The FDA has approved peginterferon alfa-2b (Sylatron™) as a treatment for malignant melanoma with lymph node involvement, if given within 84 days of full surgical resection of the primary tumour and the lymph nodes involved. This approval was based on the results of a single large Phase III clinical trial, EORTC 18991 [2], which suggest that the efficacy of this drug is equivalent to that of the standard treatment of high-dose interferon, but it is easier to administer and has fewer severe adverse reactions.

Few options are available for the adjuvant treatment of malignant melanoma, which is the least common but most deadly form of skin cancer. Interferon alfa-2b was first approved for this indication in 1995. It is a cytokine, a small protein that acts by stimulating the patient's immune system, and it must be administered by intravenous injection. Covalent attachment of polyethylene glycol polymer chains to interferon molecules, a process known as PEGylation, can significantly increase the time that the drug remains in the bloodstream, thus reducing the frequency of dosing and, potentially, reducing the frequency and severity of side effects.

The European Organization for Research and Treatment of Cancer set up clinical trial EORTC 18991 to evaluate pegylated interferon alfa-2b as a long-term treatment for advanced malignant melanoma. A total of 1256 patients from ninety-nine centres in seventeen countries were enrolled. The participants, who were all diagnosed with stage III melanoma, were randomized to receive either peginterferon alfa-2b for five years post-surgery or observation alone. Patients on the treatment arm received an injection of a high dose of the drug once a week for eight weeks followed by a lower dose once a week until the end of the trial. The primary endpoint was relapse-free survival (RFS).

After four years, the RFS rate of the treatment arm was found to be significantly higher than that of the observation arm (45.6% versus 38.9%, p = 0.01) and median RFS was estimated to be 34.8 months in the treatment arm compared to 25.5 months in the observation arm. There was, however, no significant improvement in either metastasis-free survival or overall survival. Patients with less advanced disease and fewer lymph nodes involved showed the most benefit. These results indicated that the efficacy of the pegylated drug was equivalent to that of the standard treatment of high-dose interferon alfa-2b.

Thirty-one percent (191/608) of patients on the treatment arm stopped treatment early because of toxicities, some of the most common being fatigue, depression, anorexia and elevated liver function tests. However, the incidence of severe (Grade 3 or 4) side effects was significantly lower than that recorded in earlier clinical trials of high-dose interferon alfa-2b, with, for example, severe fatigue reported by 16% of patients receiving peginterferon alfa-2b and 24% of patients receiving high dose interferon.

Therefore, although peginterferon alfa-2b is no more effective than the standard interferon treatment, its side effect and quality of life profile was sufficiently favourable to allow the FDA to approve the pegylated drug for this indication. Two further trials comparing the two types of interferon directly are still in progress. The authors of the evidence-based review [2] also conclude that, even with the approval of peginterferon alfa-2b, treatment options for metastatic malignant melanoma are still poor and there is a pressing need for drugs that prolong survival as well as improving quality of life.

References

[1]: Full text of FDA announcement: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm249263.htm

[2]: Okuyama, S., Gonzalez, R. and Lewis, K.D. (2010). Pegylated interferon alpha-2b as adjuvant treatment of Stage II malignant melanoma: an evidence-based review. Core Evid. 5: 39–48.