Pierre Fabre and its partner Pfizer present interim analysis results from Phase 3 BEACON CRC trial of encorafenib, binimetinib and cetuximab for the treatment of BRAFV600E-mutant metastatic colorectal cancer

Pierre Fabre today announced detailed results from the interim analysis of the Phase 3 BEACON CRC trial evaluating the combination of encorafenib, binimetinib, and cetuximab, in patients with advanced BRAF^V600E -mutant metastatic colorectal cancer (mCRC), following one or two lines of therapy. The results show statistically significant improvements in overall survival (OS) and objective response rates (ORR) for encorafenib+binimetinib+cetuximab and encorafenib+cetuximab, compared with cetuximab plus irinotecan-containing regimens (Control), and provide analysis of the efficacy and safety of encorafenib+binimetinib+cetuximab compared with encorafenib+cetuximab. These data will be presented today during a late-breaking oral session at the 2019 European Society for Medical Oncology (ESMO) Congress in Barcelona, Spain, and simultaneously published online in The New England Journal of Medicine (NEJM). The use of encorafenib, binimetinib and cetuximab for the treatment of patients with BRAF^V600E -mutant mCRC is investigational and not approved by the European Medicines Agency.

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As previously announced at ESMO 21st World Congress on Gastrointestinal Cancer (ESMO GI), encorafenib+binimetinib+cetuximab showed a median OS of 9.0 months for patients treated with this combination, compared with 5.4 months for the Control arm (hazard ratio (HR): 0.52; 95% confidence interval (CI): 0.39-0.70; p<0.0001). The encorafenib+binimetinib+cetuximab combination also demonstrated a statistically significantly improved ORR of 26% (95% CI: 18%, 35%) compared with 2% (95% CI: 0%, 7%) for the Control arm (p<0.0001).

“These interim findings from the BEACON trial presented at ESMO and published in NEJM, demonstrate the potential efficacy and tolerability that encorafenib and binimetinib in combination with cetuximab may offer to patients with mCRC with a BRAF^V600E mutation,” said Josep Tabernero, MD, PhD, the BEACON CRC trial lead investigator and director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain. “We look forward to reviewing the results in detail, as patients with this mutation currently have a challenging prognosis and limited treatment options.”

The study also showed improvements in secondary efficacy endpoints. As previously announced, the encorafenib+cetuximab combination demonstrated a statistically significant improvement in OS (median 8.4 months vs. 5.4 months; HR: 0.60; 95% CI: 0.45-0.79; p=0.0003), compared with the Control arm. Additional analysis showed depth of responses in favour of encorafenib+binimetinib+cetuximab.

“The interim data from the BEACON CRC trial are encouraging, as they illustrate the impact of encorafenib and binimetinib in combination with cetuximab as potentially the first chemotherapy-free, targeted regimen for patients with BRAF^V600E -mutant mCRC,” said Jean-Luc Lowinski, CEO of the Pierre Fabre Pharmaceuticals Division. “BRAF-mutant mCRC is a devastating cancer, reinforcing the need for effective treatments. These data demonstrate our committment to advance care for patients living with challenging cancers.”

Further, the data provides additional details on the primary and secondary endpoints, including observations of response rates by number of lines of prior therapy, as well as a descriptive analysis of OS comparing the encorafenib+binimetinib+cetuximab arm with encorafenib+cetuximab arm.

The BEACON CRC study was not powered to compare the two experimental arms directly and such a comparison is further limited by the interim nature of the analysis. In the data being presented at ESMO, results of the descriptive analysis of survival comparing encorafenib+binimetinib+cetuximab with encorafenib+binimetinib favoured the encorafenib+binimetinib+cetuximab study arm.

As previously reported at ESMO GI, the encorafenib+binimetinib+cetuximab and the encorafenib+cetuximab study arms showed no unexpected toxicities. Grade 3 or higher adverse events (AEs) were seen in 58%, 50% and 61% of patients in the encorafenib+binimetinib+cetuximab, encorafenib+cetuximab and Control arms, respectively. Discontinuation of therapy due to adverse events was seen in 7%, 8% and 11% of patients in the encorafenib+binimetinib+cetuximab, encorafenib+cetuximab and Control arms, respectively. The most common Grade 3 or higher AEs seen in patients treated with encorafenib+binimetinib+cetuximab were diarrhoea (10% vs 2% in the encorafenib+cetuximab arm and 10% in the Control arm), abdominal pain (6% vs 2% in the encorafenib+cetuximab arm and 5% in the Control arm) and nausea (5% vs <1% in the encorafenib+cetuximab arm and 1% in the Control arm).

