Nick Mulcahy

June 01, 2013

CHICAGO, Illinois — When ipilimumab is combined with a growth factor, a synergistic treatment effect seems to improve overall survival in some patients with metastatic melanoma, according to results from a phase 2 study.

One-year overall survival was better with ipilimumab plus the growth factor sargramostim (Leukine, Sanofi) than with ipilimumab alone (67.9% vs 51.2%; stratified log rank P 1 = 0.016, P 2 =.033).

"This is the first randomized phase 2 study looking at the combination of ipilimumab and GM-CSF in any cancer," said lead author F. Stephen Hodi, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, in a press statement.

Dr. Hodi will present the study here today at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO®).

The median overall survival for the combination was 17.5 months; for ipilimumab alone, it was 12.7 months (P = .0014). Of the 245 patients, those treated with the combination had a 35% lower risk of dying than those treated with ipilimumab alone (hazard ratio for mortality, 0.64).

The median follow-up in the trial was 13.3 months.

Ipilimumab is approved for the treatment of metastatic melanoma at a dose of 3 mg/kg, but was used at a higher dose (10 mg/kg) in this trial. Sargramostim is a granulocyte-macrophage colony-stimulating factor (GM-CSF) that is typically used to increase white blood cell counts in patients with cancer.

The addition of the growth factor did not, however, greatly improve the response rate for ipilimumab, which was a disappointing 10% in its pivotal clinical trial in 2010.

In the current trial, the response rate was higher with ipilimumab plus GM-CSF than with ipilimumab alone, but the difference was not significant (14.7% vs 11.3%).

Combining ipilimumab with GM-CSF is an idea with a solid theoretic basis, said Ashani Weeraratna, PhD, from the Wistar Institute Cancer Center in Philadelphia, Pennsylvania. She was asked by Medscape Medical News to comment on the findings.

"GM-CSF acts to boost the immune system and increase its antitumor response. However, tumor cells can shut off this response," said Dr. Weeraratna, who was not involved in the study.

Ipilimumab, in turn, can inhibit the ability of cancer cells to recognize and destroy the immune system's T-cells, which are cytotoxic, she continued.

"GM-CSF works by increasing the immune response, and ipilimumab works by shutting down the tumor cells' ability to resist this increased immune attack," Dr. Weeraratna summarized.

Given that both ipilimumab and GM-CSF are both available, should clinicians start using the combination?

Not yet, said a melanoma expert not involved with the study. "It's premature to say we're going to add GM-CSF to ipilimumab," said ASCO spokesperson Lynn Schuchter, MD, in a meeting press conference. She is from the University of Pennsylvania's Abramson Cancer Center in Philadelphia. The study results need to be replicated, she said.

Safety Might Also Be Better With GM-CSF

Adverse events related to ipilimumab necessitated a boxed warning on the drug's label and a related Risk Evaluation and Mitigation Strategy.

Toxicity continues to be a problem with the drug; however, the addition of GM-CSF was associated with reduced toxicity. "A trend toward improved tolerability is noted in the [combination] arm," write the authors in their abstract.

There were 9 treatment-related deaths in the trial (3 colonic perforations, 1 cardiac arrest, 2 hepatic failure, 1 respiratory failure, and 2 multiorgan failures). Seven of the deaths were in patients treated with ipilimumab alone; that group also had more serious adverse events.

Grade 3 to 5 adverse events (severe, life-threatening/disabling, and death, respectively) were less common for ipilimumab plus GM-CSF than for ipilimumab alone, but the difference was not significant (45% vs 57%; P 2= .078).

Dr. Hodi and colleagues randomized 245 patients to 1 of 2 treatments: intravenous ipilimumab 10 mg/kg every 3 weeks (for 4 cycles) and every 12 weeks thereafter plus GM-CSF 250 μg subcutaneously on days 1 to 14 of 21-day cycles; or ipilimumab alone on the same schedule.

Eligible patients had received 1 or no previous therapies, had no central nervous system metastases, had a good performance score (ECOG performance status 0 or 1), had adequate end-organ function, had no autoimmune disease, and had received no previous CTLA-4 blockade/CD137 agonist, which is the mechanism of action of ipilimumab.

Progression-free survival was not significantly different between the combination and ipilimumab-alone groups (3.2 vs 3.0 months).

The study was supported by the National Cancer Institute, Sanofi, and Bristol-Myers Squibb. The companies also supplied the drugs for the trial. Dr. Hodi reports serving in a consultant or advisory role for Bristol-Myers Squibb, and receiving research funding from the company. Some of his coauthors report financial ties with industry.

2013 Annual Meeting of the American Society of Clinical Oncology: Abstract CRA9007. Presented June 1, 2013.

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