Roche Holding AG and Bristol-Myers Squibb Company earlier this week agreed to collaborate on a study to evaluate a combination therapy with Roche’s investigational oral BRAF inhibitor vemurafenib and Bristol’s CTLA-4 inhibitor ipilimumab (Yervoy?) in patients with BRAF-mutated metastatic melanoma.

Vemurafenib is an investigational, oral, small molecule that is designed to selectively inhibit a cancer-driving mutated form of the BRAF protein. Vemurafenib is being co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, a member of the Daiichi Sankyo Group.

Ipilimumab, which is indicated for the treatment of unresectable or metastatic melanoma, is a recombinant, human monoclonal antibody that blocks the cytotoxic T- lymphocyte antigen-4 (CTLA-4), a negative regulator of T-cell activation. Ipilimumab binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The mechanism of action of ipilimumab?s effect in patients with melanoma is indirect, possibly through T-cell mediated anti-tumor immune responses. The drug was recently approved by the FDA.

Commenting on the clinical colaboration agreement, Hal Barron M.D., Roche’s Chief Medical Officer and Head, Global Product Development said ?We have made significant progress in treating metastatic melanoma and hope to further improve outcomes by combining two agents that target this deadly disease in different ways,? said . We look forward to working with BMS in this ground-breaking collaboration to explore new options for patients.?

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?Metastatic melanoma is one of the most aggressive forms of cancer,? said Brian Daniels, senior vice president, Development and Medical Affairs, Bristol-Myers Squibb. ?We are excited to be working with Roche to evaluate the potential that together YERVOY and vemurafenib could improve outcomes for melanoma patients.?

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Under the agreement, the two companies will conduct a Phase I/II study to determine the safety and efficacy of the combination. If appropriate, the companies may conduct further development of the combination. The agreement represents an important cross-company collaboration to explore the combined potential of two new agents in metastatic melanoma, the deadliest and most aggressive form of skin cancer.

Vemurafenib development programme
Roche is pursuing a broad development programme with vemurafenib, a BRAF inhibitor, which includes additional combinations as well as studies in other tumour types.

“We are entering a new era for melanoma, and are committed to studying exciting combinations with investigational medicines in our own pipeline.? added Barron.

MEK inhibition withGDC-0973
Roche is also conducting a trial studying the combination of vemurafenib with another of its investigational compounds, GDC-0973, a potent and highly selective MEK inhibitor, in patients who previously received vemurafenib alone. MEK is a protein, a central component of the RAS-RAF pathway involved in cell growth and proliferation of certain tumours, including melanoma. It is thought that combining a BRAF inhibitor with a MEK inhibitor could lead to improved outcomes in people with BRAF V600 mutations, which are found in about half of all metastatic melanoma cases.

BRAF V600 mutations are also associated with other types of tumours, including 8% of solid tumours. Roche has recently begun a Phase II trial of vemurafenib to assess its efficacy and safety in people with metastatic or unresectable papillary thyroid cancer whose tumours test positive for BRAF V600 mutations and are resistant to radioactive iodine therapy. Papillary thyroid cancer is the most common type of thyroid cancer; it can spread to the lymph nodes in the neck, as well as to other parts of the body. BRAF gene mutations have been implicated in 30?70% of thyroid tumours.[1]

ASCO Annual meeting
The companies announced their new clinical colaboration just days before the start of the annual meeting of the American Society of Clinical Oncology, which begins this weekend in Chicago (June 3-7, 2011). A number of highly anticipated studies discussing emerging treatments for melanoma will be presented during the meeting.

For more Information:
[1] Dienstmann, R. & Tabernero, J. BRAF as a Target for Cancer Therapy. Anticancer Agents Med Chem 11, 285-295 (2011)

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