Merck Partners with Array BioPharma and Pierre Fabre to Initiate BRAF-mutant CRC Phase III Trial

PR64681

DARMSTADT, Germany, June 4, 2016 /PRNewswire=KYODO JBN/ --

                 Not intended for UK- or US-based media

    - BEACON CRC trial will assess efficacy of combination regime Erbitux(R)

(cetuximab), binimetinib and encorafenib in BRAF-mutant metastatic colorectal

cancer (mCRC)

    Merck, a leading science and technology company, jointly announced with

Array BioPharma Inc. and Pierre Fabre, the initiation of a prospective,

randomized, global Phase III clinical trial of BRAF-mutant metastatic

colorectal cancer (mCRC), investigating a new combination of Erbitux(R)

(cetuximab), a standard-of-care treatment for RAS wild-type mCRC,  plus

encorafenib with or without binimetinib. The BEACON CRC (Binimetinib,

Encorafenib And Cetuximab Combined to treat BRAF-mutant Colorectal Cancer)

trial will assess the efficacy and safety of these two novel combinations in

patients with BRAF-mutant tumors, compared with investigator's choice of

Erbitux plus irinotecan or Erbitux plus FOLFIRI.

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    "This trial looking specifically at BRAF-mutated tumors exemplifies our

ongoing commitment to exploring Erbitux as an 'anchor' treatment in combination

with other therapies," said Luciano Rossetti, Executive Vice President, Head of

Global Research & Development at the biopharma business of Merck. "There is a

clear need for effective treatment regimens for the BRAF-mutant mCRC

population; the results of the BEACON CRC trial will hopefully provide us with

the prospective information we need to take us one step closer to achieving

that goal."

    Colorectal cancer (CRC) is one of the most challenging types of cancers,

with an estimated 10 percent of CRCs associated with an oncogenic mutation in

the BRAF gene.[1] Studies have observed that patients with BRAF-mutant mCRC

have shorter progression-free survival and overall survival.[2] Additional

treatment regimens are needed that can effectively combat these cancers.

    "Historical studies suggest that BRAF-mutant colorectal cancer patients who

have progressed after first-line systemic treatment have an estimated median

overall survival of less than 6 months," said Dr. Josep Tabernero, MD, PhD,

Head of Medical Oncology and the Institute of Oncology at Vall d'Hebron

University Hospital. "The BEACON CRC trial will explore innovative combinations

which have the potential to offer new treatment options to these patients, who

currently have few good choices remaining."

    "We are pleased to join Merck on this innovative trial for patients with

BRAF-mutant metastatic colorectal cancer," said Victor Sandor, MD, Chief

Medical Officer of Array BioPharma. "The encouraging results from our Phase II

study suggest that concurrent inhibition of EGFR and enzymes in the MAPK

signaling pathway has the potential to improve outcomes for this patient

population, and we look forward to the results of this further investigation."

    Approximately 650 patients are expected to be enrolled by 2018 and, after a

lead-in period to assess the safety and tolerability of Erbitux plus

encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor), will be

randomized to receive one of the two novel combinations, or investigator's

choice. The primary endpoint of the trial is overall survival. Key secondary

endpoints include progression-free survival, objective response rate, duration

of response, safety and tolerability. The trial will also assess health-related

quality of life.

    References

    1) Barras D. Biomark Cancer. 2015;7(Suppl 1):9-12.

    2) Saridaki Z. PLoS One. 2013 Dec 18;8(12):e84604. doi: 10.1371.

    3) Vaughn CP et al. Genes Chromosomes Cancer 2011;50(5):307-12.

    4) Bokemeyer C et al. J Clin Oncol 2014;32:(Suppl 4): abstr 3505.

    5) Van Cutsem E et al. J Clin Oncol 2015;33(7):692-700.

    6) Stintzing S et al. Ann Oncol 2014;25(Suppl 4) abstr LBA11.

    7) Lenz H et al. Ann Oncol 2014;25(Suppl 4) abstr 501O.

