New drug fights metastatic melanoma

Compound offers hope for about half of patients with advanced form of the skin cancer

A new drug may change the landscape of melanoma treatment, offering patients a treatment option that goes beyond anything previously used against the skin cancer, new research shows. Tests in people whose melanoma had spread show the drug was able to shrink tumors in most patients and, in a few cases, even wiped the growths out, scientists report in the Aug. 26 New England Journal of Medicine. The compound targets the protein encoded by a mutated version of the BRAF gene that underlies melanoma in roughly half of all patients.

“This demonstrates for the first time that a targeted therapy can work in melanoma,” says Richard Marais, a molecular biologist at the Institute of Cancer Research in London. “This is an enormous advance in the field. It’s just unparalleled.”

Early-stage melanoma that is confined to a spot on the skin can be surgically removed and in most cases stopped. But patients’ prospects take a deadly turn if the cancer metastasizes, or spreads, to other parts of the skin or to internal organs. Chemotherapy drugs benefit fewer than 20 percent of such patients. Survival outlook varies with the extent of the cancer’s spread and the age of the patient, but it is usually measured in months, not years.

The new drug is called PLX4032. Its impressive showing is actually the second dose of good news about melanoma to arrive this summer. In the Aug. 19 NEJM, scientists reported that another experimental drug, called ipilimumab, seems to extend survival in people with metastatic melanoma, and the Food and Drug Administration has fast-tracked its review of that drug.

A third study, published in 2008, found that melanomas arising from a much less common mutation — in a gene called C-kit — were susceptible to the leukemia-fighting drug Gleevec, or imatinib.

“This creates extraordinary hope for many melanoma patients,” says Alan Spatz, a pathologist at McGill University in Montreal. “For the first time in 40 years we have accumulated three studies that show extremely promising results.”

In the new study, medical oncologist Keith Flaherty of Harvard Medical School and Massachusetts General Hospital in Boston and a team of U.S. and Australian researchers treated 48 patients who had BRAF-related metastatic melanoma with PLX4032, which was devised by scientists at the pharmaceutical company Plexxikon in Berkeley, Calif. The drug neutralizes the mutant BRAF protein and stops it from triggering cell growth.

Of the 48 patients, 37 experienced tumor shrinkage of at least 30 percent. In three patients, the tumors resolved completely. This tumor suppression lasted from three months to about two years. Some patients remain on the drug.

On average, the patients getting the treatment relapsed after nearly eight months, Flaherty says. That happens because the tumors develop ways to subvert the effects of PLX4032. Those changes are the target of study now.

But the relapse rate hasn’t discouraged observers. “Patients are very rarely cured with a single drug in cancer,” Marais says. “You typically need a cocktail.”

Keiran Smalley, a molecular pharmacologist at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla., notes that metastatic melanoma is exceptionally hard to treat anyway. “I think people in the field hadn’t really believed that these kinds of responses would even be possible,” he says.

The other two new approaches to fighting melanoma target other biological pathways. Early tests suggest Gleevec or similar drugs such as nilotinib (sold as Tasigna) could thwart melanoma stemming from a mutation in the C-kit gene by stopping its rogue protein from sending growth signals to cells. But the C-kit mutation is uncommon, and such patients typically don’t have the BRAF mutation. So combining those drugs with PLX4032 wouldn’t yield an additional benefit, Marais says.

Ipilimumab might offer the possibility of a one-two punch since it works by unfettering the body’s own T cells — immune shock troops — to fight cancer. As such, it may have an additive effect when used in combination with PLX4032, Marais says.

Flaherty says a trial is being discussed now that would use both drugs against BRAF-mutation melanoma — employing PLX4032 to catch the cancer in its early stages and ipilimumab to “improve immune surveillance” and mop up tumor cells that evade the effects of PLX4032. “You’d like to think these two things would complement each other,” he says.

“This is clearly a turning point” in melanoma treatment, says study coauthor Paul Chapman, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City. “It’s the first time we’re actually treating the genetics of the tumor.” In the past, melanoma metastases were all treated about the same, he says. “Now we have the advantage of knowing their genetic differences and we are able to exploit that.”

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