Significant & Game-Changing Research in Dermatology: 2011

Graeme M. Lipper, MD


November 23, 2011

In This Article

A Banner Year for Dermatology

2011 has been a banner year for novel developments in the field of dermatology. From revolutionary new treatments for late-stage melanoma and infantile hemangiomas to revised US Food and Drug Administration (FDA) guidelines for sunscreen labeling, dermatologists have had a flurry of exciting headlines to digest. The following paragraphs spotlight some of these top stories.

Ipilimumab (Yervoy™) for Treatment of Late-Stage Melanoma

To date, high-dose interferon and melanoma vaccine trials (eg, gp100) have shown no overall survival benefit in the treatment of metastatic malignant melanoma (MM). Nevertheless, these treatments yield rare cases of long-term remission, raising a tantalizing possibility: Could the key to curing metastatic MM lie in stimulating the host's immune response?

Ipilimumab, a human monoclonal immunoglobulin (Ig)G1k antibody, targets an important immunosuppressive molecule called cytotoxic T-lymphocyte antigen-4 (CTLA-4), thereby enhancing T-cell activation and augmenting the host's antitumor immune response.[1,2] This powerful effect was fully evident in 2 recent phase 3 clinical trials designed to assess the safety and efficacy of ipilimumab, used alone or in combination with other agents, for the treatment of metastatic MM.

The first trial compared overall survival of patients with unresectable stage III or IV MM who had been randomly assigned to receive ipilimumab monotherapy (3 mg/kg administered intravenously every 3 weeks for up to 4 treatments; n = 137), ipilimumab plus gp100 (n = 403), or gp100 alone (n = 136). Patients receiving ipilimumab with or without gp100 showed a clear median overall survival benefit (10 months with ipilimumab + gp100, 10.1 months with ipilimumab alone) when compared with those receiving gp100 alone (6.4 months). Up to 15% of patients treated with ipilimumab developed grade 3 or 4 immune-related adverse events, and there were 7 immune-related deaths.[3]

A follow-up trial confirmed the benefits of ipilimumab when compared with the chemotherapy agent dacarbazine.[4] In this pivotal study, patients with previously untreated MM (n = 502) were randomly assigned to receive either ipilimumab (10 mg/kg) plus dacarbazine (850-mg/m2 body surface area) or dacarbazine plus placebo. Treatments were given at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. After this induction phase, patients who showed a clinical response without dose-limiting toxicity continued maintenance therapy with ipilimumab or placebo given every 12 weeks. As with the gp100 trial, overall survival was significantly longer in the patients who had received ipilimumab, with higher survival rates in the ipilimumab + dacarbazine group after 1 year, 2 years, and 3 years (47.3% vs 36.3%, 28.5% vs 17.9%, and 20.8% vs 12.2%, respectively). Ipilimumab-related toxicities were similar to those seen in the earlier melanoma study (eg, dermatitis, colitis, hepatitis, hypophysitis, thyroiditis), potentially lethal in some cases, and required prompt intervention with immunosuppressive agents (primarily systemic corticosteroids).

Why Is This a Game Changer?

MM is the leading cause of skin cancer-related death, accounting for 8700 deaths in the Unites States in 2010. Unfortunately, the incidence of MM continues to rise, largely as a result of risk factors such as indoor tanning and heavy recreational sun exposure. Early stages of MM are usually curable with surgical excision; however, advanced (metastatic) disease has a dismal prognosis, with previous treatments including lymph node dissection, radiation therapy, chemotherapy, and high-dose interferon failing to show statistically significant survival benefits over no treatment. After 4 decades of therapeutic "drought," however, 2 potential breakthrough therapies have emerged and been given fast-track approval by the FDA for immediate use. Ipilimumab is one of these therapies; the second is vemurafenib.

On the basis of the results of the studies described above, the FDA approved ipilimumab to treat patients with late-stage (metastatic) melanoma in March 2011. Although this treatment shows much promise, variable efficacy and significant, potentially life-threatening toxicity remain important limitations.


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