ASCO 2014: Adjuvant Ipilimumab Significantly Improves Recurrence-Free Survival in Patients With High-Risk Stage III Melanoma
Adjuvant therapy with ipilimumab (Yervoy) for patients with high-risk stage III melanoma significantly improved recurrence-free survival, the primary endpoint of the phase III EORTC 18071/CA 184-029 study. Patients randomly assigned to receive ipilimumab had a 9-month absolute improvement in recurrence-free survival, 26.1 months vs 17.1 months for patients receiving placebo (hazard ratio [HR] = 0.75; P = .003).
The recurrence-free survival benefit was consistent across prespecified subgroups: stage IIIA vs IIIB vs IIIC melanoma, microscopic vs macroscopic lymph node involvement, and ulcerated vs nonulcerated primary tumor. The study’s lead author, Alexander Eggermont, MD, PhD, Director General of the Gustave Roussy Cancer Campus Grand Paris, reported the results at the 2014 ASCO Annual Meeting in Chicago (Abstract LBA9008). Dr. Eggermont stated that adjuvant therapy with ipilimumab clearly is emerging as a new option for patients with high-risk stage III disease, but that more research is needed to fully assess the balance of benefits and risks.
Substantially Reduced Risk of Recurrence
The study randomly assigned 951 patients with surgically treated stage III cutaneous melanoma to receive ipilimumab or placebo. The primary endpoint was recurrence-free survival. Patients received 10 mg/kg of ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years.
At a median follow-up period of 2.7 years, ipilimumab reduced the relative risk of recurrence by 25% compared to placebo. Recurrences totaled 234 among the 475 patients receiving ipilimumab and 294 among the 476 receiving placebo. The additional 60 patients relapsing in the placebo arm “is a robust number of patients,” Dr. Eggermont said at an ASCO press briefing on progress in immunotherapy.
“We also looked at absolute differences in relapse-free survival rates at 2 years and at 3 years. Those kinds of numbers are much simpler to explain to patients. The difference at 2 years is 8% in absolute terms, and the difference at 3 years is 12%, favoring the ipilimumab treatment arm.” Dr. Eggermont added.
Immune-Related Adverse Events
“Immune-related adverse events are characteristic of these immune checkpoint blockers because they also have effects on the immune system at large,” Dr. Eggermont noted. Grade 3/4 events associated with ipilimumab occurred in 42% of patients, “but here you must make the split between grade 3 events, which are immune-related adverse events that will discontinue treatment, and that was 36.5%, and grade 4 immune-related adverse events, which are the really serious ones, and that was 5.5%.”
The gastrointestinal and the endocrine adverse events “are the most important ones,” Dr. Eggermont continued. Grade 3 diarrhea and colitis occurred among 12% of patients, and grade 4 among 3%. Grade 3 and 4 endocrine events affected a total of 8.5%, but “there was only 1.2% for grade 4,” he reported. Most adverse events were resolved, he noted. “The only adverse events that may linger on for a very long time are the endocrine adverse events because patients may require hormone replacement therapy for years, a very important point,” Dr. Eggermont said.
There have been five treatment-related deaths on the study, and 52% of patients discontinued treatment due to side effects, most within the first 12 to 16 weeks.
Data remain blinded for the secondary endpoints of overall survival and distant metastatic-free survival. A separate, ongoing phase III study (ECOG 1609) is comparing two different doses (3 mg/kg and 10 mg/kg) of adjuvant ipilimumab with high-dose interferon.
‘Approved’ and ‘Improved’ Drugs
Ipilimumab has been approved by the U.S. Food and Drug Administration for the treatment of inoperable stage IV melanoma, although at a dose lower than used in the current study. High-dose interferon alfa-2b (Intron A) and pegylated interferon-alfa-2b (Pegintron, Sylatron) have also been approved by the FDA for patients with stage III melanoma at high risk of recurrence.
“Although there are approved therapies, they still need to be improved,” Dr. Eggermont said at the ASCO press briefing on immunotherapies. While the current study was the first to demonstrate the clinical benefit of ipilimumab in stage III melanoma, “the magnitude of the clinical benefit, the side effects, and the dosing schedule warrant further follow up and additional comparative studies with interferon, which are ongoing,” Dr. Eggermont added.
‘Wait and See’
“This is the first randomized large global study to show ipilimumab has activity in the adjuvant setting. I want to stress activity, meaning there is a delay in the recurrence of melanoma. However, I would argue that that delay is about 10% in 3 years, and it is comparable to a drug that is already on the market, interferon,” commented Steven O’Day, MD, Clinical Professor of Medicine at the University of Southern California, Keck School of Medicine, Los Angeles, and moderator of the ASCO press briefing. The toxicity associated with the ipilimumab regimen in the trial was “slightly higher than when given in the metastatic setting,” Dr. O’Day pointed out, again noting the five treatment-related deaths in the ipilimumab arm.
“It is very important that we wait and see the overall survival data from this study, as well as the direct comparison with interferon in the randomized U.S. intergroup study which has finished accrual recently, before we come to firm conclusions about ipilimumab’s role in the adjuvant setting. Remember, we can salvage these patients in the metastatic setting,” Dr. O’Day said, “and so our tolerance for death or severe toxicity in the adjuvant setting is at a different bar than traditional approaches.”
This research was supported by Bristol-Myers Squibb. Dr. Eggermont reported a consultant or advisory role with Bristol-Myers Squibb. For full disclosures of the study authors, view the study abstract at abstract.asco.org.
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®.
