CHICAGO – Combining two approved therapies – GM-CSF and ipilimumab – extended overall survival rates by 35% and resulted in fewer grade 3-5 adverse events when compared with ipilimumab alone in a randomized study of 245 patients with metastatic melanoma.
At 1 year, the overall survival rate in the combination therapy group was 69%, with a median follow-up of nearly 18 months. At 1 year, survival in the ipilimumab-only group was 53% with a median follow-up of nearly 13 months, Dr. F. Stephen Hodi, Jr. reported at the annual meeting of the American Society of Clinical Oncology.
This is the first phase II trial to look at ipilimumab (Yervoy, Bristol-Myers Squibb) and the granulocyte macrophage colony-stimulating factor (GM-CSF) sargramostim (Leukine, Sanofi) in combination in any cancer, said Dr. Hodi, the principal investigator for the trial, which was conducted by the ECOG-ACRIN Cancer Research Group (formerly the Eastern Cooperative Oncology Group) trial. In this study, ipilimumab was used at a dose of 10 mg/kg, which is higher than the FDA-approved dose of 3 mg/kg.
"We are waiting for the data to mature in ongoing studies examining the relative efficacy of 3 mg/kg and 10 mg/kg dosing," said Dr. Hodi, director of the melanoma center at Dana-Farber Cancer Institute in Boston.
The results in the current trial are another indication of the impact that immunotherapy can have for patients with advanced melanoma. Since both GM-CSF and ipilimumab are commercially available, oncologists need to determine the best way to apply these findings in everyday practice. The next step will then be to define the role of GM-CSF in combination with other immune checkpoint targeting drugs, such as therapies that target the PD-1 and PD-L1 pathway, he said.
"We have been using GM-CSF in melanoma as a stand-alone therapy," Dr. Lynn M. Schuchter, the C. Willard Robinson Professor of Hematology-Oncology at the University of Pennsylvania, Philadelphia, and an expert on melanoma, said at a press conference where the study results were announced. "It will be interesting to see if payers will cover this (combination treatment)."
Ipilimumab targets 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.
For this study, 245 patients were randomized to receive ipilimumab plus GM-CSF or ipilimumab alone. All study participants were in otherwise good health, with an ECOG performance status of 0-1 and adequate end-organ function, no autoimmune disease, and no prior use of CTLA-4 blockade or CD137 agonists. All had radiographically measurable metastatic melanoma, but with no CNS metastases, and had received up to one prior treatment over 4 weeks before starting in the trial.
The 123 patients randomized to the combination therapy were given sargramostim at 250 micrograms injected subcutaneously on day 1-14 of a 21 day cycle. For induction therapy, ipilimumab was given at a dose of 10 mg/kg intravenously once every 3 weeks for four cycles as induction therapy and once every 12 weeks as maintenance therapy. The 122 patients randomized to ipilimumab alone received the drug on the same schedule.
In both study arms, tumor shrinkage rates were comparable at 11% and 14%, and progression-free survival was similar at about 3 months. But the overall survival rate was longer in the combination treatment arm. One year after the start of therapy and with a median follow-up of 13.3 months, 69% of patients given the combination therapy and 53% of those who got ipilimumab alone were still alive, for a 35% lower risk of death with the combination therapy (hazard ratio, 0.64; P = .014).
Additionally, the combination treatment was associated with fewer serious side effects, compared with ipilimumab alone. The most significant differences were in lung and gastrointestinal toxicities.
Grade 3-5 adverse events occurred in 45% of patients given the combination therapy and in 57% given ipilimumab alone (p2 = 0.078). There were two possible treatment-related deaths in the combination arm (one colonic perforation and one cardiac arrest) and 7 possible treatment-related deaths in the ipilimumab-only arm: (two cases of multi-organ failure, two colonic perforations, one case of liver failure, and two cases of respiratory failure).
The research was supported in part by the National Cancer Institute (Cancer Therapy Evaluation Program), Sanofi, and Bristol-Myers Squibb. Dr. Hodi disclosed receiving research funding and a being a consultant or in an advisory role with Bristol-Myers Squibb.