MAGE-A3 Vaccine Now Dropped for Lung Cancer

Zosia Chustecka

April 02, 2014

A vaccine directed against the tumor-specific antigen MAGE-A3, under development at GlaxoSmithKline (GSK), has now been dropped from development for lung cancer, although an ongoing phase 3 trial in melanoma is continuing.

The vaccine had shown promising results in lung cancer in a phase 2 trial, but results from a subsequent phase 3 trial, announced only a few weeks ago, did not reach significance. At the time it was announced, the company said that it would analyze the data to try to identify a subgroup of patients that is most likely to respond to the vaccine.

Now, however, the company says it has established that is not possible.

"We are extremely disappointed," commented Vincent Brichard, senior vice-president and head of immunotherapeutics at GSK Vaccines. "We hope that the data generated in this trial will advance our understanding of the science of immunotherapeutics, and ultimately towards development of new therapies."

Directed Against Tumor-Specific Antigen

The vaccine is directed against the MAGE-A3 protein, a tumor-specific antigen expressed in a variety of cancers, but not in normal cells.

In non-small cell lung cancer (NSCLC), in patients diagnosed with stage IB to IIIA disease, this protein is expressed in about one third of tumors, according to the company.

Results from the phase 2 trial, which were considered promising enough to launch the phase 3 trial, were published last year (J Clin Oncol. 2013:31:2396-2403).

That phase 2 trial was conducted in 182 patients with resected MAGE-A2-positive stage IB to II NSCLC who received induction with 5 doses of the MAGE-A3 vaccine or placebo every 3 weeks, followed by 8 consolidation administrations every 3 months. The long-term analysis showed a positive trend for MAGE-A3 treatment in this setting, with a nonsignificant but clinically relevant improvement in disease-free interval (hazard ratio [HR], 0.75 in favor of the vaccine), disease-free survival (HR, 0.76), and overall survival (HR, 0.81). Overall, treatment was very well tolerated, resulting in very high therapy compliance, noted a recent review of immunotherapy for lung cancer (Future Oncol. 2014;10:91-105), which describe this vaccine approach as "promising."

However, the phase 3 trial that followed failed to meet its end points.

Known as MARGRIT, this phase 3 trial was conducted in patients with stage IB, II, and IIIA completely resected MAGE-A3-positive NSCLC. Patients were given up to 13 intramuscular injections of either the vaccine or placebo over a period of 27 months.

Data from the trial announced on March 20 showed that it did not meet its first or second coprimary end points, as it did not significantly extend disease-free survival, when compared with placebo, in either the overall MAGE-A3-positive population (first coprimary end point) or in those MAGE-A3-positive patients who did not receive chemotherapy (second coprimary end point).

GSK continued with the MAGRIT trial to investigate the third coprimary end point of disease-free survival in a gene-signature-positive subpopulation, which was designed to identify a subset of MAGE-A3-positive patients that may benefit from the treatment.

However, the preplanned independent third-party analysis of a proportion of the data (to identify a gene-signature classifier) has concluded that assessment of the third coprimary end point is not feasible due to an insufficient treatment effect, the company announced.

The trial will be stopped and GSK will now gain access to the unblinded data, in order to conduct a full assessment of the findings.

Ongoing Melanoma Study

A phase 3 trial with the vaccine in melanoma patients, known as DERMA, is continuing.

The company said that it is continuing to evaluate whether a gene signature can identify a subpopulation of melanoma patients that would benefit from the product. This trial has met its first coprimary end point of disease-free survival in the overall MAGE-A3-positive population (results were announced in September 2013). Work is progressing on the mathematical model (the gene-signature classifier) to allow assessment of disease-free survival in the gene-signature population, the second coprimary end point, the company noted. This outcome is expected in 2015.

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