MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial

MAGE-A3 immunotherapeutic as adjuvant therapy for patients with resected, MAGE-A3-positive, stage III melanoma (DERMA): a double-blind, randomised, placebo-controlled, phase 3 trial.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1016/S1470-2045%2818%2930254-7
Journal or Publication Title: The Lancet Oncology
Volume: 19
Number: 7
Page Range: pp. 916-929
Date: 2018
Divisions: Melanoma Oncology and Immunology
Depositing User: General Admin
Identification Number: 10.1016/S1470-2045(18)30254-7
ISSN: 14702045
Date Deposited: 03 Jan 2021 22:51
Abstract:

Background: Despite newly approved treatments, metastatic melanoma remains a life-threatening condition. We aimed to evaluate the efficacy of the MAGE-A3 immunotherapeutic in patients with stage IIIB or IIIC melanoma in the adjuvant setting.

Methods: DERMA was a phase 3, double-blind, randomised, placebo-controlled trial done in 31 countries and 263 centres. Eligible patients were 18 years or older and had histologically proven, completely resected, stage IIIB or IIIC, MAGE-A3-positive cutaneous melanoma with macroscopic lymph node involvement and an Eastern Cooperative Oncology Group performance score of 0 or 1. Randomisation and treatment allocation at the investigator sites were done centrally via the internet. We randomly assigned patients (2:1) to receive up to 13 intramuscular injections of recombinant MAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic; 300 μg MAGE-A3 antigen plus 420 μg CpG 7909 reconstituted in AS01B to a total volume of 0·5 mL), or placebo, over a 27-month period: five doses at 3-weekly intervals, followed by eight doses at 12-weekly intervals. The co-primary outcomes were disease-free survival in the overall population and in patients with a potentially predictive gene signature (GS-positive) identified previously and validated here via an adaptive signature design. The final analyses included all patients who had received at least one dose of study treatment; analyses for efficacy were in the as-randomised population and for safety were in the as-treated population. This trial is registered with ClinicalTrials.gov, number NCT00796445.

Findings: Between Dec 1, 2008, and Sept 19, 2011, 3914 patients were screened, 1391 randomly assigned, and 1345 started treatment (n=895 for MAGE-A3 and n=450 for placebo). At final analysis (data cutoff May 23, 2013), median follow-up was 28·0 months [IQR 23·3-35·5] in the MAGE-A3 group and 28·1 months [23·7-36·9] in the placebo group. Median disease-free survival was 11·0 months (95% CI 10·0-11·9) in the MAGE-A3 group and 11·2 months (8·6-14·1) in the placebo group (hazard ratio [HR] 1·01, 0·88-1·17, p=0·86). In the GS-positive population, median disease-free survival was 9·9 months (95% CI 5·7-17·6) in the MAGE-A3 group and 11·6 months (5·6-22·3) in the placebo group (HR 1·11, 0·83-1·49, p=0·48). Within the first 31 days of treatment, adverse events of grade 3 or worse were reported by 126 (14%) of 894 patients in the MAGE-A3 group and 56 (12%) of 450 patients in the placebo group, treatment-related adverse events of grade 3 or worse by 36 (4%) patients given MAGE-A3 vs six (1%) patients given placebo, and at least one serious adverse event by 14% of patients in both groups (129 patients given MAGE-A3 and 64 patients given placebo). The most common adverse events of grade 3 or worse were neoplasms (33 [4%] patients in the MAGE-A3 group vs 17 [4%] patients in the placebo group), general disorders and administration site conditions (25 [3%] for MAGE-A3 vs four [<1%] for placebo) and infections and infestations (17 [2%] for MAGE-A3 vs seven [2%] for placebo). No deaths were related to treatment.

Interpretation: An antigen-specific immunotherapeutic alone was not efficacious in this clinical setting. Based on these findings, development of the MAGE-A3 immunotherapeutic for use in melanoma has been stopped.

Funding: GlaxoSmithKline Biologicals SA.

Copyright © 2018 Elsevier Ltd. All rights reserved.

Creators:
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Dreno, Brigitte
UNSPECIFIED
Thompson, John F
UNSPECIFIED
Smithers, Bernard Mark
UNSPECIFIED
Santinami, Mario
UNSPECIFIED
Jouary, Thomas
UNSPECIFIED
Gutzmer, Ralf
UNSPECIFIED
Levchenko, Evgeny
UNSPECIFIED
Rutkowski, Piotr
UNSPECIFIED
Grob, Jean-Jacques
UNSPECIFIED
Korovin, Sergii
UNSPECIFIED
Drucis, Kamil
UNSPECIFIED
Grange, Florent
UNSPECIFIED
Machet, Laurent
UNSPECIFIED
Hersey, Peter
UNSPECIFIED
Krajsova, Ivana
UNSPECIFIED
Testori, Alessandro
UNSPECIFIED
Conry, Robert
UNSPECIFIED
Guillot, Bernard
UNSPECIFIED
Kruit, Wim H J
UNSPECIFIED
Demidov, Lev
UNSPECIFIED
Thompson, John A
UNSPECIFIED
Bondarenko, Igor
UNSPECIFIED
Jaroszek, Jaroslaw
UNSPECIFIED
Puig, Susana
UNSPECIFIED
Cinat, Gabriela
UNSPECIFIED
Hauschild, Axel
UNSPECIFIED
Goeman, Jelle J
UNSPECIFIED
van Houwelingen, Hans C
UNSPECIFIED
Ulloa-Montoya, Fernando
UNSPECIFIED
Callegaro, Andrea
UNSPECIFIED
Dizier, Benjamin
UNSPECIFIED
Spiessens, Bart
UNSPECIFIED
Debois, Muriel
UNSPECIFIED
Brichard, Vincent G
UNSPECIFIED
Louahed, Jamila
UNSPECIFIED
Therasse, Patrick
UNSPECIFIED
Debruyne, Channa
UNSPECIFIED
Kirkwood, John M
UNSPECIFIED
Last Modified: 03 Jan 2021 22:51
URI: https://eprints.centenary.org.au/id/eprint/514

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