Adding Sargramostim to Ipilimumab Prolonged Survival in Metastatic Melanoma Trial

3D structure of a melanoma cell

The addition of sargramostim, a systemic granulocyte-macrophage colony-stimulating factor (GM-CSF), to the anti-CTLA-4 ipilimumab resulted in a significant improvement in overall survival in patients with metastatic melanoma when compared with treatment with ipilimumab alone, according to phase II study results published recently in JAMA: Dermatology. However, no difference in progression-free survival was found between the two study groups.

“The lack of correlation between overall survival and progression-free survival in this study presents challenges to clinical management and drug development because conventional radiographic criteria have not proven reliable for determining patient benefit,” wrote researchers led by F. Stephen Hodi, MD, of the Dana-Farber Cancer Institute. “This introduces important considerations for the evaluation of treatment efficacy with particular immune therapies such as ipilimumab.”

Previous research has shown therapeutic synergy between CTLA-4 blockade and GM-CSF secreting tumor cell vaccines. In addition, the combination of systemic GM-CSF with CTLA-4 blockade in patients with hormone-refractory prostate cancer resulted in clinical responses in more than half of patients with PSA declines.

In this study, Hodi and colleagues sought to determine if systemic administration of GM-CSF enhanced CTLA-4 blockade in patients with melanoma.

The clinical trial randomly assigned 245 patients with unresectable stage III or stage IV melanoma to ipilimumab plus sargramostim (n = 123) or ipilimumab alone (n = 122). The patients were followed for a median of 13.3 months.

At follow-up, the median overall survival for the group assigned combination treatment was 17.5 months compared with 12.7 for patients assigned ipilimumab alone (P = .01). One-year survival was 68.9% in the combination group compared with 52.9% in the ipilimumab group (P = .01).

“Possible mechanisms for the improved efficacy observed in this trial may relate to improved antigen presentation with GM-CSF via recruitment of dendritic cells and macrophages, or to counteracting immune regulatory cells with ipilimumab,” the researchers wrote.

Despite improved overall survival for combination therapy, no significant difference in progression-free survival was found between the two groups. Median progression-free survival was 3.1 months for both.

Grade 3 to 5 adverse events occurred in 44.9% of patients assigned combination therapy compared with 58.3% of patients assigned monotherapy. Overall, toxicity was significantly higher in patients assigned ipilimumab alone (P = .04).