Novel Therapy First to Extend Survival in Advanced Melanoma

CHICAGO, IL—The results of a randomized phase III study showed that when ipilimumab (also known as MDX-010) was administered with or without the gp100 peptide vaccine, it extended survival by 34% compared with the gp100 peptide vaccine alone in patients with previously treated advanced melanoma. “Over the past 30 years, randomized clinical trials have repeatedly failed to demonstrate an improvement in overall survival in patients with advanced melanoma, which is an extremely difficult disease to treat,” said lead researcher Steven O’Day, MD, chief of research and director, Melanoma Clinic, The Angeles Clinic and Research Institute, Los Angeles, CA. “These results are an exciting advance, both for patients with advanced melanoma and for the field of cancer immunology.”

Ipilimumab, a fully human monoclonal antibody that is administered intravenously, represents a new class of drugs that activates T-cells of the immune system to seek and destroy melanoma cells, he explained. Ipilimumab inhibits the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule. CTLA-4 suppresses the immune system’s response to disease, and blocking its activity stimulates the immune system to fight the melanoma. The gp100 vaccine is an experimental melanoma peptide vaccine that also stimulates T cells to attack melanoma cells but has modest anti-cancer activity.

The study enrolled 676 patients at 125 centers in 13 countries. Patients were randomized 3:1:1 to receive ipilimumab plus the gp100 vaccine, ipilimumab alone, or the gp100 vaccine alone. All patients had been pretreated for metastatic melanoma, and all were HLA-A0201 positive, which is a prerequisite for receiving the peptide vaccine. In both ipilimumab arms, overall median survival was improved to 10 months from 6.4 months in the vaccine-alone arm. Both 1-year and 2-year survival was almost double in patients who received ipilimumab: 1-year survival was 25% in the vaccine-alone arm and 46% in the ipilimumab-treated patients, whereas 2-year survival was 14% in the vaccine-alone arm and 24% in the ipilimumab-treated patients. O’Day said that some ipilimumab-treated patients were living at 4.5 years.

When the gp100 vaccine was added to ipilimumab, it did not improve survival or increase toxicity, O’Day noted. Ipilimumab’s side effects were generally mild to moderate and immune-related, but 10% to 15% of patients experienced severe side effects that required high-dose therapy. In addition, there were some treatment-related deaths. “This is a powerful drug,” said O’Day, who reported that treatment-related deaths occurred in 2.1% to 3.1% of patients in the ipilimumab arms. Of these deaths, 1.3% to 1.5% was immune related.

Other preliminary studies have shown that side effects typically appear soon after treatment with ipilimumab. Most commonly, gastrointestinal and skin reactions occur; less frequently, hepatitis, inflammation of the pituitary gland, eye inflammation, and nephritis can occur.

The study was sponsored by Bristol-Myers Squibb. FDA approval of ipilimumab is expected this year.

ASCO 2010 Abstract 4