GM-CSF plus ipilimumab extended OS in metastatic melanoma

Issue: July 10, 2013

CHICAGO — The addition of granulocyte-macrophage colony-stimulating factor to an increased dose of ipilimumab extended OS among patients with metastatic melanoma, according to results of a phase 2 study presented at the ASCO Annual Meeting.

Perspective from Lynn M. Schuchter, MD; Gregory A. Masters, MD, FACP; Nikhil Khushalani, MD

Granulocyte-macrophage colony-stimulating factor [GM-CSF (Sargramostim, Leukine)] is frequently used to increase white blood cell counts in patients who undergo chemotherapy. Ipilimumab (Yervoy, Bristol-Myers Squibb) targets the CTLA-4 protein, which keeps immune t-cells in an inactive state, according to background information provided by researchers.

CTLA-4 blockade and GM-secreting tumor vaccine combinations have demonstrated therapeutic synergy in pre-clinical models. In addition, GM has previously demonstrated benefit in prostate and ovarian carcinoma and is currently being evaluated in phase 3 trials for melanoma and lymphoma.

The current study included 245 patients with unresectable stage III/IV metastatic melanoma who had not undergone treatment for their disease or underwent up to one prior treatment.

Researchers assigned patients to 10 mg/kg ipilimumab plus GM-CSF or 10 mg/kg ipilimumab alone.

Median follow-up was 13.3 months.

Tumor shrinkage rates were similar between the two arms (11% for combination therapy vs. 14% for ipilimumab alone).

However, researchers reported a higher rate of 1-year OS (68.9% vs. 52.9%) and improved OS (17.5 months vs. 12.7 months) among patients assigned to combination therapy. Patients in the combination arm had a 35% lower risk for mortality compared with those assigned to ipilimumab alone.

Fewer adverse events were observed in the combination treatment arm, with the most significant differences in pulmonary and gastrointestinal side effects. Two possible treatment-related deaths occurred in the combination arm vs. seven in the single-drug arm.

“Adding GM-CSF to ipilimumab improved survival and tolerability,” principal researcher Stephen Hodi, MD, associate professor of medicine at Dana-Farber Cancer Institute, said during a press conference. “With both drugs commercially available, there are implications for current treatment for melanoma patients, as the addition of GM-CSF improved efficacy as well as the side effect profile. However, of note, the dose of ipilimumab used in this trial was 10 mg/kg and included an induction and maintenance phase.”

Another trial has completed accrual to compare a 3 mg/kg dose with the 10 mg/kg dose, Hodi said.

“These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade and the consideration of future use of GM-CSF and other immunotherapy developments,” Hodi said.

For more information:

Hodi FS. Abstract #CRA9007. Presented at: ASCO Annual Meeting; May 31-June 4, 2013; Chicago.

Disclosure: The researchers report research funding from, as well as consultant or advisory roles with, Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Merck, Novartis, Prometheus and Vical.

Perspective

Lynn M. Schuchter, MD

This melanoma study builds upon the remarkable successes and advances we have seen for patients with advanced melanoma over the past 2 years. We are going to have to see how this fits in. It’s very intriguing that there are fewer side effects, and that’s the one result in melanoma that we can think about doing something with.

Lynn M. Schuchter, MD

C. Willard Robinson Professor of Hematology-Oncology

University of Pennsylvania School of Medicine

Disclosures: Schuchter reports no relevant financial disclosures.

Perspective

Gregory A. Masters, MD, FACP

We are excited to see that immunotherapies are playing a larger role in the treatment of advanced disease. It’s especially good to see the lower toxicities.

Gregory A. Masters, MD, FACP

Director, medical oncology fellowship

Medical Oncology Hematology Consultants

Member, ASCO Cancer Communications Committee

Disclosures: Masters reports no relevant financial disclosures.

Perspective

Nikhil Khushalani, MD

Ipilimumab was the first drug to improve OS in advanced melanoma. In this study, the addition of an old drug, GM-CSF, improved the outcome of patients when combined with ipilimumab compared with ipilimumab alone. Interestingly, the toxicity of the combination arm was less when reported as an absolute number of adverse events. However, nine patients (3.6%) on this trial experienced fatal events possibly related to therapy, underscoring the importance of early recognition of immune-mediated effects from this class of drugs. This is concerning, and it is unclear whether this is related to the higher dose of ipilimumab (10 mg/kg) that was used on this trial as opposed to the FDA-approved dose of 3 mg/kg. Further refinement of this approach is needed before we can make definitive conclusions regarding the contribution of GM-CSF to the efficacy of ipilimumab.

Nikhil Khushalani, MD

Section chief of soft tissue and melanoma

Associate professor or oncology

Roswell Park Cancer Institute

Buffalo, N.Y.

Disclosures: Khushalani reports grant funding from the National Comprehensive Cancer Network from general research support provided by Allos, Pfizer and Roche; funding for investigator-initiated clinical trials from Merck and Pfizer; a speaker’s bureau role with Prometheus; and an advisory board role with Genentech.