Patients with unresectable stage III or IV melanoma treated with ipilimumab (Yervoy) plus sargramostim (Leukine) had longer overall survival and less toxicity than did those treated with ipilimumab alone, according to a phase II randomized clinical trial conducted by the Eastern Cooperative Oncology Group (ECOG). There was no difference, however, in progression-free survival. “These findings require confirmation in larger studies with longer follow-up,” F. Stephen Hodi, MD, of Dana-Farber Cancer Center in Boston, and colleagues reported in JAMA.
Ipilimumab is a fully human immunoglobulin G1 molecule that blocks cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and has been shown to prolong survival in patients with metastatic melanoma. Sargramostin is a granulocyte-macrophage colony-stimulating factor (GM-CSF). “One key unanswered question,” the authors noted in the introduction of their report, “is whether the systemic administration of GM-CSF enhances CTLA-4 blockade.”
Study participants had unresectable stage III or IV melanoma, at least one prior therapy, no central nervous system metastases, and an ECOG performance status of 0 or 1. Of the total of 245 patients, 123 were randomized to receive ipilimumab, 10 mg/kg, intravenously on day 1 plus sargramostim, 250 μg subcutaneously, on days 1 to 14 of a 21-day cycle, and 122 were randomized to receive ipilimumab alone. “Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle,” the investigators noted.
The median age was 61 years in the group receiving ipilimumab plus sargramostim and 64 years in the group receiving ipilimumab alone. Almost all patients were white, and about two-thirds were men.
The median follow-up was 13.3 months (range, 0.03–19.9). The median overall survival was 17.5 months among patients receiving ipilimumab plus sargramostim vs 12.7 months for patients receiving ipilimumab alone. “The overall survival was significantly improved with the addition of sargramostim to ipilimumab, with a stratified log-rank one-sided P value of .01,” the investigators stated. Rates for 1-year survival were 68.9% with combined therapy vs 52.9% with ipilimumab alone. The median progression-free survival was 3.1 months in both groups.
Safety analysis was performed on 120 patients in the combined-therapy group and 118 in the ipilimumab-alone group. “Toxicity was significantly lower in the ipilimumab-plus-sargramostim group than in the ipilimumab-only group (P = .04),” the investigators noted. Grade 3 to 5 adverse events occurred in 44.9% of patients on combined therapy and 58.3% of those on monotherapy. “Most notable,” according to the authors were differences in gastrointestinal toxicities (16.1% in patients treated with ipilimumab plus sargramostim vs 26.7% ipilimumab alone) and pulmonary toxicities (0% vs 7.5%). “The improved toxicity profile must be considered as contributing to the improved survival, even in light of the survival advantage remaining when patients who discontinued therapy due to toxicity are excluded,” the researchers wrote. ■
Hodi FS, et al: JAMA 312:1744-1753, 2014.