    8) Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo

M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012 v1.0, Cancer Incidence and

Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France:

International Agency for Research on Cancer; 2013. Available from:

http://globocan.iarc.fr , accessed June 2015.

    About BRAF Mutations

    BRAF is an important actor in the epidermal growth factor

receptor(EGFR)-mediated mitogen-activated protein kinase (MAPK) pathway, which

strongly impacts cell growth and proliferation, as well as cell migration, cell

death and cell survival.[1]

    About mCRC

    Approximately half of patients with mCRC have RAS wild-type tumors and half

have RAS mutant tumors.[3] Results from studies assessing RAS mutation status

in patients with mCRC have shown that anti-epidermal growth factor receptor

(EGFR) monoclonal antibody therapies,  such as Erbitux(R) (cetuximab), can

improve outcomes in patients with RAS wild-type mCRC. [4]-[7] CRC is the third

most common cancer worldwide, with an estimated incidence of more than 1.36

million new cases annually.[7] An estimated 694,000 deaths from CRC occur

worldwide every year, accounting for 8.5% of all cancer deaths and making it

the fourth most common cause of death from cancer.[8] Almost 55% of CRC cases

are diagnosed in developed regions of the world, and incidence and mortality

rates are substantially higher in men than in women.[8]

    About Erbitux (cetuximab)

    Erbitux(R) is a highly active IgG1 monoclonal antibody targeting the

epidermal growth factor receptor (EGFR). As a monoclonal antibody, the mode of

action of Erbitux is distinct from standard non-selective chemotherapy

treatments in that it specifically targets and binds to the EGFR. This binding

inhibits the activation of the receptor and the subsequent signal-transduction

pathway, which results in reducing both the invasion of normal tissues by tumor

cells and the spread of tumors to new sites. It is also believed to inhibit the

ability of tumor cells to repair the damage caused by chemotherapy and

radiotherapy and to inhibit the formation of new blood vessels inside tumors,

which appears to lead to an overall suppression of tumor growth.

    The most commonly reported side effect with Erbitux is an acne-like skin

rash that seems to be correlated with a good response to therapy. In

approximately 5% of patients, hypersensitivity reactions may occur during

treatment with Erbitux; about half of these reactions are severe.

    Erbitux has already obtained market authorization in over 90 countries

world-wide for the treatment of colorectal cancer and for the treatment of

squamous cell carcinoma of the head and neck (SCCHN). Merck licensed the right

to market Erbitux outside the US and Canada from ImClone LLC, a wholly-owned

subsidiary of Eli Lilly and Company, in 1998. Merck has an ongoing commitment

to the advancement of oncology treatment and is currently investigating novel

therapies in highly targeted areas.

    About Binimetinib & Encorafenib

    MEK and RAF are key protein kinases in the RAS-RAF-MEK-ERK-pathway.

Research has shown this pathway regulates several key cellular activities

including proliferation, differentiation, migration, survival and angiogenesis.

Inappropriate activation of proteins in this pathway has been shown to occur in

many cancers, such as non-small cell lung cancer, melanoma, colorectal and

thyroid cancer. Binimetinib is a small molecule MEK inhibitor and encorafenib

is a small molecule RAF inhibitor, each of which target key enzymes in this

pathway. There are three active Phase III trials which include these products:

NRAS-mutant melanoma (NEMO, with binimetinib), BRAF-mutant melanoma (COLUMBUS,

with binimetinib and encorafenib) and BRAF-mutant colorectal cancer (BEACON

CRC, with binimetinib and encorafenib).

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    About Merck

    Merck is a leading science and technology company in healthcare, life

science and performance materials. Around 50,000 employees work to further

develop technologies that improve and enhance life - from biopharmaceutical

therapies to treat cancer or multiple sclerosis, cutting-edge systems for

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countries.

    Founded in 1668, Merck is the world's oldest pharmaceutical and chemical

company. The founding family remains the majority owner of the publicly listed

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