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PURPOSE: This study assessed clinical activity, safety and immunogenicity of MAGE-A3 immunotherapeutic in patients with MAGE-A3-positive metastatic melanoma. PATIENTS AND METHODS: In this open-label, multicentre, uncontrolled, Phase II study (ClinicalTrials.gov NCT00896480), patients received ≤24 doses of MAGE-A3 immunotherapeutic (4-cycle schedule). At screening, two skin lesions were biopsied for MAGE-A3 expression analysis and presence/absence of a previously identified gene signature (GS) associated with favourable clinical outcome. Clinical activity was assessed in terms of clinical response, time-to-treatment failure (TTF) and progression-free survival (PFS). Adverse events (AEs) and serious AEs (SAEs) were recorded. MAGE-A3-specific immune responses were assessed. Clinical activity and immunogenicity were analysed overall and separately in patients with 2/2 (GS+/+), 1/2 (GS+/-) or 0/2 (GS-/-) biopsies presenting GS. RESULTS: Of 49 screened patients, 32 had MAGE-A3-positive tumours; 24 (8 GS+/+, 8 GS+/-, 8 GS-/-) were treated. Two complete (GS+/+ patients) and two partial responses (one GS+/+, one GS+/-) were reported; of note, one of the two complete responses was unlikely to be related to the study treatment. Median TTF and PFS were 14.8 and 7.2 months for GS+/+, 2.3 and 2.8 months for GS+/- and 2.4 and 2.9 months for GS-/- patients. Three grade 3 AEs and two SAEs unrelated to treatment were reported. All patients were seropositive for MAGE-A3 antibodies on vaccination with no differences between the different GS profiles. MAGE-A3-specific CD4+ and CD8+ T cell immunogenicity was detected; 12/16 (75.0%) of patients presented CD4+ T cell responses. CONCLUSION: Treatment with MAGE-A3 immunotherapeutic showed signs of clinical activity in GS+/+ patients. Treatment was well tolerated and immunogenic. No differences in immune responses according to GS status were observed. TRIAL REGISTRATION NUMBER: NCT00896480 (Results).
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BACKGROUND: We assessed safety, immunogenicity and clinical activity of recombinant MAGE-A3 antigen combined with AS15 immunostimulant (MAGE-A3 immunotherapeutic) in association with dacarbazine in patients with metastatic melanoma. METHODS: In this open-label, phase I/II, uncontrolled multicentre trial conducted in Belgium and France, patients with MAGE-A3-positive melanoma received up to 24 doses of MAGE-A3 immunotherapeutic (four cycles) coadministered with eight doses of dacarbazine. Adverse events (AE) were recorded until 31 days postvaccination, and serious AEs (SAE), until 30 days following the last dose. MAGE-A3-specific antibodies were measured by ELISA. Clinical activity of MAGE-A3 immunotherapeutic was assessed in patients positive/negative for previously identified gene signature (GS) associated with clinical outcome. RESULTS: Forty-eight patients were enrolled and treated (32 GS+, 15 GS-, 1 unknown GS status); two patients completed the study. All patients reported AEs, the most common were 'general disorders and administration site conditions' (94%). Treatment-related AEs were reported by 85% of patients; the most common was pain at injection site (38%). Sixteen SAEs were reported by 21% of patients; two were considered as treatment related (neutropenia and thrombocytopenia; grade 4). Postdose 4, all patients were seropositive for MAGE-A3-specific antibodies, with a geometric mean titre of 2778.7 ELISA units (EU)/mL (95% CI 1638.3 to 4712.8). One complete and three partial responses were reported (only in GS+ patients). Median overall survival was 11.4 months for GS+ and 5.3 months for GS- patients. CONCLUSION: Although this trial shows poor results compared with the new results with checkpoint inhibitors, it gives an interesting insight in rapidly developing fields like combinations of immunotherapy and chemotherapy, new generation vaccines and the use of gene profile as a predictive marker. TRIAL REGISTRATION NUMBER: NCT00849875.
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PURPOSE: The MAGE-A3 protein is expressed in approximately 35% of patients with resectable non-small-cell lung cancer (NSCLC). Several immunization approaches against the MAGE-A3 antigen have shown few, but often long-lasting, clinical responses in patients with metastatic melanoma. PATIENTS AND METHODS: A double-blind, randomized, placebo-controlled phase II study was performed assessing clinical activity, immunologic response, and safety following immunization with recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) in completely resected MAGE-A3-positive stage IB to II NSCLC. The primary end point was disease-free interval (DFI). RESULTS: Patients were randomly assigned to either MAGE-A3 immunotherapeutic (n = 122) or placebo (n = 60). After a median postresection period of 44 months, recurrence was observed in 35% of patients in the MAGE-A3 arm and 43% in the placebo arm. No statistically significant improvement in DFI (hazard ratio [HR], 0.75, 95% CI, 0.46 to 1.23; two-sided P = .254), disease-free survival (DFS; HR, 0.76; 95% CI, 0.48 to 1.21; P = .248), or overall survival (HR, 0.81; 95% CI, 0.47 to 1.40; P = .454) was observed. Corresponding analysis after a median of 70 months of follow-up revealed a similar trend for DFI and DFS. All patients receiving the active treatment showed a humoral immune response to the MAGE-A3 antigen, although no correlation was observed with outcome. No significant toxicity was observed. CONCLUSION: In this early development study with a limited number of patients, postoperative MAGE-A3 immunization proved to be feasible with minimal toxicity. These results are being investigated further in a large phase III study.