Details for the late-breaking oral presentation are below:

Title:		Encorafenib plus Cetuximab With or Without Binimetinib for BRAFV600E –Mutant Metastatic Colorectal Cancer: Expanded Results from a Randomized, 3-Arm, Phase III Study vs. the Choice of Either Irinotecan or FOLFIRI plus Cetuximab (BEACON CRC)
Presenter:		Josep Tabernero
Abstract:		LBA32
Session:		Proffered Paper 2 – Gastrointestinal tumours, colorectal
Date/Time:		Monday, 30 September, 08:00–08:45 Central European Summer Time (CEST)
Location:		Barcelona Auditorium (Hall 2)

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.¹ Every year more than 450,000 people in Europe are diagnosed with colorectal cancer and approximately 230,000 will die of their disease.² BRAF mutations are estimated to occur in approximately 8-15% of patients with mCRC and represent a poor prognosis for these patients.^3-12 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.^2,13,14

About BEACON CRC

BEACON CRC is a randomised, open-label, global trial evaluating the efficacy and safety of encorafenib, binimetinib and 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 the combination encorafenib+binimetinib+cetuximab (encorafenib 300 mg daily, binimetinib 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, encorafenib+binimetinib+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 encorafenib in combination with cetuximab with or without binimetinib compared with cetuximab and irinotecan-based therapy. 665 patients were randomised 1:1:1 to receive the encorafenib+binimetinib+cetuximab, encorafenib+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 overall survival endpoint is a comparison of the encorafenib+binimetinib+cetuximab combination with the control arm. Secondary endpoints address efficacy of encorafenib+cetuximab compared with the control arm, and the encorafenib+binimetinib+cetuximab arm compared with the encorafenib+cetuximab arm. 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 encorafenib and binimetinib

Encorafenib is an oral small-molecule BRAF kinase inhibitor and 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 encorafenib and binimetinib is currently only approved for use in metastatic melanoma with a BRAF^V600 mutation. The use of encorafenib, binimetinib and cetuximab for the treatment of patients with BRAF^V600E -mutant mCRC is investigational and not approved by the European Commission

On 20 September 2018, the EC 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.^18,19 The EC decision is applicable to all 28 European Union member states plus Iceland, Liechtenstein and Norway. Encorafenib and binimetinib have also received regulatory approval in the United States (U.S.), Australia and Japan. On 27 June 2018, Pierre Fabre’s partner Array BioPharma, which has exclusive rights for these medicines in the U.S., announced that the combination of encorafenib and binimetinib 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.^20,21 Encorafenib is not indicated for treatment of patients with wild-type BRAF melanoma. In Japan, the combination is approved for unresectable melanoma with a BRAF mutation. encorafenib and binimetinib have received regulatory approval in Australia and the Swiss Medicines Agency (Swissmedic) is currently reviewing the Marketing Authorization Applications for BRAFTOVI and MEKTOVI 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 commercialize both products in Japan and South Korea, Medison exclusive rights to commercialize both products in Israel and Pierre Fabre exclusive rights to commercialize 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

[1] 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 September 2019.
[2] Colorectal Cancer in Europe: A Framework for Improving Outcomes for Patients. EuropaColon. Available at: https://webgate.ec.europa.eu/chafea_pdb/assets/files/pdb/20124301/20124301_d04-00_en_ps_ecwhitepaper.pdf. Accessed September 2019.
[3] Tveit KM, et al. J Clin Oncol. 2012;30(15):1755–62.
[4] Sorbye H, et al. PLoS One. 2015;10(6):e0131046.
[5] Vecchione L, et al. Cell. 2016;165(2):317–30.
[6] Maughan TS, et al. Lancet. 2011;377:2103–14.
[7] Souglakos J, et al. Br J Cancer. 2009;101:465–72.
[8] Richman SD, et al. J Clin Oncol. 2009;27:5931–7.
[9] Tran B, et al. Cancer. 2011;117:4623–32.
[10] Yokota T, et al. Br J Cancer. 2011;104:856–62.
[11] Tie J, et al. Int J Cancer. 2011;128:2075–84.
[12] Loupakis F, et al. Br J Cancer. 2009;101:715.
[13] Sclafani F, et al. Crit Rev Oncol Hematol. 2013;87(1):55–68.
[14] Safaee Ardekani G, et al. PLoS One. 2012;7(10):e47054.
[15] Loupakis F, et al. Br J Cancer. 2009;101(4):715–21.
[16] De Roock W, et al. Lancet Oncol. 2010;11(8):753–62.
[17] Clinicaltrials.gov. US National Library of Medicine. S1406 phase II study of irinotecan and cetuximab with or without vemurafenib in BRAF mutant metastatic colorectal cancer.
[18] 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 September 2019.
[19] 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 September 2019.
[20] Array BioPharma. BRAFTOVI^® (encorafenib) US Prescribing Information 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf. Accessed September 2019.
[21] Array BioPharma. MEKTOVI^® (binimetinib) US Prescribing Information 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210498s001lbl.pdf. Accessed September 2019.

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Contact information

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