Pierre Fabre and its partner Array BioPharma announce interim analysis results from the BEACON CRC Trial of encorafenib + binimetinib + cetuximab for the treatment of BRAFV600E-mutant metastatic colorectal cancer

– Encorafenib combinations (encorafenib + binimetinib + cetuximab together = encorafenib Triplet; encorafenib + cetuximab together = encorafenib Doublet) showed statistically significant improvement in OS and ORR versus control –

– Data support potential to be the first chemotherapy-free, targeted regimen for patients with BRAF-mutant mCRC –

– Interim analysis results presented in an oral presentation on 6 July 2019 at the ESMO 21^st World Congress on Gastrointestinal Cancer –

Intended for international media only/not intended for UK- and US-based media

CASTRES, France–(BUSINESS WIRE)–Pierre Fabre today announced interim analysis results from the Phase 3 BEACON CRC trial evaluating the combination of encorafenib, a BRAF inhibitor, binimetinib, a MEK inhibitor, and ERBITUX^® (cetuximab), an anti-EGFR antibody (encorafenib Triplet), in patients with advanced BRAF^V600E-mutant metastatic colorectal cancer (mCRC), following one or two lines of therapy.

Results showed that patients with BRAF-mutant mCRC treated with the encorafenib Triplet combination demonstrated a statistically significant improvement in overall survival (OS) (9.0 months vs 5.4 months, hazard ratio [HR]: 0.52, 95% confidence interval [CI]: 0.39–0.70, p<0.0001) and objective response rate (ORR) (26.1% vs 1.9%, p<0.0001, as assessed by Blinded Independent Central Review [BICR]) compared with cetuximab plus irinotecan-containing regimens (Control). Median progression-free survival (mPFS) for patients treated with the encorafenib Triplet was 4.3 months (HR: 0.38, 95% CI: 0.29–0.49, p<0.0001) compared with 1.5 months observed with the Control arm.

These data, including additional analysis, were presented in an oral presentation on Saturday, 6 July, at the European Society for Medical Oncology (ESMO) 21st World Congress on Gastrointestinal Cancer in Barcelona, Spain.

“Patients with BRAF^V600E-mutant mCRC currently have limited treatment options, and these initial results of the BEACON CRC trial are highly anticipated by the oncology community and for their patients who are desperately seeking effective, new treatment options,” said Josep Tabernero, MD, PhD, BEACON CRC trial lead investigator and director of the Vall d’Hebron Institute of Oncology in Barcelona, Spain. “These results show a substantial improvement in outcomes, compared with available options for these patients. This combination could potentially offer a practice-changing first treatment specifically targeting BRAF mutations.”

The interim analysis also showed an improvement in secondary efficacy endpoints. Patients treated with the encorafenib Doublet 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) and ORR (20.4% vs 1.9%, p<0.0001, per BICR) compared with Control. Furthermore, mPFS for patients treated with the encorafenib Doublet was 4.2 months (HR: 0.40, 95% CI: 0.31–0.52, p<0.0001) versus 1.5 months with Control.

A descriptive comparison of the encorafenib Triplet to the encorafenib Doublet demonstrated a positive trend across endpoints including ORR and OS (HR: 0.79, 95% CI: 0.59-1.06).

The control arm of the BEACON CRC trial was consistent with past reported studies and historical data across efficacy endpoints, underscoring that patients with BRAF-mutant CRC generally have a poor prognosis with current available treatments. Currently there are no European Commission (EC)-approved therapies specifically indicated for this high medical need population.^1–8 BRAF mutations are estimated to occur in up to 12% of patients with mCRC and V600E is the most common mutation.^9,10

The encorafenib Triplet and Doublet were generally well tolerated with no unexpected toxicities. The safety profiles of the encorafenib Triplet and Doublet were consistent with prior reported experiences with each regimen and with effects of MEK, RAF and EGFR therapies. Grade 3 or higher adverse events were seen in 58%, 50% and 61% of patients in the encorafenib Triplet, Doublet and Control arms respectively. Discontinuation of therapy due to adverse events was seen in 7%, 8% and 11% of patients in the Triplet, Doublet and Control arms respectively.

“We are pleased with these positive top-line results from the interim analysis of the BEACON CRC trial. We are gaining a better understanding of the potential of encorafenib and binimetinib in combination with cetuximab for patients with BRAF-mutant mCRC,” said Jean-Luc Lowinski, CEO of the Pierre Fabre Pharmaceuticals Division. “These data, showing a 48% risk reduction of death compared with the Control arm, add to the growing body of clinical evidence supporting the encorafenib Triplet as a much-needed new standard of care for these patients.”

