An international phase 3 study demonstrated that ipilimumab improves the relapse-free survival of patients with advanced stage melanoma who are rendered free of disease surgically but at high risk for relapse. These findings were published in The Lancet (2015; doi:10.1016/S1470-2045(15)70122-1).

Melanoma is predicted to cause approximately 10,000 deaths in 2015. The majority of these deaths are due to advanced-stage disease that has spread or metastasized to other sites. The prognosis for patients with metastatic melanoma remains poor, with 5-year survival rates of 63% in patients who have metastatic disease in regional lymph nodes, and only 17% in patients who have metastatic disease in distant sites.

Ipilimumab is approved for the treatment of melanoma that cannot be surgically removed or that has metastasized to different sites. Ipilimumab targets the protein cytotoxic T lymphocytic antigen-4 (CTLA-4), which is found on the T cell immune cells. CTLA-4 keeps the immune system in check to avoid autoimmune disease by downregulating T cell activity. Tumors take advantage of CTLA-4 activity to avoid immune detection. By targeting CTLA-4, ipilimumab restimulates the immune system to target tumor cells.

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Researchers wanted to determine if ipilimumab could improve the survival of advanced-stage melanoma patients if it was given after the surgical removal of both their primary melanoma tumors and their regional lymph nodes.

The study, which included researchers from 19 countries, compared ipilimumab treatment in 475 people to placebo treatment in 476 people. Patients who were administered ipilimumab survived longer without experiencing melanoma recurrence, with an average recurrence-free survival of 26.1 months in patients treated with ipilimumab and 17.1 months in patients who received placebo.

In addition, 46.5% of ipilimumab-treated patients survived 3 years without experiencing recurrence, whereas 34.8% of placebo treated patients survived 3 years without recurrence.

The researchers wanted to determine if particular patient characteristics were associated with a better response to therapy. They discovered that patients who had microscopic metastatic disease in their regional lymph nodes and a tumor that had a breakdown of the overlaying skin responded best to ipilimumab treatment.

Despite these promising results, ipilimumab treatment was associated with significantly higher toxicity than placebo treatment, including higher rates of gastrointestinal disorders, alterations in kidney function, and inflammation of the pituitary gland. These adverse events resulted in 52% of patients on ipilimumab discontinuing treatment before its completion, including 39% of patients during the first four doses of the drug. Furthermore, five patients on ipilimumab died during treatment due to adverse events.

The dose used in this study was significantly higher than the dose commonly given to patients with melanoma. Additional studies are required to ensure that the benefit of this dose of ipilimumab does not outweigh the added toxicity risks.

Funding support was provided by Bristol-Myers Squibb.