Ipilimumab prolongs survival in a small but significant proportion of patients with metastatic melanoma, but the drug comes with serious side effects. In a randomized Phase II study reported at the American Society of Clinical Oncology, the addition of granulocyte macrophage colony-stimulating factor (GM-CSF) to ipilimumab increased overall survival compared with ipilimumab (Abstract CRA9007). The combination also reduced serious adverse gastrointestinal and pulmonary toxicities compared with single-agent ipilimumab.
“The data really show enhanced survival for patients with advanced melanoma, and substantially less toxicity,” said Lynn Schuchter, MD, the C. Willard Robinson Professor of Hematology-Oncology and Attending Physician at the University of Pennsylvania Hospital, in her capacity as an ASCO melanoma expert who was not involved with the study, speaking during a news conference.
“To see that when you combine two immunotherapies that you get better response is quite remarkable, but then to see fewer side effects is really, really surprising. Still, she said, “I think it is premature to say we are going to add GM-CSF [right away] to patients who are receiving ipilimumab. I think there are going to be additional studies.”
No Change in PFS
The researchers, led by F. Stephen Hodi, MD, Associate Professor of Medicine at Dana-Farber Cancer Institute, designed the cooperative group trial after experiments in mouse models showed synergy with GM-CSF and ipilimumab. The trial included 245 patients with inoperable Stage 3 or 4 disease with one or no prior therapy for advanced disease.
Patients assigned to the combination arm received 250 μg of subcutaneous GM-CSF daily on days 1-14 of a 21-day cycle and 10 mg/kg intravenous ipilimumab on day one for four cycles, plus maintenance with 10 mg/kg ipilimumab delivered on day 1 of every fourth cycle thereafter. Patients in the single-agent arm received ipilimumab on the same dose and schedule.
With a median follow-up of 13.3 months, there was no significant difference in progression-free survival. The hazard ratio of 0.92 was reflected in overlapping curves on a Kaplan-Meier plot. Nor did the researchers see a difference in overall response rate between the two arms, at 15.5 percent in the combination arm and 14.8 percent in the single-agent arm.
However, overall survival significantly improved in the combination arm, with a 36 percent reduction in risk of death compared with the control arm. The median overall survival in the combination arm was 17.5 months compared with 12.7 months in the single-agent arm. Similarly, the estimated one-year survival was 68.9 percent in the experimental arm compared with 52.9 percent in the control arm. Both differences were statistically significant, he said.
Significantly Less Toxicity
Moreover, the combination was associated with significantly fewer serious adverse events than with ipilimumab alone: In the combination arm 53 patients (about 45%) experienced some grade 3-5 toxicity compared with 70 patients (about 58%) in the single-agent arm. And when the researchers examined the serious adverse events in terms of categories, gastrointestinal events were found to be significantly reduced in the combination arm relative to the control arm (16% vs. 27%) as were pulmonary events (0% vs. 7.5%).
When asked during the news conference to speculate on why there was reduced toxicity with the combination, Hodi noted that when the gene was knocked out in mice, the animals developed inflammation in these same organs, the lung and gut. Therefore, the researchers hypothesized, he said, that GM-CSF helps regulate homeostasis in those organs and may help to keep the immune system in check there.
Following the presentation, Jeffrey Sosman, MD, Professor of Medicine and Director of the Melanoma and Tumor Immunotherapy Program at Vanderbilt-Ingram Cancer Center, raised the question about both reduced toxicity and the lack of benefit in progression-free survival: “The [overall survival] curves separate so fast and, at least in my view, that doesn't sound like immunotherapy. You would think if the curves separated so fast, you would actually see more of a progression-free survival difference, but you see none.
“Isn't it possible that the entire benefit [of the combination] has to do with this remarkable effect on the horrendous toxicity of ipilimumab?”
Hodi replied, “The fact of the matter is that the protection from high-grade effects may play a role, but I get the sense there is something else going on there too.”
He noted that when the group performed a subset analysis, excluding patients who stopped therapy due to toxicity, there was still a statistically significant survival benefit with the combination arm. “It is certainly likely that the tremendous benefit that you get in protecting patients from adverse events may have a role in it, I think that is very important. Still, I think there is more to it too.”
He pointed out that these data have immediate clinical relevance since both agents are currently available. He cautioned, though, that the ipilimumab dosing is not what is currently approved by the Food and Drug Administration, which makes translating the data into clinical care less straightforward. Moreover, it is not clear whether third-party payers would cover the use of GM-CSF in this setting based on these data.
Additionally, Kim Margolin, MD, Professor of Medicine at the University of Washington School of Medicine and a melanoma specialist at the Seattle Cancer Care Alliance, cautioned that while the data are interesting, the tails of the overall survival curves represent only a few patients at this point.
“We need to be careful in interpreting the data. We perhaps need more follow-up and larger patient numbers in a different study design,” she concluded during her discussion of the abstract.