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Dr. Jack West is a medical oncologist and thoracic oncology specialist, and Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center in Duarte, CA.

MAGE-A3 as a Vaccine Target in NSCLC
Thu, 06/14/2007 - 22:53
Howard (Jack) West, MD, Associate Clinical Professor, Medical Oncology, Executive Director, Employer Services, Founder, President and CEO of GRACE

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.

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