ESMO 2016: Ipilimumab as Adjuvant Therapy Improves Overall Survival in High-Risk Stage III Melanoma
Ipilimumab (Yervoy) as adjuvant therapy significantly improves overall survival in patients with high-risk stage III melanoma, according to the European Organisation for Research and Treatment of Cancer (EORTC) 18071 phase III trial results presented by Eggermont et al at the European Society for Medical Oncology (ESMO) 2016 Congress in Copenhagen (Abstract LBA2_PR).
“Ipilimumab is an immune checkpoint inhibitor that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4),” said lead author Alexander Eggermont, MD, PhD, Director General of the Institut Gustave Roussy in Villejuif, France. “It was approved in 2011 for first-line treatment of advanced melanoma in the United States and Europe. The next question was its utility in the adjuvant setting.”
EORTC 18071
The EORTC 18071 phase III trial evaluated ipilimumab as adjuvant therapy for patients with high-risk stage III melanoma. During 2008 to 2011, 951 patients were randomized to ipilimumab or placebo. Interferon was not used as the comparator, because in Europe, it is not routinely used nor accepted as a standard of care.
As reported in 2015 in The Lancet, the study met its primary endpoint after a median follow up of 2.3 years, with ipilimumab significantly improving recurrence-free survival. The drug was subsequently approved by the U.S. Food and Drug Administration (FDA) as adjuvant therapy for stage III melanoma.
Extended Follow-up Findings
Now, at 5.3 years median follow-up, the impact on overall survival was found to be a 28% reduction of the relative risk of death (hazard ratio = 0.72, P = .001). There was consistency across all endpoints with hazard ratios of 0.76 for recurrence-free survival and distant metastases–free survival (P < .001 and P = .002). In absolute terms, the overall survival rate at 5 years was 11% higher in the ipilimumab arm (65%) than in the placebo arm (54%).
Ipilimumab is known to create immune-related adverse events. At 5.3 years, there were no additional toxicities or deaths since the initial report at 2.3 years. The most important grade 3/4 adverse events were gastrointestinal (16%), hepatic (11%), and endocrine (8%). These were managed by established algorithms and usually resolved within 4 to 8 weeks. Endocrine adverse events took much longer to resolve or required permanent hormonal replacement therapies.
Dr. Eggermont commented, “Ipilimumab adjuvant therapy brings a significant improvement of overall survival and has a favorable risk-benefit ratio. It clearly represents a serious option for patients with stage III melanoma.”
Commentary
Commenting on the results, Olivier Michielin, MD, head of Personalised Analytical Oncology, CHUV in Lausanne, Switzerland, said, “This was the first attempt to use checkpoint blockade in the adjuvant setting of melanoma. The effect was a 28% reduction in the risk of death, which is statistically and clinically significant, and an 11% absolute gain in overall survival at 5 years.”
“This was also an important scientific discovery,” added Dr. Michielin. “Ipilimumab works by stimulating the immune system against tumor antigens. In the adjuvant setting, there is microscopic residual disease, and, until now, it was not clear if there was a sufficient amount of antigens to trigger a response.”
He continued, “The risks and benefits of this option should now be discussed with our patients. The toxicity is not negligible, and patients need to be aware of the adverse event profile. The 10-mg/kg regimen used in the trial is associated with potentially severe toxicities and should be reserved for experienced centers.”
Dr. Michielin concluded: “This trial represents an important milestone in the treatment of melanoma. These results open the door for other studies based on checkpoint blockade, to try and improve cure rates in the adjuvant setting of melanoma, as well as other disease types.”
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
