ASCO 2011: New Hope for Metastatic Melanoma

Metastatic melanoma maintains a growing presence around the world, and a steady disregard for treatment efforts. But two novel drugs presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, on Sunday, suggest that medicine might finally be ready to fight back against the deadliest form of skin cancer.

The emergence of ipilimumab and vemurafenib offers "great news and new challenges," Kim Margolin, MD, of the University of Washington and the Fred Hutchinson Cancer Research Center in Seattle, told participants.

Currently, only about 25% and 10% of patients with previously untreated metastatic melanoma remain alive after 1 and 2 years, respectively. Approximately one American dies every hour from melanoma, according to the American Melanoma Foundation.

Approved in 1975, Dacarbazine has long been the standard treatment for this aggressive disease and offers response rates up to about 20%. No other therapy proved as potent until ipilimumab entered the market last year. Other agents are now following ipilimumab's lead.

One such novel therapy is vemurafenib, which targets a specific gene mutation involved in skin tumor formation that is present in about half of all melanomas.

In their phase III study (abstract LBA4), Paul B. Chapman, MD, of Memorial Sloan-Kettering Cancer Center in New York City and his colleagues looked at 675 patients from around the world, all with previously untreated unresectable stage IIIC or stage IV melanoma that tested positive for the V600E BRAF mutation. Each patient was randomized to receive vemurafenib or the standard chemotherapy, dacarbazine.

At 6 months, overall survival significantly favored the vemurafenib group: 84% versus 64%, respectively (HR = 0.37; P < .0002).

Further, 90% of patients on vemurafenib experienced some tumor shrinkage while most patients on dacarbazine had no response.

In January 2011, a data safety and monitoring board (DSMB) determined that this evidence was compelling enough to stop the study and provide all the patients with the superior vemurafenib. (FDA approval for vemurafenib is expected within the coming months.)

"This is a promising new therapy," said Dr. Chapman, "and a foundation upon which to build therapies in the future."

Meanwhile, ipilimumab-approved by the FDA in March 2011-continues to prove its worth, offering prolonged survival and durable response, according to another phase III trial presented at the meeting.

In the study (abstract LBA5), Jedd D. Wolchok, MD, also of Memorial Sloan-Kettering Cancer Center and his colleagues randomized 502 patients with unresectable stage III or IV melanoma to dacarbazine plus ipilimumab or dacarbazine alone as a first-line therapy.

The team found that patients on the combination therapy had greater overall survival than those on the solo standard treatment, with a median of 11.2 and 9.1 months, respectively (HR = .72; P = .0009).

At 3 years, 20.8% of patients on the combination therapy were still alive compared to 12.2% of patients on dacarbazine.

Further, although about 30% of patients on both arms achieved disease control, the median duration of response was higher with the dual therapy: 19.3 vs 8.1 months.

In a discussion session, Dr. Margolin offered her thoughts on how both new therapies might be used.

"The decision is rarely simply and straightforward," said Dr. Margolin, who was not involved in either study. "You might have a rapid onset but potentially limited duration of control, or a slower onset and then a plateau of disease control."

For patients with the BRAF mutation, she recommended use of vemurafenib only if there is a high tumor burden and presence of symptoms. Otherwise, ipilimumab may be the optimal first choice, she said, further suggesting that the treatment might be better off without the added chemotherapy.

"Today's tale of melanoma is coming to end, and the sequel is just beginning," Dr. Margolin added. "Melanoma is one of the very smart cancers, and we need to be a lot smarter to stay in front of it."