Use of the granulocyte-macrophage colony-stimulating factor (GM-CSF) sargramostim (Leukine) together with the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor ipilimumab (Yervoy) prolonged overall survival but not progression-free survival in patients with metastatic melanoma, according to a phase II study reported by F. Stephen Hodi, MD, and colleagues in The Journal of the American Medical Association.¹ The difference in overall survival was detected at a planned interim analysis.

Among the activities of GM-CSF are activation of dendritic cells for antigen presentation and stimulation of T- and B-lymphocyte antitumor functions. CTLA-4 inhibits T-cell activity. Benefits of combining CTLA-4 inhibition and GM-CSF–secreting tumor vaccine have been observed in preclinical models and in patients with melanoma, prostate cancer, and ovarian cancer. Studies of responding metastases have shown infiltration of dying tumor by multiple types of immune effector cells.

Study Details

In this open-label trial, 245 patients with unresectable stage III or IV melanoma, and no more than one prior therapy, no central nervous system metastases, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were randomly assigned between December 2010 and July 2011 to receive ipilimumab at 10 mg/kg every 3 weeks intravenously for four doses, then every 12 weeks, plus sargramostim at 250 μg subcutaneously on days 1 to 14 of a 21-day cycle (n = 123) or ipilimumab alone at 10 mg/kg (n = 122). Randomization was stratified by the American Joint Committee on Cancer stage and prior therapy.

The primary endpoint was overall survival. An interim analysis of overall survival was planned when approximately 50% of events had occurred (75 of 149 expected deaths). As a result of rapid patient accrual, events initially accrued slowly but then rapidly reached 69.8% of expected events (104 deaths) in December 2012; the interim analysis was performed using the O’Brien-Fleming boundary for 69.8% of expected events.

The ipilimumab/sargramostim and ipilimumab groups were generally balanced for age (median 61 and 64 years), sex (69% and 64% men), race (99% and 98% white), ECOG performance status (0 in 56% and 64%), metastatic stage (unresectable III in 24% and 25%, M1a/M1b in 27% and 25%, M1c in 50% and 49%), elevated lactate dehydrogenase levels (42% in both), and prior therapy (none in 54% and 56%, interferon in 15% and 14%, and 1 investigational or systemic treatment in 31% and 30%).

Improved Overall Survival

The median follow-up was 13.3 months (range, 0.03 to 19.9 months). On interim analysis, the median overall survival was 17.5 months (95% confidence interval [CI] = 14.9 months to not reached) in the ipilimumab/sargramostim group vs 12.7 months (95% CI = 10.0 months to not reached) in the ipilimumab group (one-sided P = .01), and 1-year overall survival was 68.9% (95% CI = 60.6%–85.5%) vs 52.9% (95% CI = 43.6%–62.2%; one-sided P = .01).

The stratified hazard ratio was 0.64, with a one-sided 90% repeated CI of 0.90 (one-sided P = .01), crossing the O’Brien-Fleming boundary for improvement in overall survival at 69.8% of expected events. The subgroup analysis showed that hazard ratios favored ipilimumab/sargramostim in age, performance status, prior therapy, and lactate dehydrogenase subgroups but not in women. Hazard ratios were significant for men (0.44, 95% CI = 0.25–0.76) and for patients with a performance status of 0 (0.45, 95% CI = 0.25–0.80).

Progression-Free Survival and Response Rates

Both groups had a median progression-free survival of 3.1 months. There were no significant differences between treatments in the subgroup analyses; hazard ratios favored ipilimumab/sargramostim in most subgroups but not in women, patients with a performance status of 1, or patients with no prior therapy. Response rates were 15.5% vs 14.8% (P = .88).

Reduced Toxicity

Grade ≥ 3 adverse events occurred in 44.9% of ipilimumab/sargramostim patients and in 58.3% of ipilimumab patients (P = .04), with the most common being diarrhea (12.7% vs 13.3%), maculopapular rash (9.3% vs 9.2%), and colitis (5.9% vs 8.3%). By adverse-event category, there were notable differences in grade ≥ 3 gastrointestinal toxicities (16.1% vs 26.7%) and pulmonary toxicities (0% vs 7.5%). As noted by the investigators, these findings may reflect the reported roles of GM-CSF in both gastrointestinal and lung homeostasis.

Treatment-related adverse events leading to death occurred in two patients in the ipilimumab/sargramostim group (one cardiac arrest, one colonic perforation) and in seven patients in the ipilimumab group (two colonic failures, two multiorgan failures, two respiratory failures, one hepatic failure). Ipilimumab/sargramostim treatment was still associated with improved overall survival after analysis, with censoring of lethal adverse events related to treatment and lethal adverse events irrespective of causality attribution.

The investigators noted: “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.” Overall survival was also significantly better (P = .04) among the 25 patients in the ipilimumab/sargramostim group vs the 39 in the ipilimumab group who terminated treatment due to adverse events.

The investigators observed that the mechanisms for the improved efficacy with the addition of sargramostim may be related to improved antigen presentation via GM-CSF recruitment of dendritic cells and macrophages; they pointed out that an “uncoupling of overall survival and progression-free survival benefit” has also been seen in patients with advanced prostate cancer receiving sipuleucel-T (Provenge) treatment, which consisted of antigen-presenting cells activated with antigenic proteins including GM-CSF.

The investigators concluded: “Among patients with unresectable stage III or IV melanoma, treatment with ipilimumab plus sargramostim vs ipilimumab alone resulted in longer overall survival and lower toxicity but no difference in progression-free survival. These findings require confirmation in larger studies with longer follow-up.” ■

Disclosure: This study was coordinated by ECOG and supported by the U.S. Public Health Service, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services, Bristol-Myers Squibb, and Genzyme. For full disclosures of the study authors, visit http://jama.jamanetwork.com.

Reference

1. Hodi FS, Lee S, McDermott DF, et al: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: A randomized clinical trial.  JAMA 312:1744-1753, 2014.