Lay Summary: Leukine is being explored for treating melanoma. A phase II trial and a phase III trial were recently reported.
Leukine (granulocyte macrophage colony stimulating factor, GM-CSF, Sargramostim), which is approved for marketing for hematopoietic reconstitution and reversal of chemo induced neutropenia, also has activity as a macrophage activator. It has been reported that Leukine stimulates peripheral blood monocytes in vitro to become cytotoxic for human melanoma cells. It has further been shown in clinical trials that in vivo administration of Leukine at low doses also results in monocyte activation as shown by enhanced cytotoxicity. Finally, Leukine causes release of an angiogenesis inhibitor by the macrophages. Because of these effects, interest was aroused in its use for melanoma.
A trial of therapy in the adjuvant setting was favourable. The median survival was prolonged over three-fold in patients who received Leukine to 34.3 months compared to matched historical controls (median survival 10.2 months). The observed 2-year survival was 64% in the study patients vs. 15% in the controls, (p < 0.001). Toxicity was minimal, the major side effect being mild fatigue; there were no reports of Grade 4 toxicity or serious adverse events.
An interim analysis of another trial was presented at the 6th International Conference on Admuvant Therapy of Melanoma in Stockholm in 2006 and 5th International Conference on Adjuvant Therapy of Melanoma in Athens in March, 2004. It supports the results of the earlier trial and suggests that Leukine improves survival in this patient population. Results from the Phase II study (ASCO 2010 abstract #20027) show that 60 percent of the 45 high-risk patients enrolled in the trial experienced disease-free survival and 64 percent of patients achieved overall survival at 21 months. The recent study used a year of Leukine and IL2 and then a year of Leukine. NCCN has not yet incorporated this information into its guidelines. Because there have recenlty been unfavorable trials of interferon, Luekine is being used more often than in the past.
In addition, one of the cooperative study groups, the Eastern Cooperative Oncology Group, has initiated a Phase III prospective randomized trial to further evaluate this therapy (E4697). Accrual of 800 patients has been completed. In 2010, a phase III study by Lawson et al, reported that adjuvant GM-CSF improves DFS of patients with completely resected high-risk melanoma with minimal toxicity. OS improvement is less and does not achieve statistical significance. This study included completely resected disease and mucosal melanoma and the results were at one year; a three year report is being prepared for publication.
Spitler, LE, Grossbard, ML, Ernstoff MS, et al: Adjuvant therapy of Stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol 18:1614-1621, 2000
Ravaud A, Delaunay M, Chevreau C, Coulon V, Debled M, Bret-Dibat C, Courbon F, Gualde N, Nguyen Bui B Granulocyte-macrophage colony-stimulating factor alone or with dacarbazine in metastatic melanoma: a randomized phase II trial.
2001-11-16, Br J Cancer., 85(10):1467-71.
Immunological effects and clinical outcomes in patients with high-risk melanoma given adjuvant therapy with granulocyte-macrophage colony stimulating factor (GM-CSF, sargramostim)
◦Lead investigator: Lynn Spitler, Northern California melanoma Center, Saint Mary’s Medical Center, San Francisco, CA
◦Abstract e20004, ASCO 2010