MAGE-A3 Immunotherapeutic Fails in Stage III Melanoma

An antigen-specific immunotherapeutic known as MAGE-A3 was no better than placebo for the adjuvant treatment of stage IIIB or IIIC melanoma, according to results of a phase III trial. Development of the agent has now been stopped.

Despite recent advances in melanoma therapy, it remains a dangerous disease, and many with stage IIIB/C disease are at risk of relapse. MAGE-A3 is a tumor antigen expressed in as many as three-quarters of melanomas; it is silent in all normal human tissues with the exception of testis and placenta, according to study authors led by Brigitte Dreno, MD, of Hotel Dieu Nantes University Hospital in France. Earlier studies suggested the MAGE-A3 immunotherapeutic, including a recombinant MAGE-A3 protein along with an immunostimulant known as AS15, could enhance the immune response against melanoma cells.

The DERMA trial was a phase III study conducted in 31 countries. It included 1,345 patients with completely resected stage IIIB or IIIC MAGE-A3–positive cutaneous melanoma with macroscopic lymph node involvement; they were randomized 2:1 to receive either the MAGE-A3 immunotherapeutic (895 patients) or placebo (450 patients). The median follow-up for the 2 groups was 28.0 months and 28.1 months, respectively. Patients had a median age of 57 years in both groups, and approximately 60% were male. Results were published in Lancet Oncology.

The median disease-free survival was no different between the groups: 11.0 months with MAGE-A3 and 11.2 months with placebo, for a hazard ratio (HR) of 1.01 (95% CI, 0.88–1.17; P = .86).

Among a subset of patients who were positive for a potentially predictive 39-gene signature, the results were similar. The signature-positive patients had a median disease-free survival with MAGE-A3 of 9.9 months, compared with 11.6 months with placebo, for an HR of 1.11 (95% CI, 0.83–1.49; P = .48). All other sensitivity analyses of the primary outcomes were consistent, and showed no treatment effect.

At the final follow-up analysis, the median overall survival was not reached in either group, and the HR for overall survival was 1.06 (95% CI, 0.89–1.26; P = .52). Again, there was no difference in terms of overall survival among the patients positive for the predictive gene signature.

Within the first 31 days of initiation of treatment, 14% of MAGE-A3 patients and 12% of placebo patients had an adverse event of grade 3 or worse. At least one potentially serious adverse event was reported in 14% of both groups. The most common grade 3 or worse adverse events included neoplasms in 4% of both groups, infections and infestations in 2% of both groups, and others.

The authors wrote that the reasons for the lack of efficacy are not clear, but it could be related to the choice of antigen or immunostimulant, or to the absence of induction of T-cell responses. “Despite initially encouraging, but ultimately discordant, results from phase II studies, treatment with the MAGE-A3 immunotherapeutic did not improve disease-free survival, overall survival, or any other clinical outcome in the overall population of patients with advanced melanoma,” they concluded.