GM-CSF/Ipilimumab Combination Extends Melanoma Survival

Treating patients with metastatic melanoma with a combination of the granulocyte-macrophage colony-stimulating factor (GM-CSF) sargramostin (Leukine; Genzyme) and the CTLA-4 inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) prolonged survival and caused fewer serious side effects than using ipilimumab alone, according to interim results of a phase II trial. The findings were reported on June 1 at the American Society of Clinical Oncology 2013 Annual Meeting in Chicago, IL.

In the study, researchers randomly assigned 245 patients who had had no more than one previous therapy to receive ipilimumab plus GM-CSF or ipilimumab alone. One year after the start of therapy, 68.9% of patients who received the combination therapy were still alive, compared with 52.9% of patients who received ipilimumab alone.

Ipilimumab targets CTLA-4, a protein that keeps immune T cells in check. GM-CSF is a growth factor commonly used to boost white blood cell counts following high-dose chemotherapy or stem cell transplantation. Earlier studies in mice indicating that combining the two agents might improve ipilimumab's effectiveness prompted the current study.

Treatment with ipilimumab has been linked to serious adverse events, including perforation of the colon and respiratory failure. In the trial, patients receiving the combination therapy experienced fewer serious pulmonary and gastrointestinal problems than patients who received ipilimumab alone. There were two deaths in the combination therapy group possibly related to treatment versus seven in the ipilimumab-only group.

F. Stephen Hodi, MD, director of the melanoma center at Dana-Farber Cancer Institute in Boston, MA, who presented the findings, said that researchers don't know exactly why patients who received the combination therapy experienced fewer side effects. However, he noted that GM-CSF seems to play a role in pulmonary homeostasis. Also, studies in mice that developed colitis have shown that administration of GM-CSF promotes healing of the gastrointestinal mucosa, he said.

Of note, the dose of ipilimumab used in the trial was 10 mg/kg, which is higher than the dose of 3 mg/kg approved by the U.S. Food and Drug Administration (FDA). When the study was designed, Hodi explained, the drug had not been approved and 10 mg/kg was still considered a possible standard dose. Another clinical trial currently underway is comparing the benefits of GM-CSF with the 3 mg/kg and 10 mg/kg doses of ipilimumab.

Given the effectiveness of the combination therapy, Hodi said that future studies should examine the use of GM-CSF with other immune checkpoint targeting drugs, including inhibitors of PD-1 and PD-L1.

“These are really intriguing data,” said Lynn Schuchter, MD, a professor of hematology and oncology at the Abramson Cancer Center of the University of Pennsylvania in Philadelphia. “To combine two immunotherapies and get a better overall response is quite remarkable, but then to see fewer side effects is really, really surprising.”

However, Schuchter said that before doctors start prescribing GM-CSF to patients taking ipilimumab, “there need to be additional studies.”