GM-CSF Failed to Improve Survival in Resected Late-Stage Melanoma

Neither granulocyte-macrophage colony-stimulating factor (GM-CSF) nor peptide vaccination (PV), both thought to contribute to antitumor responses, significantly improved survival outcomes in patients with high-risk resected melanoma, according to the results of a phase III study.

Although GM-CSF resulted in a 10.3-month improvement in overall survival compared with placebo, this result failed to meet the hypothesized increase of 13.3 months sought by the researchers in the trial.

“These results are not statistically significant but leave open the question of whether GM-CSF may have smaller benefits,” wrote David H. Lawson, MD, of Winship Cancer Institute of Emory University, and colleagues in the Journal of Clinical Oncology. “Other possible contributors to this lack of significant benefit include lack of efficacy, pre-existing immune status of patients, immunologic response to GM-CSF, development of neutralizing antibodies to GM-CSF, effects of GM-CSF on suppressor elements (such as myeloid-derived suppressor cells), and possible suboptimal dose and/or duration of treatment.”

Lawson and colleagues evaluated GM-CSF and PV in 815 patients with completely resected stage IV or high-risk stage III melanoma. Patients were grouped according to human leukocyte antigen (HLA)-A2 status. HLA-A2–positive patients were randomly assigned to GM-CSF, PV, both, or placebo; HLA-A2–negative patients were assigned to GM-CSF or placebo.

No significant improvements in overall survival or recurrence-free survival were found between patients assigned to GM-CSF compared with those assigned to placebo.

Patients assigned to GM-CSF had a 10.3-month improvement in overall survival, but this difference was not statistically significant. The median overall survival for treatment with GM-CSF was 69.6 months compared with 59.3 months for the placebo group. Five-year overall survival probability rates were 52.3% for GM-CSF compared with 49.4% for the placebo group.

The median recurrence-free survival was 11.4 months with GM-CSF compared with 8.8 months for placebo. The 5-year recurrence-free survival probability rates were 31.2% for GM-CSF compared with 27.0% for placebo.

The researchers also looked at treatment according to HLA-A2 status. Patients with HLA-A2–positive status were also treated with PV (n = 220). The median overall survival was 68.6 months in patients treated with PV compared with 63.3 months in placebo-treated patients, a nonsignificant difference.

Finally, the researchers found no significant improvements in overall survival or recurrence-free survival between HLA-A2–positive and HLA-A2–negative patients, regardless of the type of assigned treatment.

“Although, overall, this study did not support the hypothesis that adjuvant GM-CSF could make a significant impact on recurrence-free survival or overall survival of the study population, trials that test GM-CSF in patients with resected visceral melanoma metastases are worthy of consideration,” wrote the researchers. “Such studies may target a patient population unable, unlikely, or unwilling to tolerate current immunotherapeutic adjuvant agents (eg, IFN [interferon], cytotoxic T-cell lymphocyte-4 blockade) on the basis of a borderline performance status or other comorbid conditions, such as symptomatic lung disease, inflammatory bowel disease, or significant autoimmune diseases.”