MAGE-A3 Antigen-Specific Vaccine Fails to Extend DFS in NSCLC

The MAGE-A3-specific immunotherapeutic GSK1572932A failed to significantly extend disease-free survival (DFS) in two out of three patient populations enrolled in the large phase III MAGRIT study that explored the vaccine in non-small cell lung cancer (NSCLC), according to an interim analysis conducted by an Independent Data Monitoring Committee (IDMC).

GlaxoSmithKline (GSK), the company developing the drug, plans to continue the study to measure the efficacy of the vaccine specifically in patients who tested positive for a specific gene signature that may predict benefit from the treatment. Findings from the interim analysis remain blinded and a final analysis is expected in 2015.

The phase III placebo-controlled study assessed DFS with the MAGE-A3-directed therapy in the adjuvant setting for 2312 patients with stage IB, II, and IIIA resected NSCLC. All patients enrolled in the study expressed the MAGE-A3 gene, which occurs in approximately 35% of patients with resectable NSCLC.

“We are disappointed that the trial did not demonstrate a benefit for overall MAGE-A3 positive patient population, but we remain committed to the effort to identify a sub-population of NSCLC patients who may benefit from this investigational treatment,” Vincent Brichard, Senior Vice-President & Head of Immunotherapeutics for GSK Vaccines, said in a statement.

In September 2013, the MAGE-A3 vaccine failed to extend DFS in certain patients with postsurgical melanoma when compared with a placebo in the phase III DERMA study. This study enrolled 1345 patients with MAGE-A3-positive stage IIIB or IIIC melanoma. In a similar fashion to the MAGRIT study, the IDMC recommended continuing the study in select patients who expressed the gene signature.

The genetic signature that continues to be explored in both studies was described in a retrospective analysis published in the Journal of Clinical Oncology. This study examined patients from two phase II studies that investigated the vaccine. This analysis identified 84 genes that correlated with response, from mRNA samples using microarray analysis and quantitative polymerase chain reaction. The majority of the genes identified in the study were immune-related, including those in the interferon gamma pathway and specific chemokines.

This analysis found that patients with melanoma who expressed the specific genetic signature saw an improvement in overall survival (OS) compared with placebo. This advantage was more pronounced when the AS15 immunostimulant was utilized (HR = .37; P = .06) compared with AS02_B (HR = .84; P = .7). This same signature was applied to patients with resected NSCLC who received treatment with MAGE-A3 plus AS02_B. Overall, patients who tested positive for the genetic signature experienced an improvement in DFS (HR = 0.42; P = .06) compared with negative patients (HR = 1.17; P = .65).

The MAGRIT trial followed a similar design to a previous phase II study that randomized 182 patients with resected NSCLC in a 2:1 ratio to receive the MAGE-A3 immunotherapy (n = 122) or placebo (n = 60). The vaccine and placebo were administered in 13 intramuscular injections over a period of 27 months.

Treatment with the vaccine failed to statistically significantly extend disease-free interval (HR = .75, P = .254), DFS (HR = .76, P = .248), and OS (HR = .81, P = .454) when compared with placebo. However, the authors of this study concluded that immunization with the MAGE-A3-directed vaccine was feasible and had minimal toxicity.

Based on these results, the MAGRIT study was formed and labeled the largest-ever phase III lung cancer trial to study a tumor-specific approach to therapy. The study had a secondary endpoint aimed at the prospective validation of the predictive value for the 84-gene signature.