PIERRE-FABRE

Pierre Fabre today announced updated safety and efficacy results, including mature overall survival (OS), from the safety lead-in of the Phase 3 BEACON CRC trial evaluating the triplet combination of BRAFTOVI^® (encorafenib), a BRAF inhibitor, MEKTOVI^® (binimetinib), a MEK inhibitor and ERBITUX^® (cetuximab), an anti-EGFR antibody, in patients with BRAF ^V600E -mutant metastatic colorectal cancer (mCRC). The results showed that mature median OS was 15.3 months (95% CI, 9.6–not reached) for patients treated with the triplet combination therapy. These data will be presented on Saturday 19 January at the ASCO 2019 Gastrointestinal Cancers Symposium in San Francisco, California.

Updated median progression-free survival (mPFS) and updated confirmed overall response rate (ORR) results for patients treated with the triplet in the safety lead-in remain the same, as previously reported, with 8 months mPFS (95% CI, 5.6–9.3) and a 48% ORR (95% CI, 29.4–67.5). Among the 17 patients who received only one prior line of therapy, the ORR was 62%.

“We are delighted to see such encouraging data from the BEACON CRC trial, where the mature median overall survival of 15.3 months represents a marked improvement in comparison with the current standards of care for patients with BRAF -mutant mCRC,” said Josep Tabernero, MD, PhD, BEACON CRC trial lead investigator and director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain. “These latest data bring us one step closer to understanding the full potential of this triplet therapy, as a possible new treatment option for these patients.”

A BRAF mutation is present in up to 15% of all patients with mCRC, and V600E is the most common BRAF mutation.^1–5 BRAF ^V600E -mutant mCRC patients have a mortality risk more than double that of mCRC patients without the mutation, and currently there are no European Commission (EC)-approved therapies specifically indicated for this high unmet need population.^3–10

The most common grade 3 or 4 adverse events seen in at least 10% of patients were fatigue (13%), anaemia (10%), increased creatine phosphokinase (10%), increased aspartate aminotransferase (10%) and urinary tract infections (10%). The rate of grade 3 or 4 skin toxicities continued to be lower than generally observed with ERBITUX in mCRC.

“The encouraging OS data from the updated BEACON CRC safety lead-in trial clearly demonstrate the therapeutic potential of the triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment patients with BRAF ^V600E -mutant mCRC, a notoriously difficult-to-treat cancer,” said Frédéric Duchesne, President & CEO of the Pierre Fabre Pharmaceuticals Division. “We are extremely delighted with these recent results, which are in line with our R&D strategy to target those cancers where the greatest patient need exists through an emphasis on biomarker-driven treatments.”

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 detected by a validated test.^11,12 The EC decision is applicable to all 28 European Union member states plus Liechtenstein, Iceland and Norway.

On 7 August 2018, the US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to BRAFTOVI, in combination with MEKTOVI and ERBITUX, for the treatment of patients with BRAF ^V600E -mutant mCRC as detected by an FDA-approved test, after failure of one to two prior lines of therapy for metastatic disease.¹³

The triplet combination of BRAFTOVI, MEKTOVI and ERBITUX for the treatment of patients with BRAF ^V600E -mutant mCRC is investigational and not approved by the EC.

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 1.4 million new diagnoses in 2012. Globally in 2012, approximately 694,000 deaths were attributed to colorectal cancer.¹⁴ In the US alone, an estimated 140,250 patients will be diagnosed with cancer of the colon or rectum in 2018, and approximately 50,000 are estimated to die of their disease.¹⁵ BRAF mutations are estimated to occur in 10% to 15% of patients with mCRC and represent a poor prognosis for these patients.^1–5 The V600 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 .^1,10,16 Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established observed historical published benchmarks in BRAF ^V600E -mutant mCRC patients, whose disease has progressed after one or two prior lines of therapy. These benchmarks include ORR of 4% to 8%, mPFS of 2 to 3 months and median OS of 4 to 6 months.

About BEACON CRC
BEACON CRC is a randomised, open-label, global trial evaluating the efficacy and safety of BRAFTOVI, MEKTOVI and ERBITUX 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 triplet combination (BRAFTOVI 300 mg daily, MEKTOVI 45 mg twice daily and ERBITUX per label). Of the 30 patients, 29 had a BRAF ^V600 mutation. MSI-H, resulting from defective DNA mismatch repair, was detected in only 1 patient. As previously announced, the triplet combination demonstrated good tolerability, supporting 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 ERBITUX with or without MEKTOVI compared with ERBITUX and irinotecan-based therapy. Approximately 615 patients are expected to be randomised 1:1:1 to receive triplet combination, doublet combination (BRAFTOVI and ERBITUX) or the control arm (irinotecan-based therapy and ERBITUX). The study has been amended to include an interim analysis of endpoints including ORR. The primary overall survival endpoint is a comparison of the triplet combination to the control arm. Secondary endpoints address efficacy of the doublet combination compared with the control arm, and the triplet combination compared with the doublet therapy. Other secondary endpoints include PFS, 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. Trial recruitment was completed in 2018. The BEACON CRC trial is being conducted with support from Ono Pharmaceutical Co., Pierre Fabre 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 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 and others.

In Europe, the combination is approved for adult patients with unresectable or metastatic melanoma with a BRAF ^V600 mutation, as detected by a validated test. 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.^18,19 BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. BRAFTOVI and MEKTOVI have also received regulatory approval in Japan. The Swiss Medicines Agency (Swissmedic) is currently reviewing the Marketing Authorization Applications for BRAFTOVI and MEKTOVI submitted by Pierre Fabre.

www.pierre-fabre.com
@PierreFabre

References
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[11] European Medicines Agency. BRAFTOVI^® Summary of Product Characteristics, November 2018. Available at: https://www.ema.europa.eu/documents/product-information/braftovi-epar-product-information_en.pdf . Accessed January 2019.
[12] European Medicines Agency. MEKTOVI^® Summary of Product Characteristics, November 2018. Available at: https://www.ema.europa.eu/documents/product-information/mektovi-epar-product-information_en.pdf . Accessed January 2019.
[13] Array BioPharma. Array Biopharma Receives FDA Breakthrough Therapy Designation For Braftovi™ In Combination With Mektovi^® And Cetuximab For BRAFV600E-Mutant Metastatic Colorectal Cancer. Available at: http://investor.arraybiopharma.com/news-releases/news-release-details/array-biopharma-receives-fda-breakthrough-therapy-designation . Accessed January 2019.
[14] Global Cancer Facts & Figures 3rd Edition. American Cancer Society. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/global-cancer-facts-and-figures/global-cancer-facts-and-figures-3rd-edition.pdf . Accessed January 2019.
[15] Cancer Facts & Figures 2018. American Cancer Society. Available at: https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf . Accessed January 2019.
[16] Safaee Ardekani G, et al. PLoS One . 2012;7(10):e47054.
[17] Seymour MT, et al. Lancet Oncol . 2013;14(8):749–759 (supplementary appendix).
[18] Array BioPharma. BRAFTOVI^® US Prescribing Information 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf . Accessed January 2019.
[19] Array BioPharma. MEKTOVI^® US Prescribing Information 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210498lbl.pdf . Accessed January 2019.

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

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