New Treatments for Advanced Melanoma
In 2012, it is estimated that over 76,000 men and women in the United States will be diagnosed with melanoma, and close to 9,200 will die of the disease.1 Over 800,000 men and women have a history of melanoma, with a lifetime risk of 1 in 51 for both sexes.2 Melanoma, a major form of morbidity and mortality in the U.S., accounts for approximately 5% of skin cancers, but is the cause of the vast majority of skin cancer deaths.1 It is the fifth most common type of cancer among men and seventh among women.3 Melanoma is the second most common type of invasive cancer in young adults, second only to breast cancer.4 This trend is of particular concern, since the incidence of cutaneous melanoma is rapidly rising among young adults, especially women.5 With melanoma cases on the rise, there is a definite need for new treatment options.
Current research is focusing on regulatory pathways that stimulate the immune response against cancer cells. This can be done by blocking inhibitory immune checkpoint receptors such as cytotoxic T-lymphocyte-associated-protein 4 (CTLA-4) that down-regulates T-cell activation pathways. Anti-CTLA-4 is one of the first immunostimulatory monoclonal antibodies that has been used in malignant melanoma.6 Ipilimumab (Yervoy, Bristol-Myers Squibb), a fully human monoclonal antibody (IgG1) indicated for the treatment of unresectable or metastatic melanoma, blocks CTLA-4 and promotes antitumor immunity.7,8,9 Ipilimumab monotherapy in Phase 2 clinical trials has demonstrated antitumor activity in patients with metastatic melanoma.10,11,12 It has also demonstrated antitumor activity when combined with other anticancer agents, including vaccines such as the anticancer vaccine HLA-A*0201-restricted peptides derived from the melanosomal protein, glycoprotein 100 (gp100).13,14
Hodi and colleagues evaluated the efficacy of ipilimumab with or without gp100 compared to gp100 alone in 676 HLA-A*0201-positive patients with unresectable stage 3 or 4 melanoma whose cancer had progressed while receiving therapy for metastatic disease.15 Patients were randomized in a 3:1:1 ratio to receive either ipilimumab 3mg/kg gp100 (N=403), ipilimumab 3mg/kg alone (N=137), or gp100 alone (N=136). Each regimen was administered every 3 weeks. The primary endpoint was overall survival. The median overall survival time was 10.0 months in patients receiving ipilimumab plus gp100 compared to 6.4 months in those receiving gp100 alone (P<0.001; HR 0.68). Median survival time was 10.5 months for patients receiving ipilimumab alone compared with 6.4 months for gp100 alone (P=0.003: HR 0.66). No differences in overall survival were observed between the 2 ipilimumab groups. Grade 3 or 4 immune-related adverse events occurred in 10% to 15% of patients receiving ipilimumab, and in 3% of those receiving gp100 alone. Even though adverse events were severe, long-lasting, or both, they were reversible with appropriate therapy. Hodi and colleagues concluded that ipilimumab with or without gp100 improved overall survival in patients with metastatic melanoma.