Earlier today Incyte Corporation and Merck & Co., Inc , known as MSD outside the United States and Canada, announced that they have agreed to expand the ongoing clinical trial collaboration to include a Phase III study evaluating the combination of epacadostat, Incyte?s investigational selective Indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor, with pembrolizumab (Keytruda?)*, Merck?s anti-PD-1 therapy, as first-line treatment for patients with advanced or metastatic melanoma.

The Phase III study, which is expected to begin in the first half of 2016, will be co-funded by Incyte and Merck.

Proof of Concept
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. The investigational drug epacadostat is an orally bioavailable small molecule inhibitor of IDO1 that has nanomolar potency in both biochemical and cellular assays and has demonstrated potent activity in enhancing T lymphocyte, dendritic cell and natural killer cell responses in vitro, with a high degree of selectivity. Epacadostat has shown proof-of-concept clinical data in patients with unresectable or metastatic melanoma in combination with the CTLA-4 inhibitor ipilimumab, and is currently in four proof-of-concept clinical trials with PD-1 and PD-L1 immune checkpoint inhibitors in a variety of cancer histologies.


…the initiation of this large Phase III study in the first-line advanced melanoma treatment setting is an important addition to [a] robust immunotherapy clinical development program…


Melanoma, the most serious form of skin cancer, strikes adults of all ages and accounts for approximately five percent of all new cases of cancer in the United States each year. The number of new cases of melanoma continues to rise by almost three percent each year which translates to 76,000 new cases yearly in the U.S. alone.[1] The 5-year survival rate for late-stage or metastatic disease is 15%.[2]

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Collaboration
?We are very pleased to expand our collaboration with Merck and to move the clinical development program for epacadostat in combination with Keytruda into Phase III,? said Herv? Hoppenot, President and Chief Executive Officer of Incyte. ?We believe the combination of these two immunotherapies shows promise and, if successfully developed, may help to improve clinical outcomes for patients with metastatic melanoma.?

?The initiation of this large Phase III study with Incyte in the first-line advanced melanoma treatment setting is an important addition to our robust immunotherapy clinical development program for pembrolizumab,? noted Roger Dansey, MD, senior vice president and therapeutic area head, oncology late-stage development, Merck Research Laboratories. ?We continue to explore the benefit that pembrolizumab brings to patients suffering from advanced melanoma when used alone, and we are pleased to be able to add this important combination study with epacadostat to our Keytruda development program.?

Combination therapy
Under the terms of the agreement Incyte and Merck have also agreed, for a period of two years, not to initiate new pivotal studies of an IDO1 inhibitor in combination with a PD-1/PD-L1 antagonist as first-line therapy in advanced or metastatic melanoma with any third party. During this time, the companies will each offer the other the opportunity to collaborate on any new pivotal study involving an IDO1 inhibitor in combination with a PD-1/PD-L1 antagonist for types of melanoma and lines of therapy outside of the current collaboration agreement.

Immunotherapies
Epacadostat and pembrolizumab are part of a class of cancer treatments known as immunotherapies that are designed to enhance the body?s own defenses in fighting cancer; the two therapies target distinct regulatory components of the immune system. IDO1 is an immunosuppressive enzyme that has been shown to induce regulatory T cell generation and activation, and allow tumors to escape immune surveillance. Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Preclinical evidence suggests that the combination of these two agents may lead to an enhanced anti-tumor immune response compared with either agent alone.

Safety and efficacy data from the ongoing Phase I/II study evaluating the combination of epacadostat with pembrolizumab in patients with advanced malignancies is scheduled to be highlighted as a late-breaking oral presentation (Abstract #142) at the upcoming Society for Immunotherapy of Cancer 30th Anniversary Annual Meeting & Associated Programs, November 4?8, 2015 at the Gaylord National Resort & Convention Center in National Harbor, MD.

Reference:
[1] Siegel R, Naishadham MA, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. Jan- 2012;62:10-29.
[2] American Cancer Society. Melanoma Skin Cancer. Atlanta, GA: American Cancer Society (ACS); 2015. http://www.cancer.org/cancer/skincancer-melanoma/index. Accessed May 13, 2015.


* Pembrolizumab a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. By binding to the PD-1 receptor and blocking the interaction with the receptor ligands, Keytruda releases the PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. Keytruda is indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. This indication is approved under accelerated approval based on tumor response rate and durability of response. An improvement in survival or disease-related symptoms has not yet been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.


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