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) David 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, and John M. Kirkwood David H. Lawson, Winship Cancer Insti- tute of Emory University, Atlanta, GA; Sandra Lee and Fengmin Zhao, Dana- Farber Cancer Institute; Michael B. Atkins, Beth Israel Deaconess Medical Center, Boston, MA; Ahmad A. Tarhini, Theresa L. Whiteside, Lisa H. Butter- field, and John M. Kirkwood, University of Pittsburgh Medical Center, Pitts- burgh, PA; Kim A. Margolin, Seattle Cancer Care Alliance, Seattle, WA; Marc S. Ernstoff, Dartmouth-Hitchcock Medical Center, Lebanon, NH; and Gary I. Cohen, Greater Baltimore Medical Center, Baltimore, MD. Published online ahead of print at www.jco.org on September 8, 2015. Support information appears at the end of this article. Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article. Clinical trial information: NCT01989572. Corresponding author: David H. Lawson, MD, 1365C Clifton Rd, Atlanta, GA 30322; e-mail: dlawson@ emory.edu. © 2015 by American Society of Clinical Oncology 0732-183X/15/3334w-4066w/$20.00 DOI: 10.1200/JCO.2015.62.0500 A B S T R A C T Purpose 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. J Clin Oncol 33:4066-4076. © 2015 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 33  NUMBER 34  DECEMBER 1 2015 4066 © 2015 by American Society of Clinical Oncology Downloaded from ascopubs.org by 52.200.192.149 on June 19, 2022 from 052.200.192.149 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.