfizer, which has exclusive rights to BRAFTOVI in the USA and Canada, announced that BRAFTOVI, in combination with cetuximab, was approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with mCRC with a BRAFV600E mutation, as detected by an FDA-approved test, after prior therapy.16 Additional submissions of the BEACON data to health authorities around the world are planned.
 

 

About Colorectal CancerWorldwide, colorectal cancer (CRC) 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 CRC.17 Every year more than 450,000 people in Europe are diagnosed with CRC and approximately 230,000 will die of their disease.18 BRAF mutations are estimated to occur in approximately 8–12% of patients with mCRC and represent a poor prognosis for these patients.4–12 The V600E mutation is the most common BRAF mutation and the risk of mortality in CRC patients with the BRAFV600E mutation is more than two times higher than for those with wild-type BRAF.18–20 

About BEACON CRC

BEACON CRC is a randomised, open-label, global Phase 3 trial evaluating the efficacy and safety of BRAFTOVI (encorafenib) ± binimetinib in combination with cetuximab in patients with BRAFV600E-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 combination targeted therapy in BRAFV600E-mutant mCRC. A total of 665 patients were randomised 1:1:1 to one of the following treatment arms:

  • BRAFTOVI 300 mg orally once daily in combination with cetuximab (BRAFTOVI/cetuximab arm)
  • BRAFTOVI 300 mg orally once daily in combination with cetuximab and binimetinib
  • Irinotecan with cetuximab or FOLFIRI with cetuximab (control arm)

The study was amended to include an interim analysis of endpoints, including ORR. The primary OS endpoint is a comparison of BRAFTOVI+binimetinib in combination with cetuximab with the control arm. Secondary endpoints address the efficacy (OS) of BRAFTOVI in combination with cetuximab, compared with the control arm and compared with BRAFTOVI+binimetinib in combination with cetuximab. Other secondary endpoints include progression-free survival, duration of response, safety and tolerability. 

The trial was conducted at over 200 investigational sites in North America, South America, Europe and the Asia Pacific region. The BEACON CRC trial was conducted with support from Ono Pharmaceutical Co. Ltd., Pierre Fabre, Pfizer and Merck KGaA, Darmstadt, Germany (support is for sites outside of North America).

About BRAFTOVI® (encorafenib) 

BRAFTOVI (encorafenib) is an oral small-molecule BRAF kinase inhibitor that targets a key enzyme 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 and others. 

On 20 September 2018, the EC granted marketing authorisations for BRAFTOVI and MEKTOVI to be used in combination for the treatment of adult patients with unresectable or metastatic melanoma with a BRAFV600 mutation.1,21 The EC decision is applicable to all 27 EU member states as well as Iceland, Liechtenstein, Norway and the United Kingdom. BRAFTOVI and MEKTOVI have also received regulatory approvals in the USA, Australia, Japan, Argentina and Switzerland. 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 BRAFV600E or BRAFV600K mutation, as detected by an FDA-approved test.22,23 BRAFTOVI and MEKTOVI are not indicated for treatment of patients with wild-type BRAF melanoma.  

On 8 April 2020, the US FDA granted the approval for BRAFTOVI, in combination with cetuximab, for the treatment of adult patients with mCRC with a BRAFV600E mutation, as detected by an FDA-approved test, after prior therapy. BRAFTOVI is not indicated for treatment of patients with wild-type BRAF CRC.16 

Pfizer has exclusive rights to BRAFTOVI in the USA and Canada. Pfizer has granted Ono Pharmaceutical Co. Ltd. exclusive rights to commercialise BRAFTOVI in Japan and South Korea; Medison exclusive rights to commercialise BRAFTOVI in Israel; and Pierre Fabre exclusive rights to commercialise BRAFTOVI in all other countries in Africa, Asia (excluding Japan and South Korea), Europe, and Latin America.
 

Références 
[1] European Medicines Agency. BRAFTOVI® (encorafenib) Summary of Product Characteristics.. Available at: http://www.ema.europa.eu. En attente de publication (juin 2020).
[2] Kopetz S, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E–mutated colorectal cancer. N Engl J Med. 2019;381:1632–43.
[3] European Medicines Agency. Brexit: the United Kingdom’s Withdrawal from the European Union. Available at: https://www.ema.europa.eu/en/about-us/brexit-united-kingdoms-withdrawal-european-union#transition-period-section. Accessed May 2020. 
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[16] Pfizer. U.S. FDA Approves Braftovi® (encorafenib) in Combination with Cetuximab for the Treatment of BRAFV600E-Mutant Metastatic Colorectal Cancer (CRC) After Prior Therapy. Available at: https://investors.pfizer.com/investor-news/press-release-details/2020/US-FDA-Approves-BRAFTOVI-Encorafenib-in-Combination-with-Cetuximab-for-the-Treatment-of-BRAFV600E-Mutant-Metastatic-Colorectal-Cancer-CRC-After-Prior-Therapy/default.aspx. Accessed May 2020.
[17] The Global Cancer Observatory, 2018. International Agency for Research on Cancer, World Health Organization. Available at: https://gco.iarc.fr/today/online-analysis-multi-bars. Accessed May 2020.
[18] EuropaColon. Colorectal Cancer in Europe: A Framework for Improving Outcomes for Patients. Available at: https://webgate.ec.europa.eu/chafea_pdb/assets/files/pdb/20124301/20124301_d04-00_en_ps_ecwhitepaper.pdf. Accessed May 2020.
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[20] Safaee Ardekani G, et al. PLoS One. 2012;7:e47054.
[21] 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 May 2020.
[22] Array BioPharma. BRAFTOVI® (encorafenib) US Prescribing Information 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf. Accessed May 2020.
[23] Array BioPharma. MEKTOVI® (binimetinib) US Prescribing Information 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210498s001lbl.pdf. Accessed May 2020.