Experimental Drugs Show Promise Against Melanoma
Article date: August 27, 2010
By: Melissa Weber
People with metastatic melanoma lived an average of almost four months longer while taking a new drug that boosts the immune system, raising hopes that a long period of stalled progress against the stubborn cancer may be coming to an end.
The drug, ipilimumab, is one of two promising metastatic melanoma treatments highlighted this month in The New England Journal of Medicine. Early tests for a second drug, PLX4032, showed tumors shrank by at least one-third in more than 80% of patients with a certain mutated gene.
Currently, metastatic melanoma patients are mostly limited to treatments that are often big on side effects but rarely provide long-term benefits. Ipilimumab and PLX4032, on the other hand, showed what one doctor called a dramatic response.
“This was beyond what we were able to achieve with prior medications that we’ve tested for metastatic disease. What we’ve done for melanoma in the past has unfortunately been pretty ineffective,” says Martin A. Weinstock, MD, PhD, chair of the skin cancer advisory committee for the American Cancer Society and professor of dermatology and community health at Brown University. Weinstock was not involved in either study.
Targeting the immune system
Ipilimumab is the first drug to improve survival in patients with metastatic melanoma, says one of the study’s lead authors, Steven O’Day, MD, director of the melanoma program at The Angeles Clinic and Research Institute. By taking the brake off the body’s immune response, ipilimumab activates the soldiers of the immune system—known as T cells—to seek out and destroy cancer cells.
In a phase III study, 676 patients with previously treated metastatic melanoma were randomly assigned to receive either ipilimumab, an experimental vaccine called gp100, or the two combined. For patients receiving ipilimumab alone, median overall survival reached 10.1 months compared with 6.4 months for those receiving gp100 alone. Survival for patients who got both drugs was 10 months.
Ipilimumab also proved beneficial over the long-term, with 24% of patients still alive after two years compared with 14% for gp100. “We have patients on this trial out as far as four and a half years still alive, which is phenomenal,” O’Day says.
But the drug, which is given intravenously, has some potentially serious side effects. Common side effects in the study included diarrhea, fatigue, nausea, and rash. About 15% of patients on ipilimumab experienced serious immune-related side effects, including inflammation of the colon and severe diarrhea, which required steroid treatment. There were 14 deaths related to the drug treatment, including 7 linked to immune-related toxicities. “Its side effects can be severe and need to be managed, but pretty much anyone with melanoma should be eligible to receive treatment,” O’Day says.
The Food and Drug Administration (FDA) is currently considering ipilimumab for approval in previously treated metastatic melanoma. A decision is expected by December 25.
Exploiting a genetic mutation
In roughly half of melanoma patients, a mutation in a gene called BRAF keeps it turned on all the time, which fuels the cancer. A new targeted agent called PLX4032 turns off this defective gene—and with “unprecedented” results, says the study’s senior author Paul Chapman, MD.
In a two-part phase I study, researchers first pinpointed the ideal dose for PLX4032—a pill given twice a day—before then giving the drug to 32 patients with metastatic melanoma who had the requisite BRAF gene mutation. Two patients saw their tumors disappear completely, and tumors shrank by at least a third in another 24 patients. With 16 patients still responding to the therapy, researchers estimate median progression-free survival—the length of time the cancer didn’t get worse—at more than 7 months.
For patients in the initial dosing phase of the study, the duration of response ranged from 2 months to more than a year and a half and counting. The longest response so far among patients in the second part of the study is 10 months, says Chapman, an attending physician on the Melanoma and Sarcoma Service at Memorial Sloan-Kettering Cancer Center.
This early study wasn't designed to look at survival times, so it’s too early to know for sure if PLX4032 will help patients live longer. Chapman notes that tumors frequently developed a resistance to the drug at some point.
Side effects of PLX4032 included rash, nausea, fatigue, joint pain, and sun sensitivity. The drug also caused some patients to develop a common, low-grade form of skin cancer called squamous cell carcinoma. These cancers were easily removed and didn’t result in a treatment delay for any of the patients, the researchers reported.
A larger phase III study comparing PLX4032 with the chemotherapy drug dacarbazine is currently under way in newly diagnosed patients with BRAF mutations. Chapman, who is leading the study, says he expects initial results sometime next year.
A brighter future for melanoma treatment?
Current FDA-approved treatments for metastatic melanoma include dacarbazine and the immune therapy interleukin-2—neither of which have great results in the majority of patients and usually cause a lot of side effects. O’Day and Chapman say the next step will be to combine ipilimumab and PLX4032—both with each other and other agents—in hopes of achieving even better, longer-lasting responses.
Weinstock anticipates ipilimumab and PLX4032 will both gain the FDA’s seal of approval at some point. “These agents promise to be better than anything currently approved. … This is just the beginning,” he says.
Reviewed by members of the ACS Medical Content Staff
Citations: “Improved Survival with Ipilimumab in Patients with Metastatic Melanoma.” Published in the Aug. 19, 2010 issue of The New England Journal of Medicine. First author, F. Stephen Hodi, Dana-Farber Cancer Institute.
“Inhibition of Mutated, Activated BRAF in Metastatic Melanoma.” Published in the Aug. 26, 2010 issue of The New England Journal of Medicine. First author, Keith T. Flaherty, Massachusetts General Hospital Cancer Center.
ACS News Center stories are provided as a source of cancer-related news and are not intended to be used as press releases.
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