NEW YORK (Reuters Health) Sep 18 - Vaccination with ganglioside GM2-KLH/QS-21 does not improve outcomes in patients with stage II melanoma, according to a report from the European Organization for Research and Treatment of Cancer (EORTC).
GM2 ganglioside is expressed in most melanomas but less so in normal melanocytes and most normal tissues. The vaccine was previously shown to stimulate significant anti-GM2 IgM and IgG antibody responses in stage III melanoma patients.
Based on promising results in an earlier study, Dr. Alexander M. M. Eggermont from Gustave Roussy Comprehensive Cancer Center in Paris and colleagues in EORTC compared vaccination with GM2-KLH/QS-21 versus observation in a phase 3 trial of 1,314 patients with a primary tumor >1.50 mm with a moderate risk of relapse.
The study, online September 9 in the Journal of Clinical Oncology, was funded by Progenics Pharmaceuticals, which also provided the vaccine.
In the study's second interim analysis, at a median follow-up of 1.8 years, the criteria for ending the trial for futility were met. Not only was there no appreciable difference in relapse-free survival between the groups, the analysis of distant metastasis-free survival (DMFS) and overall survival revealed a trend favoring the observation arm.
As a result, the vaccine was stopped in those patients still receiving treatment, but the researchers continued to observe patients for the trial end points.
In the final analysis, at a median follow-up of 4.2 years, there was no difference in the number of relapse events between vaccine (205 events) and observation (204 events).
There were more distant metastases in the vaccine group (139) than in the observation group (121), and median overall survival was shorter with vaccine (1.29 years) than with observation (1.87 years).
Thirty-two of the 648 patients who actually received the vaccine had a 50% reduction in dose during the induction phase, and 39 had similar dose reductions during the maintenance phase. Thirty patients had to discontinue vaccination because of toxicity.
This marks the second trial of adjuvant therapy for melanoma that has been stopped at the second interim analysis, either for futility or inferior outcomes.
"It remains speculative at this point whether novel immune-modulatory agents such as anti-CTLA4 or anti-PD-1/PD-L1 could be helpful in the development of therapeutic vaccines," the researchers write. "The EORTC Melanoma Group has completed accrual of a double-blind study comparing adjuvant ipilimumab with placebo in patients with stage III disease. In light of the encouraging reports of the multicohort phase II trial (...) the results of the EORTC 18071 trial are awaited with great interest."
While not an author of this report, Dr. Angus Dalgleish from St. George's University of London served on the Progenics advisory board. He told Reuters Health, "The trend to reduced efficacy with the vaccine is due to the adjuvant which was too powerful, pushing the response beyond a TH-1 one to a strong TH-2 one, which is known to be detrimental in nearly all cancer vaccine cohorts."
"The early studies by Livingstone et al. produced good results with BCG (good for TH-1) as an adjuvant," Dr. Dalgleish said in an email. "However, they thought that a stronger one would be better. They were advised against this but persisted, thus wrecking the study."
"The Cuba group have a very active program on GM2, GM3 based vaccines," he added. "The results look good, as they don't over-adjuvant."
Dr. Eggermont did not respond to a request for comments.
SOURCE: http://bit.ly/18mqfRC
J Clin Oncol 2013.
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