PITTSBURGH, Oct. 16 - Interferon alfa 2b (INTRON� A) unequivocally improves overall and relapse-free survival in adult patients who have surgically treated melanoma considered at high risk of recurring, according to results of a definitive study evaluating the use of this agent and comparing it with one of the best-developed anti-melanoma vaccines, GMK. Results of this National Cancer Institute-funded study (E1694), led by John Kirkwood, M.D., at the University of Pittsburgh Cancer Institute (UPCI), are being presented Oct. 16 at the Presidential Symposium of the European Society of Medical Oncology in Hamburg, Germany. *

"This report indisputably proves that high-dose interferon alfa 2b is the standard adjuvant therapy for high-risk melanoma patients," stated Dr. Kirkwood, director of the UPCI's Melanoma Center. "It is my hope and expectation that these results will motivate many more physicians who treat melanoma to consider aggressive therapy with this regimen, as well as new clinical trials that build upon this regimen. Doing so could improve patient outcomes for thousands of individuals," added Dr. Kirkwood, who also is vice chairman for research at the University of Pittsburgh's department of medicine.

Study results of E1694 showed that when given at a high dose (20MIU/m2 intravenously and 10MIU/m2 subcutaneously), interferon alfa 2b extends overall survival in surgically treated patients, as well as relapse-free survival, or the amount of time free of disease recurrence. Patients who received the GMK vaccine, by contrast, showed significantly lower overall survival and relapse-free survival. (This study did not include an observation group as a control).

Melanoma is the most life-threatening type of skin cancer, causing nearly 8,000 deaths each year in the United States alone. High-risk patients have a 50 to 80 percent chance of disease recurrence without adjuvant treatment, or additional treatment after surgery, according to Dr. Kirkwood. Furthermore, once this type of cancer recurs, it is often more difficult to treat.

This latest report on E1694 reaffirms the significant and consistent efficacy of high-dose interferon alfa 2b, as reported from a prior study led by Dr. Kirkwood, which led the FDA in 1995, to approve it as the first effective adjuvant therapy for high-risk melanoma. Five years later, interferon alfa 2b remains the only FDA-approved adjuvant therapy for this disease.

The current study also puts to rest lingering concerns about the effectiveness of interferon alfa 2b in terms of survival impact. These concerns probably account for the current reluctance on the part of some clinicians in the United States, Europe and Asia to use high-dose interferon alfa 2b in appropriate high-risk settings, according to Dr. Kirkwood.

Run from 1996 to 1999, the ECOG-Intergroup trial E1694 involved 880 surgically treated, high-risk melanoma patients who had primary tumors that were greater than 4mm in depth or who had melanomas that had spread to nearby lymph nodes. Patients were randomized to receive either a course of interferon alfa 2b (20 MIU/m2 administered by IV infusion five days per week for 4 weeks, followed by 10MIU/m2 administered subcutaneously three times per week for 48 weeks) or to receive the GMK vaccine (given weekly for one month and then at three-month intervals for two years).

Interferon alfa 2b is a recombinant version of naturally occurring leukocyte (white cell) alfa interferon, which has been shown to exert both antiviral and immunomodulatory effects. Schering-Plough Corporation (Kenilworth, N.J.) markets interferon alfa 2b (INTRON A�) for 16 major antiviral and anticancer indications worldwide. A major concern with interferon alfa 2b use has been that most patients experience flu-like side effects, such as muscle pains, headache, fever and chills, over the course of therapy, and they may also show reduced white blood cells.

The comparison vaccine used in E1694, GMK, contains an antigen called GM2, which has been shown to stimulate the immune system to produce antibodies against this marker of melanoma. Melanoma patients with anti-GM2 antibodies have a better outcome than those who do not have anti-GM2 antibodies. This has been shown in multiple studies, including one early randomized, controlled clinical trial that demonstrated a trend to improved relapse-free survival in patients treated with a GM2 vaccine. GMK is manufactured by Progenics, Inc.

E1694 was closed in April 2000, when an interim data analysis showed compelling evidence that interferon alfa 2b was significantly superior to GMK in prolonging both overall and relapse-free survival. Dr. Kirkwood's presentation in Hamburg provides the full, final analysis of this overall survival and relapse-free survival impact. At two years, the evidence reveals that deaths and relapses were reduced by 33 percent in patients receiving interferon alfa 2b.

Interferon alfa 2b is the first, and to date, the only adjuvant therapy indicated for high-risk patients with melanoma that has been completely treated with surgery. It won FDA approval in 1995 on the basis of a clinical trial (ECOG's E1684 study) showing that this immunobiological therapy improved overall survival and relapse-free survival in high-risk patients. The study compared high-dose interferon alfa 2b (20MIU/m2) to observation in a similar population of patients, and showed nearly identical benefit in terms of both prolonging survival and in reducing the frequency of relapse. Patients receiving high-dose interferon alfa 2b in that initial trial had significant benefit, in terms of both overall survival and relapse-free survival.

At the same time ECOG's E1684 study was being completed, however, investigators led by Dr. Kirkwood began a second, large-scale study (ECOG's E1690 study) comparing high-dose interferon alfa 2b and low-dose interferon alfa 2b, both in reference to observation. E1690 evaluated a somewhat larger number of high-risk patients with deep primary tumors (irrespective of whether nearby lymph nodes were cancerous). Results of this study, published after the 1995 FDA approval of interferon alfa 2b, showed significantly improved relapse-free survival, but they did not confirm the overall survival benefit seen in E1684.

"We think that the overall survival benefit was not seen in E1690 because patients initially randomized to receive no interferon alfa 2b received the drug after relapse from the observation arm of the study. This crossover in our study design confounded our results so that an overall survival benefit of interferon alfa 2b could not be measured. E1694 is a two-fold larger study, and it confirms the overall survival benefit of high-dose interferon alfa 2b in a decisive and unequivocal manner."

Unfortunately, according to Dr. Kirkwood, the controversial outcome of E1690 may have contributed to the hesitation of some members of the medical community, both in the United States and in Europe, to use high-dose interferon alfa 2b in a high-risk setting.

Although interferon alfa 2b proved superior to the GMK in the E1694 study, Dr. Kirkwood cautioned that GMK may still have therapeutic benefit in combination with interferon alfa 2b, or with a variety of other vaccines in the treatment of melanoma. Some of these vaccines are designed to induce more effective T cell responses to melanoma, a goal that is quite distinct from the goal of inducing antibody responses as tested in E1694. In 1994 when the currently reported trial was designed, GMK was the most promising vaccine the ECOG Melanoma Committee evaluated, according to Dr. Kirkwood, and the data that support it remain a strong impetus to evaluate vaccines more carefully along both antibody and T cell lines.

The ECOG has just initiated a trial of a triple vaccine with or without interferon alfa 2b, or a growth factor (GM-CSF) for immune cells, with the goal of inducing better T cell responses to melanoma. The UPCI has just initiated a novel vaccine that also targets a form of T cell that previously has not been capable of being stimulated by vaccines, the helper CD4 T cell. According to Dr. Kirkwood, as the preliminary results of each of these approaches shows promise, they will be factored into the interferon approach that now has become the foundation of new adjuvant therapy for melanoma.

* Dr. Kirkwood chairs the Eastern Cooperative Oncology Group's (ECOG's) Melanoma Committee, which is headquartered at the University of Pittsburgh. The study reported on was done in collaboration with the Southwest Cooperative Oncology Group and the Cancer/Leukemia Group B.