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).
OBJECTIVE
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.


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.


CONCLUSIONS
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.
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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. dlawson@emory.edu.
David H
DH
Lawson
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
Sandra
S
Lee
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
Fengmin
F
Zhao
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
Ahmad A
AA
Tarhini
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
Kim A
KA
Margolin
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
Marc S
MS
Ernstoff
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
Michael B
MB
Atkins
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
Gary I
GI
Cohen
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
Theresa L
TL
Whiteside
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
Lisa H
LH
Butterfield
David H. Lawson, Winship Cancer Institute 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. Butterfield, and John M. Kirkwood, University of Pittsburgh Medical Center, Pittsburgh, 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.
John M
JM
Kirkwood
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D015789:HLA-A2 Antigen / Q000276:immunology*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D009367:Neoplasm Staging; D010446:Peptide Fragments / Q000627:therapeutic use*; D011379:Prognosis; D012878:Skin Neoplasms; D015996:Survival Rate; D014611:Vaccination; D022223:Vaccines, Subunit / Q000276:immunology*; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
D015789:HLA-A2 Antigen; D010446:Peptide Fragments; D022223:Vaccines, Subunit; D016178:Granulocyte-Macrophage Colony-Stimulating Factor