ASCO 2013: Adding GM-CSF to Ipilimumab Significantly Improves Survival for Patients with Metastatic Melanoma
Adding granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine) to ipilimumab (Yervoy) at a 10 mg/kg dose significantly improved survival compared to the same dose of ipilimumab alone, according to results of a proof-of-principle phase II trial. One year after the start of therapy, 68.9% of patients who received the combination therapy were alive, compared to 52.9% of patients who received ipilimumab alone. The results were reported at the 2013 ASCO Annual Meeting (Abstract CRA9007).
“This is the first randomized phase II study looking at the combination of ipilimumab and GM-CSF in any cancer,” said the study’s lead author F. Stephen Hodi, MD, Associate Professor of Medicine at Dana-Farber Cancer Institute in Boston. While the results “provide another important sign that immunotherapy can have a big impact for patients with advanced melanoma,” Dr. Hodi added, “we still need to clarify the best way to apply these findings in everyday practice.”
Comparable Tumor Shrinkage
The study enrolled 245 patients with metastatic melanoma, but without central nervous system metastasis, who had received no more than one prior treatment completed 4 or more weeks before enrollment. Patients randomly assigned to arm A received ipilimumab at 10 mg/kg every 3 weeks intravenously × 4 then every 12 weeks, plus GM-CSF 250 µg subcutaneously on days 1 to 14 of 21 day cycles. Patients in arm B received only the ipilimumab at the same doses and schedule as in arm A.
The ipilimumab regimen differs from the regimen currently approved by the Food and Drug Administration for the treatment of unresectable or metastatic melanoma, which is 3 mg/kg administered intravenously every 3 weeks for a total of four doses. Dr. Hodi noted that a trial to compare 3 mg/kg to 10 mg/kg with ipilimumab has completed accrual but the data are not yet mature.
At a median follow-up of 13.3 months, tumor shrinkage rates were comparable in both arms—11.3% in arm A vs 14.7% in arm B. “One-year overall survival for arm A was 68.9% (95% confidence interval [CI] = 60.6–85.5), and 52.9% for arm B (95% CI = 43.6–62.2) (stratified log-rank P = .014),” the investigators reported. “The median overall survival with ipilimumab was 12.7 months vs 17.5 months in the combination,” Dr. Hodi added.
Fewer Serious Side Effects
The combination treatment with GM-CSF and ipilimumab was associated with fewer serious side effects compared to ipilimumab alone. Grade 3 to 5 adverse events occurred in 45% of patients in arm A and 58% of patients in arm B (P2 = .038). The grade 5 toxicities in arm A were colonic perforation in one patient and cardiac arrest in one patient. The grade 5 toxicities in arm B were hepatic failure in one patient, multiorgan failure in two patients, colonic perforation in two patients, and respiratory failure in two patients.
There were two possible treatment-related deaths in the combination arm vs seven in the single-drug arm.
Builds on Previous Advances
“This melanoma study builds upon the remarkable successes and advances we have seen for patients with advanced melanoma over the past 2 years,” said Lynn Schuchter, MD, Division Chief, Hematology/Oncology, University of Pennsylvania, Philadelphia. “These data show enhanced overall survival in patients with advanced melanoma with substantially less toxicity,” she said. She noted, however, that it would be premature to just add GM-CSF to patients currently receiving ipilimumab and that more studies are expected.
Additional immune system boosters are being explored in early clinical trials, though the advantage of GM-CSF is that it improves both efficacy and safety of immunotherapy, the researchers noted. The next step is to better define the role of GM-CSF in combination with other immune checkpoint targeting drugs, such as PD-1 and PD-L1.
This research was designed and conducted by the ECOG-ACRIN Cancer Research Group (formerly the Eastern Cooperative Oncology Group) and supported in part by the National Cancer Institute (Cancer Therapy Evaluation Program), Sanofi, and Bristol-Myers Squibb. Dr. Hodi reported a consultant or advisory role with Bristol-Myers Squibb and research funding from Bristol-Myers Squibb. Dr. Schuchter reported research funding from Genentech, GlaxoSmithKline, Merck, and Roche.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
