Ipilimumab Plus Sargramostim in Metastatic Melanoma

Results from a randomised phase II clinical trial

Among patients with unresectable stage III or IV melanoma, treatment with a combination of the drugs ipilimumab plus sargramostim, compared with ipilimumab alone, resulted in longer overall survival (OS) and lower toxicity, but no difference in progression-free survival (PFS). These findings from a randomised phase II study require confirmation in larger studies with longer follow-up. The results are published by Dr Stephen Hodi of the Dana-Farber Cancer Institute, Boston, and colleagues in the 5th November 2014 issue of JAMA.

Cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) blockade with ipilimumab prolongs survival in patients with metastatic melanoma. CTLA-4 blockade and granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting tumour vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade, according to information in background of the study.

The researchers from the Eastern Cooperative Oncology Group (ECOG) conducted this USA-based trial from December 2010 until July 2011 among 245 patients with unresectable stage III or IV melanoma, at least one prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1.

Patients were randomised to receive ipilimumab, intravenously on day 1 plus sargramostim subcutaneously on days 1 to 14 of a 21-day cycle (123 patients) vs. ipilimumab alone (122 patients). Treatment with ipilimumab included induction for 4 cycles followed by maintenance every fourth cycle.

The study primary endpoint was OS; the secondary endpoints were PFS, response rate, safety, and tolerability.

Median follow-up was 13.3 months. The OS was significantly improved with the addition of sargramostim to ipilimumab. The median OS was 17.5 months for the ipilimumab plus sargramostim group and 12.7 months for the ipilimumab-only group. The 1-year OS rate was 68.9% for the combination treatment group and 52.9% for the ipilimumab-only group (stratified log-rank 1-sided p = 0.01; mortality hazard ratio 0.64). Planned interim analysis was crossed for improvement in OS. However, there was no difference in PFS with median PFS of 3.1 months in both groups.

Grade 3 to 5 adverse events were more common in the ipilimumab-only group. Toxicity was significantly lower in the ipilimumab plus sargramostim group.

"This randomized phase 2 study supports the evidence that the addition of sargramostim to ipilimumab therapy improved overall survival in patients with metastatic melanoma," the authors write. "These findings require confirmation in larger sample sizes and with longer follow-up."

Reference

Hodi S, Lee S, McDermott D, et al. Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma. :  A Randomized Clinical Trial.  JAMA. 2014;312(17):1744-1753. doi:10.1001/jama.2014.13943.
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