title: Ipilimumab plus sargramostim vs ipilimumab alone for treatment of metastatic melanoma: a randomized clinical trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Patients 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 (n = 123) vs ipilimumab alone (n = 122). Ipilimumab treatment included induction for 4 cycles followed by maintenance every fourth cycle.
  
  
  METHODS
  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). Median OS as of December 2012 for ipilimumab plus sargramostim was 17.5 months (95% CI, 14.9-not reached) vs 12.7 months (95% CI, 10.0-not reached) for ipilimumab. The 1-year survival rate for ipilimumab plus sargramostim was 68.9% (95% CI, 60.6%-85.5%) compared to 52.9% (95% CI, 43.6%-62.2%) for ipilimumab alone (stratified log-rank 1-sided P = .01; mortality hazard ratio 0.64 [1-sided 90% repeated CI, not applicable-0.90]). A planned interim analysis was conducted at 69.8% of expected events (104 observed with 149 expected deaths). Planned interim analysis using the O'Brien-Fleming boundary was crossed for improvement in OS. There was no difference in PFS. Median PFS for ipilimumab plus sargramostim was 3.1 months (95% CI, 2.9-4.6) vs 3.1 months (95% CI, 2.9-4.0) for ipilimumab alone. Grade 3 to 5 adverse events occurred in 44.9% (95% CI; 35.8%-54.4%) of patients in the ipilimumab plus sargramostim group vs 58.3% (95% CI, 49.0%-67.2%) of patients in the ipilimumab-alone group (2-sided P = .04).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01134614.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts3Harvard Medical School, Harvard University, Boston, Massachusetts.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts5Harvard Medical School, Boston, Massachusetts.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: University of Pittsburgh Department of Pathology, Pittsburgh, Pennsylvania.
authors.forename: Uma N
authors.initials: UN
authors.lastname: Rao
authors.affiliation: University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.affiliation: University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Tarhini
authors.affiliation: Hematology and Oncology, The Christ Hospital Cancer Center, Cincinnati, Ohio9University of Cincinnati Department of Medicine, Cincinnati, Ohio.
authors.forename: Philip
authors.initials: P
authors.lastname: Leming
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts3Harvard Medical School, Harvard University, Boston, Massachusetts.
authors.forename: Donghoon
authors.initials: D
authors.lastname: Shin
authors.affiliation: University of Pittsburgh Department of Medicine, Pittsburgh, Pennsylvania.
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects; D012878:Skin Neoplasms / Q000188:drug therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D011994:Recombinant Proteins; C081222:sargramostim; D016178:Granulocyte-Macrophage Colony-Stimulating Factor