Interim results of a randomized, proof-of-concept, phase II study, part of a NCI-CTEP/ECOG-ACRIN Cancer Research Group (formerly the Eastern Cooperative Oncology Group)trial, shows that GM-CSF (Sargramostim/Leukine?; Sanofi-aventis) added to an increased dose of the immunotherapy ipilimumab (Yervoy?, Bristol-Myers Squibb Company) extends survival for patients with metastatic melanoma. More than two-thirds of patients were alive after one year of combination therapy vs. half of those treated with ipilimumab alone, a significant advance for metastatic melanoma.

GM-CSF is a white blood cell growth factor “booster” used for support in patient undergoing high-dose chemotherapy. The drug also helps present invading proteins to the immune system for attack in fighting infections.

Treatment with the two drugs combined also appears to be safer for patients than treatment with ipilimumab alone ? GM-CSF decreased some of the serious side effects of ipilimumab. “The combination was better tolerated, in terms of fewer high-grade adverse events, particularly those affecting the gastrointestinal system and the lungs,? said lead author F. Stephen Hodi, MD, an associate professor of medicine at Dana-FarberCancer Institute in Boston, Mass. and principal investigator for this ECOG-ACRIN clinical trial. “Treatment with ipilimumab has been associated with serious side effects, including perforation of the colon and respiratory failure. Ipilimumab is a monoclonal antibody that binds to a protein, CTLA-4, which in effect ‘takes the brakes off’ the immune system?s attack on cancer cells,” he further noted.

Activating the immune system
Both ipilimumab and GM-CSF work by activating the immune system to fight cancer. Ipilimumab is a new treatment for advanced melanoma targeting CTLA-4, a protein that keeps immune T-cells in an inactive state. GM-CSF is a growth factor commonly used to boost white blood cell counts after chemotherapy or stem cell transplantation.

Adding GM-CSF to ipilimumab extends overall survival comparedto ipilimumab alone – concept of combining immunotherapy approaches may be beneficial to patients.

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?This is the first randomized phase II study looking at the combination of ipilimumab and GM-CSF in any cancer,? Hodi said. ?The results of the E1608 study provide another important sign that immunotherapy can have a big impact for patients with advanced melanoma. At the same time, we still need to clarify the best way to apply these findings in everyday practice.?

In this study, 245 patients with metastatic melanoma who had undergone up to one prior treatment were assigned to receive ipilimumab plus GM-CSF or ipilimumab alone (at a dose of 10 mg/kg). The median follow up time was 13.3 months. Tumor shrinkage rates were comparable in both arms (11-14%) but the overall survival rate was longer in the combination treatment arm: one year after the start of therapy, 68.9% of patients who received the combination were alive, compared to 52.9% of patients who received ipilimumab alone. Patients who received the combination treatment had a 35% lower risk of dying compared with those that received ipilimumab alone.

Serious Adverse Events
In addition, the combination treatment was associated with fewer serious side effects compared to ipilimumab alone. The most significant differences were in lung and gastrointestinal toxicities.

There were two possible treatment-related deaths in the combination arm vs. seven in the single-drug arm. ?This melanoma study builds upon the remarkable successes and advances we have seen for patients with advanced melanoma over the past two years,? noted Lynn Schuchter, MD, a melanoma expert and ASCO spokesperson.

Hodi noted that said the study used doses of ipilimumab higher than those approved by the U.S. Food and Drug Administration (FDA). Depending on how individual clinicians interpret the study, he added, ?these results could be practice-changing; there really is no downside to adding GM-CSF.?

Additional immune system boosters are being explored in early clinical trials, though the advantage of GM-CSF is that it improves both efficacy and safety of immunotherapy. The next step is to better define the role of GM-CSF in combination with other immune checkpoint targeting drugs, such as PD-1 and PD-L1.

For more information:
Abstract #CRA9007: Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus ipi alone in metastatic melanoma: E1608.
Oral Abstract Session: Melanoma/Skin Cancers Study
Author: Stephen Hodi, MD, Dana-Farber Cancer Institute, Boston, MA
Date: Saturday, June 1, 2013, 3:30 ? 3:45 PM CDT
Location: Room: S406

Photo: Stephen Hodi speaks during the Melanoma Oral Abstract Session at the American Society for Clinical Oncology (ASCO) Annual Meeting. Photo Courtesy: ? ASCO/Scott Morgan.

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