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® (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.
"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. Studies have observed that patients with BRAF-mutant mCRC have shorter progression-free survival and overall survival. 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.
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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.
Approximately half of patients with mCRC have RAS wild-type tumors and half have RAS mutant tumors. 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® (cetuximab), can improve outcomes in patients with RAS wild-type mCRC.- CRC is the third most common cancer worldwide, with an estimated incidence of more than 1.36 million new cases annually. 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. 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.
About Erbitux (cetuximab)
Erbitux® 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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