The Food and Drug Administration has approved the use of ipilimumab to treat patients with late-stage (metastatic) melanoma. The drug is made by Bristol-Myers Squibb under the trade name Yervoy.
"Late-stage melanoma is devastating, with very few treatment options for patients, none of which previously prolonged a patient's life," Richard Pazdur, MD, the FDA's Director of the Office of Oncology Drug Products, said in a statement. "Yervoy is the first therapy approved by the FDA to clearly demonstrate that patients with metastatic melanoma live longer by taking this treatment."
Yervoy is a monoclonal antibody that blocks the cytotoxic T-lymphocyte antigen (CTLA-4), which may play a role in slowing down or turning off the body's immune system, affecting the ability to fight off cancerous cells. Ipilimumab, which is given intravenously, may work by allowing the body's immune system to recognize, target, and attack cells in melanoma tumors.
"Ipilimumab is the first in a new class of drugs that has been shown to offer a survival benefit for metastatic melanoma, which is often a fatal disease, and hopefully, this will lead to the development of related treatments for other cancers," said one of the lead investigators of the national clinical study of the agent, F. Stephen Hodi, MD, Director of the Melanoma Treatment Center at Dana-Farber Cancer Institute.
Dr. Hodi reported at last year's ASCO Annual Meeting and in the New England Journal of Medicine findings from a Phase III trial involving 676 patients with advanced inoperable melanoma that had worsened during prior therapy for metastatic disease.
Patients were randomly assigned to receive one of three treatment regimens: ipilimumab and the gp100 vaccine; ipilimumab alone; or gp 100 alone.
The median survival for patients receiving either the combination or ipilimumab alone was about 10 months, vs 6.4 months for those receiving gp100 alone.
In the ipilimumab-alone group, nine of 15 patients continued to benefit from the therapy for at least two years, as did four of 23 patients in the combination group.
Regarding side effects, about 60% of the patients receiving ipilimumab had adverse side effects, as did 32% of the patients treated with gp100. The complications were generally immune system-related and most often affected the skin and GI tract-most commonly diarrhea, nausea, constipation, fatigue, decreased appetite, and rash. While the adverse effects could be severe and long-lasting, most were reversible with appropriate treatment.
"While ipilimumab, on average, extended the lives of patients by four months, there is also a group of patients who experienced a greater benefit and lived many months while being treated with this drug," Dr. Hodi said in a news release from Dana-Farber. "This is a big step in the right direction because it demonstrates that this class of drugs can benefit cancer patients."
An FDA news release notes that due to the "unusual and severe" side effects associated with ipilimumab, the FDA approval is with a Risk Evaluation and Mitigation Strategy to inform health care professionals about these serious risks. A medication guide will also be provided to patients to inform them about the therapy's potential side effects.
Also newly approved for melanoma is peginterferon alfa-2b (Sylvatron, Schering) for adjuvant treatment of patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.
The approval was based on EORTC 18991, an open-label, multicenter trial of 1,256 patients. Patients who had been adequately surgically resected for their primary cutaneous melanoma and affected regional lymph nodes were randomized (1:1) to receive either Sylatron or observation for five years.
Stratification factors included the type of nodal involvement (microscopic vs gross), the number of positive nodes (one, two to four, five or more, or not assessed), Breslow primary thickness (less than 1.5 mm, 1.5 to 4 mm, or 4 mm or more, ulceration of primary tumor (present or absent or unknown), sex, and study center.
Patients were assessed for local and regional recurrence or distant metastases every three months for the first two years of treatment and subsequently every six months through the end of the trial.
Based on 696 relapse-free survival (RFS) events, an improvement in RFS for Sylatron-treated patients was observed.
The estimated median RFS was 34.8 months for the patients receiving interferon vs 25.5 months for the observation patients. Following 525 deaths on study, there was no difference in overall survival between the two groups.
Safety was evaluated in 608 Sylatron-treated patients. The most common (occurring in more than 60% of patients) Grade 1-4 adverse reactions experienced by Sylatron-treated patients were fatigue, increased ALT, increased AST, pyrexia, headache, anorexia, myalgia, nausea, chills, and injection site reactions. The most common serious adverse reactions were fatigue, increased ALT, increased AST, and pyrexia.
Thirty-three percent of patients receiving Sylatron had to stop treatment due to adverse reactions. The most common of these present at the time of treatment discontinuation were fatigue, depression, anorexia, increased ALT, increased AST, myalgia, nausea, headache, and pyrexia.
Five deaths were reported within 30 days of the last Sylatron dose. Two were attributed to recurrent disease, two to cardiovascular disease possibly related to Sylatron, and one to an accident.The recommended dose and schedule for Sylatron is 6 mcg/kg/week, subcutaneously for eight doses, followed by 3 mcg/kg/week subcutaneously. The maximum treatment period is five years (260 weeks).
Ipilimumab Treatment How-To's
coming in the next issue of OT, and now available as an Online-First article is "Melanoma Care Enters New Phase with FDA Approval of Ipilimumab: Clinical Care Suggestions from Trialists" by Rabiya Tuma, PhD (http://bit.ly/OT-Ipilimumab)