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Randomized, Placebo-Controlled, Phase III Trial of Yeast-Derived Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus Peptide Vaccination Versus GM-CSF Plus Peptide Vaccination Versus Placebo in Patients With No Evidence of Disease After Complete Surgical Resection of Locally Advanced and/or Stage IV Melanoma: A Trial of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group (E4697).

AbstractPURPOSE:
We conducted a double-blind, placebo-controlled trial to evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) and peptide vaccination (PV) on relapse-free survival (RFS) and overall survival (OS) in patients with resected high-risk melanoma.
PATIENTS AND METHODS:
Patients with completely resected stage IV or high-risk stage III melanoma were grouped by human leukocyte antigen (HLA) -A2 status. HLA-A2-positive patients were randomly assigned to receive GM-CSF, PV, both, or placebo; HLA-A2-negative patients, GM-CSF or placebo. Treatment lasted for 1 year or until recurrence. Efficacy analyses were conducted in the intent-to-treat population.
RESULTS:
A total of 815 patients were enrolled. There were no significant improvements in OS (stratified log-rank P = .528; hazard ratio, 0.94; 95% repeated CI, 0.77 to 1.15) or RFS (P = .131; hazard ratio, 0.88; 95% CI, 0.74 to 1.04) in the patients assigned to GM-CSF (n = 408) versus those assigned to placebo (n = 407). The median OS times with GM-CSF versus placebo treatments were 69.6 months (95% CI, 53.4 to 83.5 months) versus 59.3 months (95% CI, 44.4 to 77.3 months); the 5-year OS probability rates were 52.3% (95% CI, 47.3% to 57.1%) versus 49.4% (95% CI, 44.3% to 54.3%), respectively. The median RFS times with GM-CSF versus placebo were 11.4 months (95% CI, 9.4 to 14.8 months) versus 8.8 months (95% CI, 7.5 to 11.2 months); the 5-year RFS probability rates were 31.2% (95% CI, 26.7% to 35.9%) versus 27.0% (95% CI, 22.7% to 31.5%), respectively. Exploratory analyses showed a trend toward improved OS in GM-CSF-treated patients with resected visceral metastases. When survival in HLA-A2-positive patients who received PV versus placebo was compared, RFS and OS were not significantly different. Treatment-related grade 3 or greater adverse events were similar between GM-CSF and placebo groups.
CONCLUSION:
Neither adjuvant GM-CSF nor PV significantly improved RFS or OS in patients with high-risk resected melanoma. Exploratory analyses suggest that GM-CSF may be beneficial in patients with resected visceral metastases; this observation requires prospective validation.
AuthorsDavid H Lawson, Sandra Lee, Fengmin Zhao, Ahmad A Tarhini, Kim A Margolin, Marc S Ernstoff, Michael B Atkins, Gary I Cohen, Theresa L Whiteside, Lisa H Butterfield, John M Kirkwood
JournalJournal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 33 Issue 34 Pg. 4066-76 (Dec 01 2015) ISSN: 1527-7755 [Electronic] United States
PMID26351350 (Publication Type: Clinical Trial, Phase III, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Copyright© 2015 by American Society of Clinical Oncology.
Chemical References
  • HLA-A2 Antigen
  • Peptide Fragments
  • Vaccines, Subunit
  • Granulocyte-Macrophage Colony-Stimulating Factor
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Granulocyte-Macrophage Colony-Stimulating Factor (administration & dosage)
  • HLA-A2 Antigen (immunology)
  • Humans
  • Male
  • Melanoma (mortality, pathology, therapy)
  • Middle Aged
  • Neoplasm Staging
  • Peptide Fragments (therapeutic use)
  • Prognosis
  • Skin Neoplasms
  • Survival Rate
  • Vaccination
  • Vaccines, Subunit (immunology)
  • Young Adult

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