Memorial Sloan Kettering clinician-researchers presented new research on treatments for two different types of melanoma this weekend as part of the 49th annual meeting of the American Society of Clinical Oncology (ASCO). The studies are shedding light on new therapies for advanced uveal melanoma, a rare cancer of the eye, and advanced skin melanoma – two cancers that have always been difficult to treat.
The first study showed that the experimental drug selumetinib is the first therapy able to improve progression-free survival and shrink tumors in patients with advanced uveal melanoma. If confirmed in another clinical trial, the findings might change the way this cancer has been treated for decades.
The second study, which was also published on June 2 in The New England Journal of Medicine, found that more than half of patients with advanced skin melanoma experienced tumor shrinkage of more than 80 percent when given the combination of the immunotherapy drug ipilimumab (YervoyTM) and the investigational antibody drug nivolumab, suggesting that these two drugs may work better together than on their own.
Targeted Drug for Uveal Melanoma
On Saturday, June 1, medical oncologist Richard Carvajal presented findings from a study testing the experimental drug selumetinib as a treatment for patients with metastatic uveal melanoma. This treatment more than doubled the time to progression when compared with chemotherapy. Many patients receiving selumetinib experienced tumor shrinkage, making selumetinib the first systemic therapy ever to benefit patients with this cancer. The findings are potentially practice changing for a disease that has previously had no known effective therapy.
In the Phase II trial, researchers randomly assigned 47 patients with metastatic uveal melanoma to receive selumetinib and 49 patients to receive the current standard therapy, temozolomide. In the selumetinib group, 50 percent of patients experienced tumor shrinkage, with 15 percent achieving major shrinkage.
In comparison, no patients in the temozolomide group achieved significant tumor shrinkage. However, patients whose disease worsened while on temozolomide were able to begin taking selumetinib.
In addition, selumetinib was shown to control tumor growth more than twice as long as temozolomide – for nearly 16 weeks versus seven weeks. Side effects caused by selumetinib were managed by modifying the dosage if needed.
“This is the first randomized study to show that a systemic therapy can provide significant benefit to advanced uveal melanoma patients, who have always had extremely limited treatment options,” says Dr. Carvajal, who is currently planning a confirmatory international, randomized trial for selumetinib led by Memorial Sloan Kettering.
“Confirming these results could form a foundation for new drug combinations that would maximize selumetinib’s effect, offering a whole new way to treat this historically untreatable disease,” he adds.
Although uveal melanoma is rare – there are only 2,500 cases diagnosed in the United States each year – about half of patients diagnosed eventually develop metastatic disease. The survival time for patients with advanced disease has held steady at nine months to a year for decades. There is currently no drug approved specifically for treatment of this cancer, which does not respond to the drugs given to patients with skin melanoma.
Dr. Carvajal and his team decided to test selumetinib because it blocks the activity of the MEK protein, a key component of a cellular process called the MAPK pathway. This pathway is activated by mutations in the genes Gnaq and Gna11 that occur in more than 85 percent of patients with uveal melanoma, inducing the growth and progression of tumors. Nearly 85 percent of the patients in the trial had such mutations.
Combination of Immunotherapies for Advanced Melanoma
On Sunday, June 2, medical oncologist Jedd Wolchok presented data at ASCO that on the same day was published online in The New England Journal of Medicine. Results from this Phase I study showed that some patients with advanced melanoma of the skin might benefit from a combination treatment that includes the immunotherapy drug ipilimumab (YervoyTM) and the investigational antibody drug nivolumab. Patients who received this combination experienced dramatic tumor shrinkage.
“We pursued the ipilimumab and nivolumab combination because they each impact the immune system in a distinct but complementary way,” says Dr. Wolchok. “Ipilimumab activates a person’s immune system, prompting their T cells to begin attacking the tumor, while nivolumab further activates those T cells in a different manner, allowing them to continue the attack.”
Previous studies had shown that ipilimumab alone could prolong overall survival in advanced melanoma patients, and nivolumab alone could produce durable tumor responses in melanoma and other cancers. Combining the drugs was “quite logical,” Dr. Wolchok adds, and well supported by preclinical and clinical trial data.
Side effects from the drug combination were manageable. A multicenter, randomized phase III trial of the ipilimumab and nivolumab combination as a therapy for patients who are newly diagnosed with advanced melanoma is scheduled to begin in June 2013 and will be led by Dr. Wolchok.
“We are very excited about how well these two drugs work together. The major and complete response rates that these patients are experiencing are unprecedented for immunotherapy in advanced skin melanoma, and we are hopeful that this combination strategy will continue to be effective in the Phase III trial,” says Dr. Wolchok.
Read more about Dr. Wolchok’s study in stories appearing in The Wall Street Journal, New York Times, Reuters, Bloomberg, and watch a segment featuring Dr. Wolchok on NBC Nightly News.