Treatment Breakthroughs for Advanced Melanoma

Two new experimental treatments for melanoma, the deadliest form of skin cancer, are extending patients’ lives by months or even years. The treatments, PLX4032 and ipilimumab, are forms of immunotherapy, which uses medications to enhance the immune system’s ability to fight disease.


In a report recently published in the New England Journal of Medicine, patients with advanced melanoma that had spread to distant organs were treated orally with PLX4032, which targets the BRAF gene. Mutations (abnormal changes) in this gene are found in 40-60 percent of all melanomas; these mutated versions of BRAF can become stuck in the “on” position, promoting uncontrolled (cancerous) cell growth. PLX4032 can slow or even halt this growth.

In the study, 960 mg of PLX4032 given twice a day was found to be safe and effective. This dose was given to 32 melanoma patients with the BRAF mutation, and 81 percent saw their tumors completely or partially shrink. Thus far, patient responses have lasted anywhere from two to more than 18 months, significantly extending patients’ lives. However, most will eventually relapse, so the researchers are seeking to combine PLX4032 with other therapies to help prevent recurrences.


Ipilimumab has had similarly promising results. As reported at the 2010 meeting of the American Society for Clinical Oncology, in a study of 676 patients with advanced, inoperable melanoma, 24 percent of those treated with ipilimumab were alive after two years, compared with just 14 percent of patients treated with other immunotherapies.

Ipilimumab is an “anti-CTLA-4” therapy. CTLA-4 acts as a “brake” on the immune system, a protein that prevents overproduction of disease-fighting white blood cells called T-cells. Ipilimumab essentially turns off this brake; treated patients produce more healing T-cells, enabling them to mount a stronger defense against melanoma.

Swift Approvals Sought

The findings have raised hopes for quick approvals of ipilimumab and PLX4032 by the US Food and Drug Administration (FDA). The FDA most often approves medications for sale only after successful Phase I, II, and III clinical trials have proven drug safety and efficacy. The recent ipilimumab study was a Phase III trial, and the FDA has promised to review the latest study results promptly. The treatment could be approved by early 2011.

The PLX4032 study was a Phase II trial, but “There is precedent for targeted therapies with an acceptable safety profile to be approved by the FDA on the basis of Phase II data,” PLX4032 lead researcher Keith T. Flaherty, MD, of Massachusetts General Hospital Cancer Center, Boston, told Sun & Skin News.

“In an area of unmet need like metastatic melanoma, it is our hope that the FDA would consider this [early approval], so that we can have these treatments avail- able as soon as possible.” A PLX4032 Phase III trial is ongoing, and “we will eventually have that data,” noted Dr. Flaherty. “But having seen how this drug can pull patients back from the edge, I don’t want to wait another year and a half or two for those results to mature.”

Published on December 10, 2010