Incidence of Melanoma Continues to Increase

Orlando—Between 1985 and 2010, the incidence of melanoma in the United States increased significantly, according to data from the National Cancer Institute. This year, 76,690 people will be diagnosed with, and 9480 people will die from, melanoma. As the number of patients with melanoma has increased, the treatment options have also expanded.

Evan J. Lipson, assistant professor of medical oncology at Johns Hopkins University, discussed several of the therapies at the Spring Managed Care Forum during a session titled Recent Advances in the Treatment and Management of Metastatic Melanoma. Bristol-Myers Squibb and Prometheus Laboratories Inc. supported the session with educational grants.

Many patients with melanoma undergo chemotherapy regimens that include dacarbazine, temozolomide, or paclitaxel. The response rates of these drugs are typically between 5% and 25%, according to Dr. Lipson, but they are also associated with toxicities such as nausea, vomiting, hair loss, and fatigue.

Although chemotherapy is common for melanoma, Dr. Lipson said it is not curative and has a limited role in the disease. He recommends chemotherapy only for patients whose melanoma has progressed after using other therapies and for those with a poor performance status.

Another FDA-approved option is Zelboraf^®(vemurafenib), an oral, twice-daily kinase inhibitor intended to treat patients with unresectable or metastatic melanoma who have the BRAF V600E mutation. In a phase 3 trial published in the New England Journal of Medicine [2011;364(26):2507-2516], the authors randomized 675 patients with previously untreated, metastatic melanoma to receive 960 mg of vemurafenib twice daily (n=337) or dacarbazine administered intravenously every 3 weeks (n=338).

The authors screened patients at 104 centers in 12 countries from January 2010 through December 2010. The vemurafenib and dacarbazine groups were well balanced. The median age was approximately 54 years, and 56% were male. The authors originally had a primary end point of overall survival, but they revised it in October 2010 to a coprimary end point of overall survival and progression-free survival.

After 6 months, the overall survival was 84% in the vemurafenib group and 64% in the dacarbazine group. Patients who took vemurafenib had a 63% relative reduction in the risk of death and a 74% relative reduction in the risk of death or disease progression compared with the dacarbazine group (P<.001 in all comparisons). In addition, the response rates were 48% for patients taking vemurafenib and 5% for patients taking dacarbazine.

Dr. Lipson noted that 38% of patients who received vemurafenib experienced an adverse event that led to dose modification or interruption compared with 16% of patients in the dacarbazine group. Common side effects associated with vemurafenib included arthralgia, rash, fatigue, alopecia, photosensitivity, nausea, and diarrhea. Dr. Lipson said that vemurafenib is effective in patients who need an immediate response. However, the responses are not sustained, and patients develop resistance to the drug within 6 to 8 months after beginning treatment.

He said that patients seeking a more durable response should consider Yervoy^® (ipilimumab), which the FDA approved in March 2011, 5 months before approving vemurafenib. The drug, a human cytotoxic T-lymphocyte antigen-4 antibody, is intended to treat patients with metastatic or unresectable melanoma. It is administered intravenously for 90 minutes every 3 weeks.

In a double-blind, phase 3 trial published in the New England Journal of Medicine [2010;363(8):711-23], the authors randomized 676 patients with unresectable, advanced melanoma whose disease had progressed after receiving previous treatments to receive ipilimumab plus the gp100 peptide vaccine (n=403), ipilimumab alone (n=137), or gp100 alone (n=136).

The mean age of patients was 56.2 years, and 59.3% were male. They were randomized between September 2004 and August 2008. The original primary end point was the best overall response rate, but the authors changed it to overall survival on January 15, 2009.

Patients receiving ipilimumab plus gp100 had a median overall survival of 10.0 months compared with 6.4 months for patients receiving gp100 alone (P<.001). There was also a significant difference in overall survival in the ipilimumab-alone group (median of 10.1 months) compared with the gp100-alone group (P=.003). Dr. Lipson said it was the first time a drug showed significant improvement in overall survival in patients with melanoma.

In trials involving ipilimumab, 17% to 23% of patients experienced serious, drug-related adverse events, and the mortality rate was 2%. Common immune-related adverse events associated with the drug included colitis, hepatitis, dermatitis, and neuropathies. In the phase 3 trial, approximately 60% of patients had immune-related adverse events. Most of the events affected the skin and gastrointestinal tract, and 10% to 15% of them were considered as grade 3 or 4.

Before determining whether an adverse event is immune-related, Dr. Lipson suggested healthcare professionals rule out other etiologies such as an infection, neoplasm, metabolic causes, and effects of other drugs. If patients have severe enterocolitis, they should permanently stop using ipilimumab and switch to systemic corticosteroids or infliximab. If the enterocolitis is moderate in severity, patients should withhold taking ipilimumab and take a prescription antidiarrheal medication. If the moderate enterocolitis persists >1 week, they should begin taking prednisone or another corticosteroid.

Dr. Lipson added that some patients with late-stage melanoma receive high-dose recombinant interleukin-2 therapy, which is administered in the intensive care units of approximately 100 centers in the United States. Approximately 15% to 20% of patients respond to treatment, but side effects include hypotension, tachycardia, capillary leak syndrome, and altered mental status.

The National Comprehensive Cancer Network’s updated guidelines indicate the preferred regimens for metastatic melanoma are ipilimumab, vemurafenib, and high-dose recombinant interleukin-2 therapy. Other active regimens for advanced disease include dacarbazine, tomozolomide, imatinib, and paclitaxel.

There are several drugs in the pipeline. In an open label, phase 1/2 trial, patients with metastatic melanoma and BRAF V600 mutations who took a combination of dabrafenib and trametinib had a median progression-free survival of 9.4 months compared with 5.8 months for patients taking dabrafenib monotherapy (P<.001). In addition, 76% of patients in the combination group had a complete or partial response compared with 54% of patients who took the monotherapy (P=.03).

Results of the trial were published in the New England Journal of Medicine [2012;367(18):1694-1703]. Dr. Lipson said dabrafenib plus trametinib is likely superior to the FDA-approved single agents, although healthcare professionals will know more later this year when more trial results are released.

Nivolumab, an anti-PD-1 drug, is also being evaluated for use in patients with metastatic melanoma. A study presented at the 2012 European Society for Medical Oncology Congress found that 52% of the patients who were followed for at least 1 year maintained a response to the treatment for at least 1 year.