Uveal melanoma, which can arise in the anterior (iris) or the posterior (ciliary body or choroid) uveal tract, is the most common primary intraocular malignancy in adults. It is a rare cancer of melanocytes or cells that produce the pigment melanin found in the eye. The disease is also called intraocular melanoma.

In the United States only 2,000 – 2,500 new cases melanoma of the eye or uveal melanoma are diagnosed every year. [2] While most patients are diagnosed with early-stage disease, about half eventually develop metastatic disease, with survival ranging from nine to 12 months.

Most uveal melanomas are initially completely asymptomatic. In most cases patients have no demonstrable evidence of metastatic disease at the time of initial diagnosis. Over time, as the tumor enlarges, uveal melanoma may cause distortion of the pupil (iris melanoma), blurred vision (ciliary body melanoma), or markedly decreased visual acuity caused by secondary retinal detachment (choroidal melanoma). As result of disease progression, within 5 years, metastases appear in 19?35% of these patients. The median relapse-free interval for these patients is 2?4 years. [1] Unlike cutaneous melanoma, uveal melanoma most commonly metastasises to the liver. In more than 50% of patients the liver is the sole site or the initial site of metastasis. [1]

The targeted drug selumetinib shows strong clinical activity in patients withadvanced melanoma of the eye harboring common Gnaq/Gna11 gene abnormalities.

New treatment options
Final analysis of data from a phase II cross-over study in patients with metastatic uveal melanoma or melanoma of the eye finds that selumetinib (AstraZeneca), presented on Saturday, June 1, 2013 at the 49th annual meeting of the American Society of Clinical Oncology(ASCO), resulted in tumor shrinkage in half of all patients treated and a duration of disease control more than twice that achieved with temozolomide (Temodar?, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.).While temozolomide is a long-time standard therapy for skin melanoma, it has little effect in most patients with eye melanoma, and alternate treatment options are urgently needed.

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Unmet need
There is no known effective systemic therapy for metastatic melanoma of the eye. The disease does not respond to the drugs given to patients with melanoma on the skin, and, in fact, there is no drug approved specifically for treatment of the disease. Patients with uveal melanoma receive surgery to remove the tumor ? and in some advanced cases, the entire eye ? as well as radiation therapy or chemotherapy.

Of the 157 patients treated on eight different clinical trials testing potential new therapies for this cancer, including chemotherapy, targeted therapy and immunotherapy, over the past decade, only two patients experienced major tumor shrinkage. This clinical trial is the first to ever identify a drug that improves clinical outcome in patients with advanced melanoma of the eye.

?This is the first study to show that a systemic therapy provides significant clinical benefit in a randomized fashion to advanced uveal melanoma patients, who have very limited treatment options,? notedRichard D. Carvajal, MD (Photo 1, right), a medical oncologist at Memorial Sloan-KetteringCancer Center inNew York, NYand lead author on the study. ?This clinical benefit has never been demonstrated with other conventional or investigational agents, which is all we have been able to offer patients for decades.?

Importance of clinical trials
?Ours is the largest randomized study of patients with melanoma of the eye. It proves that inhibiting the MAPK pathway in this unique molecular subset of melanoma, which is commonly characterized bymutations in Gnaq and Gna11, is effective, more than doubling progression-free survival,? Carvajal said?While we are hopeful an agent like selumetinib will be commercially available in the near future, in the meantime we must continue to steer patients towards clinical trials.?

Gnaq and Gna11 alterations activate the MAPK pathway, which fuels cancer cell growth. These alterations occur in greater than 85% of patients with this disease. Selumetinib blocks the MEK protein, a key component of the MAPK pathway. The drug is being investigated for the treatment of various cancers, including cancers of the thyroid and lung.

In this study, 98 patients with metastatic melanoma of the eye were randomly assigned to receive selumetinib or temozolomide, with 48 receiving selumetinib and 50 receiving temozolomide. Forty-seven
percent of patients had Gna11 alterations in their tumors, thirty-seven percent had Gna11 alterations, and the rest did not have alterations in either of those genes. Patients whose disease worsened on temozolomide were permitted to cross over to selumetinib. Fifty percent of patients experienced tumor shrinkage, with 15% achieving major tumor shrinkage in the selumetinib group. None achieved significant shrinkage in the temozolomide group.

The median time to disease worsening (progression-free survival) was 15.9 weeks in the selumetinib arm vs. seven weeks in the temozolomide arm. No detrimental effects of selumetinib were observed in terms of overall survival, with a median survival of 10.8 months in the selumetinib arm and 9.4 months in the temozolomide arm.

?Melanoma of the eye, or uveal melanoma, is one the most difficult cancers to treat. Uveal melanoma patients are now also benefiting from the targeted therapy revolution. This new pill focuses on the genesbroken in uveal melanoma. This represents the first real advance for these patients,? said Lynn Schuchter, MD, melanoma expert and ASCO spokesperson.

Confirmatory trial
Carvajal and his team are currently planning a confirmatory multi-center, randomized trial that will enroll approximately 100 patients and be led by Memorial Sloan-Kettering. ?If we can confirm selumetinib?s effectiveness in treating advanced uveal melanoma in this follow-up trial, it will become the standard therapy for this disease, forming a foundation for new drug combinations that could maximize selumetinib?s MEK-inhibitor effect,? he said. ?It could offer a whole new way to treat this historically untreatable disease.?

This study was supported in part by a Conquer Cancer Foundation of ASCO Career Development Award, the National Institutes of Health, Cycle for Survival, and the Fund for Ophthalmic Knowledge.

[1] Pyrh?nen S, The treatment of metastatic uveal melanoma. European Journal of Cancer 34, Supp 3, 1998 (4); 27-30 [Abstract]
[2] Singh AD, Bergman L, Seregard S: Uveal melanoma: epidemiologic aspects. Ophthalmol Clin North Am 18 (1): 75-84, viii, 2005.

For more information:
Abstract #CRA9003: Phase II study of selumetinib (sel) versus temozolomide (TMZ) in gnaq/Gna11 (Gq/11) mutant (mut)uveal melanoma (UM).
Oral Abstract Session: Melanoma/Skin Cancers Study
Author: Richard D. Carvajal, MD, Memorial Sloan-Kettering Cancer Center, New York, NY
Date: Saturday, June
1, 2013, 2:15 ? 2:30 PM CDT
Location: Room: S406

Clinical trials
NCT01143402 -Temozolomide or Selumetinib in Treating Patients With Metastatic Melanoma of the Eye

Photo:Richard D. Carvajal, MD.Photo courtesy:? ASCO/Scott Morgan 2013.

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