Phase III Trial Shows No Benefit of Adjuvant GM-CSF or Peptide Vaccine in High-Risk, Resected Melanoma


Key Points

  • No benefit was observed for GM-CSF or peptide vaccination among all patients with resected stage IV or high-risk stage III melanoma.
  • GM-CSF appeared to be of benefit among patients with visceral metastases.

In a phase III trial (Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Cancer Research Group E4697 trial) reported in the Journal of Clinical Oncology, Lawson et al found no relapse-free or overall survival benefit with adjuvant yeast-derived granulocyte-macrophage colony-stimulating factor (GM-CSF) or peptide vaccination in patients with completely resected stage IV or high-risk stage III melanoma. An exploratory analysis suggested benefit of GM-CSF in patients with visceral metastases.

Study Details

In the double-blind, placebo-controlled trial, 815 patients were grouped by HLA-A2 status. HLA-A2–positive patients (n = 436) were randomly assigned to receive GM-CSF plus peptide vaccine (n = 109), peptide vaccine plus placebo (n = 110), GM-CSF plus placebo (n = 109), or placebo (n = 107); HLA-A2–negative patients (n = 379) were randomly assigned to receive GM-CSF (n = 190) or placebo (n = 189).

In addition to HLA-A2 status, randomization was stratified for the number of metastatic lesions and site of metastases. Treatment lasted for 1 year or until recurrence. The primary endpoints were relapse-free survival and overall survival in the intent-to-treat population. Overall, disease stage was III in 61% of patients and IV in 39%. The metastasis site was visceral in 17%, not visceral in 70%, and both in 2%, and 64% of patients had one metastatic lesion.

Relapse-Free and Overall Survival

Median overall survival was 69.6 months among patients receiving GM-CSF (n = 408) vs 59.3 months in those receiving placebo (n = 407; hazard ratio [HR] = 0.94, P = .528); probability of 5-year overall survival was 52.3% vs 49.4%. Median relapse-free survival was 11.4 vs 8.8 months (HR = 0.88, P = .131), with 5-year relapse-free survival probability of 31.2% vs 27.0%.

Among the 436 HLA-A2–positive patients, 220 received peptide vaccine (109 with and 111 without GM-CSF) and 216 received placebo (109 with and 107 without GM-CSF). Median overall survival was 68.6 months in those receiving peptide vaccine vs 63.3 months in those receiving placebo (HR = 0.93, P = .598). Median relapse-free survival was 11.5 vs 9.8 months (HR = 0.96, P = .708).

There was no significant difference in median overall survival (68.6 vs 57.9 months, P = .519) or relapse-free survival (11.3 vs 9.2 months, P = .285) between HLA-A2–positive and HLA-A2–negative patients regardless of treatment.  

Outcome in Visceral Metastases

On exploratory analysis, no effect of GM-CSF vs placebo on overall or relapse-free survival was observed in patients with stage IIIA, IIIB, or IIIC/M1a disease. However, among patients with visceral metastases (M1b or M1c), median overall survival was 72.4 vs 37.3 months (P < .001), and median relapse-free survival was 10.2 vs 5.8 months (P = .261).

Adverse Events

Overall, the incidence of treatment-related grade ≥ 3 adverse events was similar in patients who received GM-CSF (12.3%) and those who did not (9.9%; P = .306) and in those who received peptide vaccine (13.6%) and those who did not (11.4%). The most common treatment-related grade ≥ 3 adverse events were injection-site reactions (2.2%) and headache (2.0%).

The investigators concluded: “Neither adjuvant GM-CSF nor [peptide vaccination] significantly improved [relapse-free survival] or [overall survival] 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, MD, of Winship Cancer Institute of Emory University, is the corresponding author of the Journal of Clinical Oncology article.

The study was supported by Public Health Service grants and the National Institutes of Health and National Cancer Institute. For full disclosures of the study authors, visit

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