GM-CSF Boosts Survival Benefit of Ipilimumab in Metastatic Melanoma 

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With both drugs commercially available, these findings have implications for the current treatment of melanoma patients. At the same time, we still need to clarify the best way to apply these findings in everyday practice.

—F. Stephen Hodi, MD

For metastatic melanoma, the activity of ipilimumab can be boosted by the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine), according to a phase II study that found the combination improved overall survival, vs ipilimumab alone. The results were presented at the 2013 ASCO Annual Meeting.1

“Ipilimumab has been shown to improve survival in metastatic melanoma and is FDA-approved. The question then becomes, ‘How can we improve on this treatment?’” said lead investigator F. Stephen Hodi, MD, Associate Professor of Medicine at Harvard Medical School and Director of the Melanoma Center at Dana-Farber Cancer Institute, Boston.

“Adding GM-CSF to ipilimumab improved survival and also tolerability of treatment. These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade,” he said at an ASCO press briefing.

Study Rationale

GM-CSF is a chemical signal in the immune system that enhances granulocytes and macrophages. Ipilimumab is an antibody that “takes the brakes off” the CTLA-4–associated immune blockade. In mice, CTLA-4 blockade and GM-CSF–secreting tumor vaccine combinations have demonstrated synergy, which provides the rationale for trying this approach in metastatic melanoma patients, Dr. Hodi explained.

Eastern Cooperative Oncology Group (ECOG) 1608 randomly assigned 245 previously treated metastatic melanoma patients to receive ipilimumab at a dose of 10 mg/kg every 3 weeks for four cycles, then maintenance treatment at a dose of 10 mg/kg every 12 weeks, or the same ipilimumab schedule plus sargramostim at 250 µg subcutaneously (self-administered) daily for days 1 to 14 of a 21-day cycle, for four cycles.

Dr. Hodi pointed out that ipilimumab was dosed at 10 mg/kg—higher than the FDA-approved dose of 3 mg/kg—because the minimally effective dose had not been established at the time the trial was designed. He said future studies will evaluate the combination using the approved dose of ipilimumab.  

Improved Overall Survival with GM-CSF

After a median of 13.3 months follow-up, the addition of GM-CSF to ipilimumab significantly improved overall survival, from a median of 12.7 months with ipilimumab alone to 17.5 months, yielding a statistically significant 36% reduction in mortality risk (P = .014). One-year survival rates were 52.9% with ipilumumab alone vs 68.9% with the combination.

Progression-free survival was not significantly different: 34.0% with the combination and 29.6%, with ipilimumab alone. Response rates were also comparable between the arms: 15.5% vs 14.8%, respectively.

The relatively low response rate represents a “discordance” with clinical outcomes that is often seen with immunotherapies, Dr. Hodi pointed out.

“Ipilimumab and GM-CSF cause a proinflammatory microenvironment in the tumor, and radiographic studies may not adequately assess their clinical benefit,” he said. “Progression by standard criteria does not necessarily correlate with the gold standard of benefit, which is overall survival.”

Combination Better Tolerated

Interestingly, the combination was associated with fewer serious side effects, the greatest differences observed in pulmonary and gastrointestinal adverse events.

Grade 3 to 5 adverse events occurred in 45% of the combination arm and 58% of the single-agent ipilimumab arm (P = .038). Grade 5 adverse events, in particular, were more common with ipilimumab alone, including multiorgan failure (n = 2), colonic perforation  (n = 2), hepatic failure
(n = 1), and respiratory failure (n = 2); in patients receiving both drugs, colonic perforation (n = 1) and cardiac arrest (n = 1) were observed. There were two possible treatment-related deaths in the combination arm and seven with the single agent.

“With both drugs commercially available, these findings have implications for the current treatment of melanoma patients,” Dr. Hodi suggested. “At the same time, we still need to clarify the best way to apply these findings in everyday practice,” he added. ■

Disclosure: Dr. Hodi reported he has served in a consulting or advisory role with and has received research funding from Bristol-Myers Squibb.


1. Hodi FS, Lee SJ, McDermott DF, et al: Multicenter, randomized phase II trial of GM-CSF plus ipilimumab versus ipi alone in metastatic melanoma: E1608. 2013 ASCO Annual Meeting. Abstract CRA9007. Presented June 1, 2013.

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