Safety and immunogenicity of MAGE-A3 cancer immunotherapeutic with dacarbazine in patients with MAGE-A3-positive metastatic cutaneous melanoma: an open phase I/II study with a first assessment of a predictive gene signature

Abstract

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.

Keywords: immunotherapy; melanoma.

Conflict of interest statement

Competing interests: MG, JL and SJ are employees of the GSK group of companies. FFL was an employee of the GSK group of companies during the conduct of the study. FFL, JL and SJ own stock/stock options in the GSK group of companies. BD received grant/personal fees from GSK group of companies during the conduct of the study and from BMS, Roche and Novartis outside the submitted work. LM declares that his institution received support from GSK group of companies and Novartis to carry out clinical studies. LM reports personal fees from Roche, BMS, AMGEN, Novartis and GSK group of companies outside submitted work. JJG reports personal fees from GSK group of companies for his participation to an advisory board during the conduct of the study. CR received personal fees for participating to advisory boards for GSK, Novartis, Amgen, Roche, BMS and MSD. CL declares personal fees from Novartis, Roche, BMS, MSD and AMGEN for her participation to advisory boards.

Figures

Figure 1

Study design.  *Tumour evaluation. ^Blood sampling for evaluation of MAGE-A3-specific antibody response. no., number; V, visit.

Figure 2

Participant flow. *Patient was withdrawn after visit 4 due to a non-AE/SAE-related reason, that is, ‘neutropenia induced delay’. †All data collected after protocol violation were eliminated from the ATP immunogenicity analyses. AE, adverse event; ATP, according to protocol; N, number of patients; SAE, serious adverse event.

Figure 3

MAGE-A3-specific geometric mean concentrations (ATP population for immunogenicity). The numbers indicate the number of patients analysed at each timepoint. The error bars represent 95% CI. Due to a large CI for the last timepoint (21.3–1657225), the error bars for this timepoint are not shown. ATP, according to protocol; EU, ELISA units; GMC, geometric mean concentration; Post-2, postdose 2 (week 7); Post-4, postdose 4 (week 13); Post-8, postdose 8 (week 25); Post-12, postdose 12 (week 37); Post-16, postdose 16 (week 59); Pre, before first MAGE-A3 immunotherapeutic administration.

Figure 4

Overall survival (OS) by gene signature (total treated population). GS+, patients presenting gene signature; GS−, patients without gene signature.