GM-CSF Boosts Ipilimumab Efficacy in Metastatic Melanoma

Ben Leach
Published: Sunday, Jun 02, 2013

Dr. F. Stephen Hodi

F. Stephen Hodi, MD

Adding the white blood cell booster granulocyte-macrophage colony-stimulating factor (GM-CSF) to the immunotherapy ipilimumab extended survival in patients with metastatic melanoma when compared with ipilimumab alone and may be a safer alternative than monotherapy, according to the results of a phase II proof-of-concept study presented at the 49th Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, from May 31-June 4, 2013.

According to the results of the study, more than two-thirds of patients who received the combination were still alive after one year of receiving the treatment compared with slightly more than half of patients who were still alive after receiving ipilimumab alone. Additionally, some serious side effects associated with ipilimumab were reduced in patients who received the combination.

“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 side-effect profile,” said F. Stephen Hodi, MD, an associate professor of Medicine at Dana-Farber Cancer Institute in Boston, Massachusetts, and principal investigator and lead author for this trial.

Ipilimumab is an intravenously administered monoclonal antibody that blocks the cytotoxic T-lymphocyte antigen (CTLA-4) molecule, which is implicated in suppressing antitumor immune responses. Ipilimumab is essentially able to take off the “brakes” placed on the immune system by CTLA-4. The immunotherapy was approved for the treatment of metastatic melanoma in 2011. GM-CSF is used to increase white blood cell counts after a patient receives chemotherapy or stem cell transplantation. Preclinical studies showed that a combination of CTLA-4 blockade plus a vaccine that secretes GM-CSF was able to demonstrate synergy between the two agents.

This phase II trial, ECOG 1608, enrolled 245 patients with metastatic melanoma who had received up to one prior treatment that was not a CTLA-4 blockade, had good performance status, and whose disease had not metastasized to the central nervous system. Patients were randomized to receive either a combination of ipilimumab and GM-CSF (n=123) or ipilimumab alone (n=122). Hodi noted that the dose used in the study was 10 mg/kg intravenous injection, which is different than the 3 mg/kg dose that was approved by the FDA. This study was initiated at a time when the investigators were not sure what the approved dose of ipilimumab would eventually be. The primary endpoint of the study was overall survival (OS).

The survival rate after one year of treatment in the combination arm was 68.9%  compared with 52.9% in the monotherapy arm, with a hazard ratio for mortality on the combination arm compared with the monotherapy arm of 0.64 (stratified one-sided log rank P = .014). The median OS in the combination arm was 17.5 months compared with 12.7 months in the group of patients that received ipilimumab alone. The rate of grade 3-5 adverse events was 45% in the combination arm compared with 57% in the monotherapy arm (P = .078), suggesting a trend toward improved tolerability. Grade 5 adverse events in the combination arm included colonic perforation and cardiac arrest in one patient each, while grade 5 events in the monotherapy arm included multi-organ failure, colonic perforation, and respiratory failure in two patients each and hepatic failure in one patient.

In particular, Hodi noted the reduction of gastrointestinal and pulmonary side effects observed in the combination arm of the study. While Hodi said the investigators were not certain as to why this was observed, he explained that some preclinical studies have led them to develop a hypothesis.

“The assumption at this point is that maybe GM-CSF is regulating the immune system and the organs that protect us all from outside invaders, and that would be the lung and the gut,” Hodi said. “And the GM-CSF probably plays a role in that microenvironment that's different than other organs. In this case, it may play a role in keeping the immune system in check.”

Hodi also said that the effectiveness of this combination leads to the hope that other combinations with immunotherapies are possible.

“These data represent an important avenue for combining cytokine therapy with immune checkpoint blockade, and the consideration of the future use of GM-CSF and other immune therapies in development, such as the PD-1 blockade,” Hodi said.


Hodi FS, Lee SJ, McDermott DF, et al. Multicenter, randomized phase II trial of GM-CSF (GM) plus ipilimumab (Ipi) versus ipi alone in metastatic melanoma: E1608. J Clin Oncol. 2013;31(suppl; abstr CRA9007).

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Online CME Activities
TitleExpiration DateCME Credits
Medical Crossfire®: Evolving Roles for Targeted Melanoma Therapies: Assessing Rapid Progress in the Field and Looking Toward Future CombinationsFeb 28, 20191.5
Advances in™ Melanoma: Exploring BRAF/MEK in Adjuvant and Neoadjuvant SettingsSep 28, 20191.5
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