Vaccine Improves Survival Rates From Metastatic Melanoma

Norra MacReady

June 02, 2011

June 2, 2011 — Adding an immunity-boosting vaccine to treatment with interleukin 2 (IL-2) significantly improves survival with metastatic melanoma, researchers have found.

Patients who received the vaccine along with IL-2 were more than twice as likely to have a clinical response as patients receiving IL-2 alone, the investigators report in an article published online June 2 in the New England Journal of Medicine.

"Our study showed that a vaccine can enhance cytokine therapy in patients with melanoma and highlights the potential of using rational combinations of immune agents in treating patients with metastatic cancer," write the authors, led by Douglas J. Schwartzentruber, MD, from the Indiana University Health Goshen Center for Cancer Care.

Metastatic melanoma has a grim prognosis, with 5-year survival rates of less than 10%, the authors explain. Treatment with IL-2, which promotes T-cell activation and proliferation, is associated with response rates of 13% to 16%. Six percent of patients experience a complete response that can be "quite durable."

So far, vaccines for metastatic cancer have not yielded clear benefits, but it has been hypothesized that their efficacy might be improved if they are administered in combination with agents that drive the immune response, such as cytokines. One vaccine, the peptide gp100:209-217(210M), has been shown to elicit very high levels of T cells that recognize and attack melanoma cells in vitro. In a previous, single-group study of people with metastatic melanoma, administration of the vaccine followed by treatment with high-dose IL-2 was associated with a clinical response rate of 42%, which is higher than anything previously reported for just IL-2. This finding "provided the impetus for the current randomized trial comparing vaccine plus IL-2 with IL-2 alone."

The current randomized, phase 3 study included 185 patients at 21 centers across the United States. Of 94 patients randomly assigned to receive only IL-2, 93 received treatment and could be evaluated for a response. Of 91 patients in the vaccine–IL-2 group, 86 received treatment, and 85 were evaluated for a response. All 185 patients were included in the analysis of progression-free and overall survival.

IL-2 was administered to all patients in a dose of 720,000 IU/kg body weight as an intravenous bolus every 8 hours, for a maximum of 12 doses per cycle. Each cycle was repeated every 3 weeks. Therapy was discontinued in patients with progressive disease and continued for another 2 cycles in patients with stable disease.

Patients in the vaccine group received the vaccine as a subcutaneous injection in the thigh while they received the IL-2. Tumor response was assessed every 6 weeks in both groups.

As assessed by the investigators, a complete or partial response was achieved by 10% of the patients in the IL-2 group compared with 20% in the vaccine group (P = .05). On blinded, central radiologic review, the response rates were 6% and 16%, respectively (P = .03).

Median progression-free survival, defined as time from randomization until documented progression or death from any cause, was 1.6 months among patients receiving IL-2 alone and 2.2 months in the vaccine group (P = .008). A trend toward better overall survival also was observed in the vaccine group, although the study was not powered to detect a difference.

Grade 3 to 5 toxic effects were experienced by 74 (80%) of 93 patients in the IL-2 group and 73 (86%) of 85 patients in the vaccine group (P = .27). Patients receiving the vaccine reported significantly higher rates of cardiac arrhythmias, abnormal laboratory test results, constitutional symptoms, and neurologic symptoms than patients receiving IL-2 alone; the rates of all other toxicities were similar between the groups.

Overall, patients who received the vaccine "were more than twice as likely to have a clinical response as those receiving [IL-2] alone," the authors state. "This randomized study showed the clinical benefit of a vaccine in the treatment of patients with measurable metastatic melanoma," they conclude, adding, "[o]ur study showed that a vaccine can enhance cytokine therapy in patients with melanoma and highlights the potential of using rational combinations of immune agents in treating patients with metastatic cancer."

This study was supported by the National Cancer Institute, Indiana University Health Goshen, Goshen Hospital and Health Care Foundation, Chiron, and Novartis. Several authors have disclosed receiving lecture payments and/or consultancy fees, serving on boards, and/or other financial relationships with one or more of the following institutions: Advanced Cancer Therapeutics, Antisoma Inc, Bayer-Onx, Bristol Meyer Squibb, Chiron, Genzyme, GlaxoSmithKline, Kentucky Bioprocessing Inc, Nekktar, Neogenix Oncology, Novartis, Physician’s Education Resource, Precision Therapeutics, and Prometheus Pharmaceuticals.

N Engl J Med. 2011;364:2119-2127.

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