Ipilimumab Plus Sargramostim vs Ipilimumab Alone for Treatment of Metastatic Melanoma A Randomized Clinical Trial

IMPORTANCE 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 tumor vaccine combinations demonstrate therapeutic synergy in preclinical models. A key unanswered question is whether systemic GM-CSF (sargramostim) enhances CTLA-4 blockade. OBJECTIVE To compare the effect of ipilimumab plus sargramostim vs ipilimumab alone on overall survival (OS) in patients with metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS The Eastern Cooperative Oncology Group (ECOG) conducted a US-based phase 2 randomized clinical trial from December 28, 2010, until July 28, 2011, of patients (N = 245) with unresectable stage III or IV melanoma, at least 1 prior therapy, no central nervous system metastases, and ECOG performance status of 0 or 1. INTERVENTIONS Patients were randomized to receive ipilimumab, 10mg/kg, intravenously on day 1 plus sargramostim, 250 mu g subcutaneously, on days 1 to 14 of a 21-day cycle (n = 123) vs ipilimumab alone (n = 122). Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle. MAIN OUTCOMES AND MEASURES Primary end point: comparison of length of OS. Secondary end point: progression-free survival (PFS), response rate, safety, and tolerability. RESULTS Median follow-up was 13.3 months (range, 0.03-19.9). As of December 2012, median OS and 1-year survival for the ipilimumab plus sargramostim group vs ipilimumab alone were significantly different. [GRAPHICS] A planned interim analysis was conducted at 69.8% of expected events (104 observed of 149 expected deaths) and the O'Brien-Fleming boundary was crossed for improvement in OS. There was no difference in PFS. Adverse events were more common in the ipilimumab-only group. CONCLUSION AND RELEVANCE Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer OS and lower toxicity, but no difference in PFS. These findings require confirmation in larger studies with longer follow-up. Copyright 2014 American Medical Association. All rights reserved.