Although the incidence of many common cancers is declining, the incidence of melanoma continues to increase at a rate faster than any of the seven most common cancers. An estimated 70,230 new cases of melanoma will be diagnosed in the United States in 2011, resulting in nearly 8,790 deaths according to the National Cancer Institute (NCI).1 However, significant advances in the laboratory are translating into new standards of care for melanoma and reason to believe that new approaches may soon reduce its morbidity and mortality.
Immunotherapy agents and therapeutic vaccines are changing the way patients with malignant melanoma are counseled and treated. Currently, the American Cancer Society (ACS) estimates the 5-year survival rate for persons with stage IV disease at 15% to 20%.2 However, new therapies are demonstrating an ability to improve overall survival for persons with melanoma. This article reviews some of the new developments in melanoma treatment.
“Until recently, we’ve had limited options for our patients, and little hope for long-term survival. In the past 2 years, we’ve seen remarkable progress with immunotherapy, and now, a promising targeted therapy,” said Lynn Schuchter, MD, professor of hematology-oncology and division chief at the Abramson Cancer Center at the University of Pennsylvania, Philadelphia.
A randomized, international phase III trial found that vemurafenib (Zelboraf), which targets the V600E mutation in the BRAF gene, is the first drug to improve overall survival compared with standard chemotherapy in patients with advanced melanoma.3 Approximately 50% of all melanomas harbor a V600E mutation in the BRAF gene. Researchers compared the effectiveness of vemurafenib with dacarbazine (DTIC-Dome, generics) in terms of progression-free survival (PFS) and overall survival (OS) in 675 patients with previously untreated, inoperable stage IIIC and stage IV metastatic melanoma and a V600E mutation in the BRAF gene.3
In the planned interim analysis at a median of 3 months, the risk of death was reduced by 63% in patients receiving compared with those receiving dacarbazine. The risk of disease progression was reduced by 74% in the vemurafenib group compared with the dacarbazine group. The response rate was robust. The patients in the vemurafenib group had a 48.4% response rate, whereas the response rate was 5.5% in the dacarbazine group. At the first trial interim analysis, investigators recommended that those patients receiving dacarbazine switch to vemurafenib.
“This is really a huge step toward personalized care in melanoma,” said lead study author Paul Chapman, MD, who is an attending physician at Memorial Sloan-Kettering Cancer Center, New York, New York. “This is the first successful melanoma treatment tailored to patients who carry a specific gene mutation in their tumor.”
Chapman said vemurafenib is the first drug to show improved PFS and overall survival rates in this patient population. If approved by the FDA, vemurafenib could become a new standard treatment for patients with melanoma who have this gene mutation.
Fewer than 10% of patients who received vemurafenib experienced problems with high levels of toxicity (grade 3 or higher).3 The most common adverse effects in the vemurafenib group were diarrhea, rash, alopecia, photosensitivity, fatigue, arthralgia, and keratoacanthoma/skin squamous cell carcinoma. The researchers currently are planning to test vemurafenib in combination with other agents in patients with advanced melanoma. A Phase I trial has already begun with vemurafenib and ipilimumab (Yervoy), an immunotherapy that received approval earlier this year.
IMMUNOTHERAPY PLUS CHEMOTHERAPY
Immunotherapy for melanoma patients is becoming an option. First-line treatment with a combination of the immunotherapy drug ipilimumab and dacarbazine has been found to improve OS in patients with previously untreated metastatic melanoma, according to a new phase III randomized study of 502 patients.4 It is the first to show that combining chemotherapy with immunotherapy is safe and effective in this patient population.
“This trial’s 3-year end point is significant. No randomized trial for metastatic melanoma has followed patients for this long, and it demonstrates the durability of this survival benefit, now out to 3 years in this population, and even 4 years in some cases,” said lead study investigator Jedd Wolchok, MD, who is director of immunotherapy clinical trials and an associate attending physician at Memorial Sloan-Kettering Cancer Center, New York, New York. “It is one of the advantages of immunotherapy. The immune system is a living drug able to adapt itself to changes in the tumor that might otherwise lead to resistance when treated with chemotherapy or a pathway inhibitor.”