Data presented included primary and secondary endpoints, waterfall plots describing tumour reduction, subgroup analyses and exploratory analyses comparing overall survival of the encorafenib Triplet and encorafenib Doublet in a subset of patients with mature follow-up, including the first 331 randomised patients, as well as safety and tolerability.

In March 2019, the National Comprehensive Cancer Network^® (NCCN) updated its Clinical Practice Guidelines in Oncology for Colon and Rectal Cancer to include encorafenib in combination with binimetinib and an anti-EGFR antibody as a Category 2A treatment for patients with BRAF^V600E-mutant mCRC, after failure of one or two prior lines of therapy for metastatic disease. The NCCN based its recommendation on data from the safety lead-in of the BEACON CRC trial.¹¹

The use of encorafenib, binimetinib and cetuximab for the treatment of patients with BRAF^V600E-mutant mCRC is investigational and not approved by the EC. Pierre Fabre will work with the necessary regulatory authorities to potentially give patients access to this new targeted therapy combination.

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.¹² Every year more than 450,000 people in Europe are diagnosed with colorectal cancer and approximately 230,000 will die of their disease.¹³ BRAF mutations are estimated to occur in up to 12% of patients with mCRC and represent a poor prognosis for these patients.^9,14,15 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.^10,13,16 Several irinotecan and cetuximab-containing regimens, similar to the BEACON CRC control arm, have established observed historical published benchmarks in patients with BRAF^V600E-mutant mCRC, whose disease has progressed after one or two prior lines of therapy. These benchmarks include ORR of 4% to 8%, median PFS of 2 to 3 months and median OS of 4 to 6 months.^2,5,17

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 triplet combination (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, 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 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 triplet combination, doublet combination (encorafenib and 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 triplet combination with 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. 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.

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. Encorafenib and binimetinib have also received regulatory approval in Japan. The Swiss Medicines Agency (Swissmedic) is currently reviewing the Marketing Authorisation Applications for encorafenib and binimetinib submitted by Pierre Fabre.

In Japan, the combination is approved for unresectable melanoma with a BRAF mutation.

Array has exclusive rights to encorafenib and binimetinib in the U.S. and Canada. Array 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 in Europe, Latin American 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 47 countries and enjoys distribution agreements in over 130 countries. In 2018, Pierre Fabre dedicated 187 million euros to R&D efforts, split between oncology, consumer healthcare, dermatology 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] Saridaki Z, et al. PLoS One. 2013;8(12):e84604.

[2] Loupakis F, et al. Br J Cancer. 2009;101(4):715–21.

[3] Corcoran RB, et al. Cancer Discov. 2012;2(3):227–35.

[4] Kopetz S, et al. J Clin Oncol. 2017;35(15 suppl):3505.

[5] De Roock W, et al. Lancet Oncol. 2010;11(8):753–62.

[6] Ulivi P, et al. J Transl Med. 2012;10:87.

[7] Peeters M, et al. J Clin Oncol. 2014;32(15 suppl):3568.

[8] Ardekani R, et al. PLoS One. 2012;7(7):e40506.

[9] Tveit KM, et al. J Clin Oncol. 2012;30(15):1755–62.

[10] Sclafani F, et al. Crit Rev Oncol Hematol. 2013;87(1):55–68.

[11] NCCN Clinical Practice Guidelines in Oncology for Colon Cancer. Version 3.2018. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed July 2019.

[12] 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 July 2019.

[13] 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 July 2019.

[14] Sorbye H, et al. PLoS One. 2015;10(6):e0131046.

[15] Vecchione L, et al. Cell. 2016;165(2):317–30.

[16] Safaee Ardekani G, et al. PLoS One. 2012;7(10):e47054.

[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.  https://clinicaltrials.gov/ct2/show/results/NCT02164916. Accessed July 2019. 

[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 July 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 July 2019.

[20] Array BioPharma. BRAFTOVI^® (encorafenib) US Prescribing Information 2018. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210496lbl.pdf. Accessed July 2019.

[21] Array BioPharma. MEKTOVI^® (binimetinib) US Prescribing Information 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210498s001lbl.pdf. Accessed July 2019.

Contacts

Pierre Fabre

Valérie Roucoules

(33) 1 49 10 83 84

[email protected]