Vaccination Fails to Improve Stage
II Melanoma Patients
Idea of treating cancer with a
vaccine has been around since first vaccines against infectious disease
By John Bean,
PhD, EORTC Medical
13, 2013 - Results of an EORTC study published in the
Journal of Clinical Oncology show that vaccination with
GM2/KLH-QS-21 does not benefit patients with stage II melanoma.
Vaccination with GM2/KLH-QS-21 stimulates the production of antibodies
to the GM2 ganglioside, an antigen expressed by many melanomas.
Serological response to GM2 was shown to be a positive prognostic factor
in patients with melanoma and was the rationale for this trial.
The idea of treating cancer with a
vaccine has been around since the first vaccines against infectious
disease were developed. The GM2 ganglioside, an antigen expressed in
most melanomas but with limited expression in normal tissues, was
thought to offer a suitable target for such therapeutic vaccination.
Previous studies had shown that
serological response against GM2 was a favorable prognostic factor. The
five and ten year survival rates for patients with melanoma having
primary tumors with a Breslow thickness greater than 1.5 mm are just of
74% and 61%, respectively, so EORTC trial 18961 was launched to compare
vaccination to observation in these patients.
“These results clearly indicate
that we do not fully comprehend the impact, on the whole, of multiple
vaccinations” according to Prof. Alexander M.M. Eggermont of the
Institut Gustave Roussy, Villejuif, Paris-Sud, and Université Paris-Sud,
Kremlin Bicêtre, France and Coordinator of this study.
“The effects of such vaccinations
might well be detrimental as was clear at the time of the interim
analysis that stopped this trial. Now that we have entered a new era in
immunotherapy in melanoma with checkpoint inhibitors like anti-CTLA4,
and especially with anti-PD1/PDL1, a new opportunity for vaccine
development may have arrived.”
In this phase III EORTC 18961
trial, 1314 patients with stage II melanoma (primary melanoma thicker
than 1.5 mm, T3-4N0M0; AJCC Stage II) were randomized to either
vaccination with GM2-KLH-QS21, 657 patients, or observation, 657
patients. The vaccination treatment consisted of subcutaneous injections
given once a week during the first month, then once every three months
for the first two years, and once every six months during the third
Analyses were by intent to treat,
and at a median follow-up of 1.8 years the trial was stopped for
futility and patients did not receive further vaccinations. For
relapse-free survival, the primary endpoint, the hazard ratio (HR) was
1.00 and P = 0.99, and an unfavorable outcome was seen for
patients in the vaccination arm compared to the observation arm in terms
of overall survival (HR 1.66; P=0.02). Following the IDMC
recommendations, all patients in the vaccination arm stopped their
At final analysis, the median
follow-up was 4.2 years. There were 400 relapses, nine deaths without
relapse, and a total of 236 deaths. Decreases in both the relapse-free,
1.2%, and overall, 2.1%, survival rates were observed in the vaccination
arm at 4 years. For these two endpoints, the estimated HRs were 1.03 and
Toxicity was acceptable; 4.6% of
patients went off study because of toxicity.
EORTC trial 18961 was coordinated
by the EORTC Melanoma Group and was conducted in 78 sites located in 18
countries: Australia, Belgium, the Czech Republic, Denmark, Finland,
France, Germany, Israel, Italy, Norway, Poland, Portugal, Russia,
Serbia, Spain, Switzerland, The Netherlands, and the United Kingdom.
This trial was fully supported by Progenics Pharmaceuticals, Inc.
a form of cancer that begins in melanocytes (cells that make the
pigment melanin). It may begin in a mole (skin melanoma), but
can also begin in other pigmented tissues, such as in the eye or
in the intestines.
men and women (44,250 men and 32,000 women) were expected to be
diagnosed with and 9,180 men and women to die of
melanoma of the skin
the median age at diagnosis for melanoma of the skin was 61
years of age.
0.6% were diagnosed under age 20; 6.8% between 20 and 34; 10.7%
between 35 and 44; 18.2% between 45 and 54; 21.6% between 55 and
64; 18.8% between 65 and 74; 16.7% between 75 and 84; and 6.6%
85+ years of age.
age-adjusted incidence rate was 21.0 per 100,000 men and women
the median age at death for melanoma of the skin was 68 years of
age. Approximately 0.1% died under age 20; 2.6% between 20 and
34; 5.6% between 35 and 44; 13.5% between 45 and 54; 19.9%
between 55 and 64; 21.2% between 65 and 74; 24.1% between 75 and
84; and 12.9% 85+ years of age.
age-adjusted death rate was 2.7 per 100,000 men and women per
year. These rates are based on patients who died in 2005-2009 in
Based on rates
from 2007-2009, 1.99% of men and women born today will be
diagnosed with melanoma of the skin at some time during their
lifetime. This number can also be expressed as 1 in 50 men and
women will be diagnosed with melanoma of the skin during their
lifetime. These statistics are called the
lifetime risk of
Sometimes it is
more useful to look at the
probability of developing
melanoma of the skin between two age groups. For example, 0.99%
of men will develop melanoma of the skin between their 50th and
70th birthdays compared to 0.60% for women
On January 1,
2009, in the United States there were approximately 876,344 men
and women alive who had a history of melanoma of the skin -
427,810 men and 448,534 women.