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MAGE-A3 as a Vaccine Target in NSCLC

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One of the more intriguing presentations at ASCO this year was the one in which a novel vaccine against a protein called MAGE-A3 was tested in patients who underwent surgery and then received the vaccine post-operatively. What is MAGE-A3? It’s a nearly tumor-specific antigen, which means that it’s a protein seen almost exclusively on cancer cells, including lung cancer, head & neck, bladder, and melanomas. The only normal non-cancer tumor tissue it’s seen on in the testicles, but there have been no problems with auto-immune or other complications against testicular tissue, as these cells don’t have the capacity to generate an immune response.

The limited available evidence suggests that expression of MAGE-A3 is associated with a worse prognosis, and along with that is the finding that it’s more commonly seen in higher cancer stages. It’s seen in only about 16% of stage IA NSCLC tumors, about 35% of stage II and IIIA resected NSCLC tumors, and about 50% of more advanced NSCLC cancers.

The trial that made such a splash was presented by Vansteenkiste and colleagues (abstract here), and had a design of 2 to 1 randomization of patients after surgery to vaccine vs. placebo:

MAGE-A3 trial schema (click to enlarge)

The trial enrolled 182 patients with stage IB or II NSCLC and tumors that demonstrated MAGE-A3 expression (again, about 1/3 of those screened). The protocol was for the vaccine every three weeks for 5 cycles, followed by a maintenance phase of injections once every three months for two years. The total time of treatment was a little more than two years. The goal of the trial was to detect an improvement in the median time to recurrence (hopefully reducing the likelihood of the cancer recurring).

Typical for vaccines, the treatment was quite well tolerated, with the majority of side effects mild or moderate. Most were “local”, meaning things like redness, swelling, and pain at the injection site, and some patients get fevers and other flu-like symptoms.

The trial demonstrated a 27% reduced risk of recurrence in the group that received the active vaccine:

MAGE A3 DFS curves

While this difference didn’t quite reach statistical significance (p-value was a little higher than p = 0.05), that is a pretty encouraging improvement, and if the trial were just a little larger, this difference would have been statistically significant.

Based on these results, the manufacturer of the vaccine (GlaxoSmithKline) is moving forward with an international trial called MAGRIT in order to test the vaccine in approximately 2270 patients with MAGE-A3-positive stage IB, II, or IIIA resected tumors. Treatment can start directly after surgery, in patients who aren’t good candidates for or just don’t want post-op chemo, or patients can have received up to four cycles of platinum-based adjuvant chemotherapy. Unlike the smaller trial, patients on the larger phase III trial will be evenly divided between the active vaccine and placebo. The focus of the trial will be to detect a significant improvement in disease-free survival, and the planned enrollment will make it the largest post-operative NSCLC trial ever, which is particularly ambitious because only a fraction of the people screened for the trial will be eligible because of the requirement for MAGE-A3 expression on the tumor. Information on the trial, which is not yet enrolling patients but should be soon, is here.


4 Responses to MAGE-A3 as a Vaccine Target in NSCLC

  • raneyf says:

    Dr. West,
    Can you explain to me why this vaccine, and others like Stimuvax, don’t appear to help people with Advanced NSCLC? Is it just that the tumor burden is too high, or performance status is generally too low? It just seems that maybe they could help in conjunction with chemo or other agents.
    Thank you.
    Raney

  • Dr. West says:

    Raney,

    Stimuvax was tested in that setting along with locally advanced disease, and it looked like it was helpful only in the stage III patients.

    I would consider two main challenges with advanced disease. The first is the bulk of disease. Vaccines have generally been used for treating very low burden of infection (or cancer), not a raging infection or very large tumor burden. So cancer vaccines are felt to be far more likely to help people with earlier stage disease. The other issue is that chemotherapy is likely to decrease the immune response of people, at least transiently, and people with advanced cancer may also have diminished immune responsiveness just due to their active cancer, sometimes diminished nutrition, etc.

    So while this hasn’t been tested directly with MAGE-A3 (which is more frequently expressed on more advanced tumors), the evidence does indicate that, for one reason or another, Stimuvax has shown more favorable results only in the patients with less advanced disease.

    -Dr. West

  • Dr. West,
    Most doctors I talk to seem to agree with you in that they tend to think vaccines work best in earlier stage patients or possibly advanced stage if they are stable or are in remission. Do you think this trial sounds similar to most of the other vaccines?
    http://www.clinicaltrials.gov/ct/show/NCT00073398?order=1

    I realize this is a phase I/II trial so there isn’t much to talk about yet but would be interested in any comments.

    It sounds sort of like the GVAX if I remember correctly?

    Terri

  • Dr. West says:

    If I’m reading the information right, there’s a difference between this and the GVAX approach, in that GVAX required patients to have fresh tissue harvested in order to make a vaccine. It doesn’t appear that this is the case here. I don’t know about this particular vaccine or the targete of it, but it’s an early stage trial, which means that they’re really focusing on safety and finding an appropriate dose to move forward with. It doesn’t sound like there are any efficacy results yet. I and many other oncologists remain skeptical about vaccine approaches in cancer because they have really been disappointing for decade after decade, and I think that if they do make a meaningful contribution, it’s more likely to be in earlier stage patients with minimal residual disease.

    -Dr. West

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