CHICAGO -- Adding a growth factor to the immune-stimulating drug ipilimumab significantly improved overall survival in patients with metastatic melanoma, a proof-of-principal phase II study showed.
A total of 67.9% of patients given ipilimumab plus granulocyte-macrophage colony-stimulating factor (GM-CSF) were alive at 1 year, compared with 51.2% given ipilimumab alone (P=0.014), reported F. Stephen Hodi, MD, of the Dana-Farber Cancer Institute in Boston at the annual meeting American Society of Clinical Oncology.
GM-CSF is often given to stimulate or prime the immune system in patients who are undergoing chemotherapy. Ipilimumab removes the "brakes" on the immune system's attack on melanoma by blocking the molecule cytotoxic T-lymphocyte–associated antigen 4, or CTLA-4, that acts as a checkpoint to down-regulate T-cell activation pathways.
The new study builds on Hodi's previous research which demonstrated the first-ever overall survival benefit with any treatment in a metastatic melanoma clinical trial with the immune-stimulating agent ipilimumab (Yervoy). In that study, adding the gp100 vaccine to ipilimumab did not boost the effect.
But in mice, CTLA-4 blockade and GM-CSF vaccines have demonstrated synergy. Also, GM-CSF and immunotherapy combinations have shown demonstrated benefit in colon and ovarian carcinoma and are being evaluated in phase III trials for lymphoma and melanoma.
For the new study, Hodi and colleagues randomized 245 patients to intravenous ipilimumab 10 mg/kg every 3 weeks for four cycles, followed by the same regimen every 12 weeks, plus GM-CSF 250 µg subcutaneously on days one to 14 of 21-day cycles; or ipilimumab alone on the same schedule. Patients had received one or no previous therapies.
The median follow-up time was 13.3 months.
The median overall survival for the combination treatment was 17.5 months versus 12.7 months for ipilimumab alone (P=0.0014).
Patients treated with the combination were 36% less likely to die than those treated with ipilimumab alone (hazard ratio=0.64).
The response rate was 14.7% for ipilimumab plus GM-CSF versus 11.3% for ipilimumab alone, but the difference did not reach significance.
Ipilimumab is approved at a dose of 3 mg/kg, considerably lower than the 10 mg/kg dose used in this trial.
Even at this lower dose, ipilimumab carries a black box warning of severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation that may involve any organ system, noted ASCO spokesperson Lynn Schuchter, MD, of the University of Pennsylvania's Abramson Cancer Center in Philadelphia.
Interestingly, the addition of GM-CSF was associated with reduced toxicity, Hodi said. "A trend toward improved tolerability is noted in the [combination] arm," the authors wrote in their abstract.
There were nine treatment-related deaths in the trial, seven in patients treated with ipilimumab alone. The Grade 3 to 5 adverse event rate was 45% in the combination arm versus 57% for ipilimumab alone, but the difference was not significant (P=0.078).
"Adding GM-CSF to ipilimumab improved survival and tolerability," Hodi said. "With both drugs commercially available, there are implications for the current treatment of melanoma patients," he said.
But Schuchter stressed that the combo is not ready for prime-time. "It's premature to say we're going to add GM-CSF to ipilimumab," she said, adding that the results need to be replicated.
The work was supported in part by the National Cancer Institute, sanofi-aventis, and Bristol-Myers Squibb.
Hodi has financial ties to Bristol-Myers Squibb. Some of his co-authors report financial ties with industry.
Schuchter reported no relevant financial ties.
Primary source: American Society of Clinical Oncology
Source reference:
Hodi FS, et al "Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus ipi alone in metastatic melanoma: E1608" ASCO 2013; Abstract CRA9007.
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