Association of homogeneous inflamed gene signature with a better outcome in patients with metastatic melanoma treated with MAGE-A3 immunotherapeutic

Abstract

PurposeThis study assessed clinical activity, safety and immunogenicity of MAGE-A3 immunotherapeutic in patients with MAGE-A3-positive metastatic melanoma.Patients and methodsIn 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.ResultsOf 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.ConclusionTreatment 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 numberNCT00896480 (Results).

Introducing a new ESMO Open article series: how I treat side effects of immunotherapy

“…Recent data from lung cancer, melanoma and glioblastoma indicate that immune checkpoint inhibition may even be of relevant clinical benefit in neoadjuvant therapy, thus opening novel avenues for further development of cancer immunotherapy 10–23. In addition, novel molecular insights drive refined selection of patients with cancer for targeted treatments including immunotherapies and the development of new approaches to effective anti-cancer immunomodulation 24–26. Notwithstanding the economical issues and implications,27–29 all of these developments lead to a quickly increasing number of patients with cancer being exposed to modern immunotherapy in clinical routine worldwide.…”