Adjuvant Ipilimumab Reduces Risk of Recurrence in Stage III Melanoma

Alexander Eggermont, MD, PhD

The immunotherapy drug ipilimumab (Yervoy) reduced the relative risk of cancer recurrence in the adjuvant setting by 25% compared to placebo for patients with high-risk, lymph-node positive (stage III) melanoma, according to study results presented to the media June 2 during the 2014 ASCO Annual Meeting.

The results, a final analysis of recurrence-free survival (RFS) from the randomized phase III study EORTC 18071,¹ were presented by lead author Alexander Eggermont, MD, PhD, director general of the Gustave Roussy Cancer Campus Grand Paris in France. They showed that ipilimumab could represent a third effective adjuvant treatment for these patients, who currently face a 37% to 89% 5-year relapse rate; two therapies already approved for use in this setting are interferon alfa-2b and peginterferon alfa-2b.

An immune checkpoint inhibitor, ipilimumab is approved by the FDA for the treatment of inoperable stage IV (metastatic) melanoma based on an overall survival (OS) benefit, although it is given in those patients at a lower dose than in the study presented by Eggermont.

High-dose interferon alpha-2b was approved by the FDA in 1995 as a post-surgery treatment for patients with melanoma who are at a high risk of relapse; pegylated interferon alpha-2b was approved in 2011 for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of complete surgical resection, including compete lymphadenectomy.²

RFS was the primary endpoint of the study presented by Eggermont, and secondary endpoints were OS, distant metastasis-free survival, adverse events profile, and quality of life.

“This is a promising treatment—we saw substantially fewer recurrences among patients who are at high risk of relapse,” Eggermont said in an ASCO press release. “We’ve seen many impressive new treatments for advanced melanoma in recent years. This trial with ipilimumab is the first to show we may be able to give these new drugs earlier in the course of disease, where they can do more good and potentially cure more patients.”

Press conference moderator Steven O’Day, MD, clinical associate professor of Medicine at the University of Southern California’s Keck School of Medicine, cautioned that ipilimumab’s hazard ratio and median delay in relapse made it comparable to the approved interferon drugs, with side effects that were slightly more severe than with ipilimumab in stage IV disease. Thus, he said, it will be important to eventually gauge ipilimumab’s success in prolonging OS and its performance in head-to-head studies with interferon; those results are still pending.

Eggermont pointed out, though, that ipilimumab has already demonstrated a benefit that interferon drugs have not.

He said a recent meta-analysis, which he planned to present during the ASCO meeting, showed that “the adjuvant interferon trials have been lacking in any significant activity in palpable nodal disease, whereas, with ipilimumab, this is one of most striking differences—it has the same hazard ratio, almost, for palpable nodal disease as for microscopic nodal involvement alone.” Ipilimumab’s RFS benefit was consistent across stages IIIA, IIIB, and IIIC melanomas and in both ulcerated and non-ulcerated primary melanomas, he said.

Eggermont added that interferon drugs have demonstrated hazard ratios of 0.86 for RFS and 0.91 for OS in adjuvant stage IIB and III melanoma, meaning there is still a need for a more effective strategy.

In the ipilimumab study, 951 patients with surgically treated stage III cutaneous melanoma were randomized 1:1 to receive ipilimumab or placebo. A sizeable proportion of patients had a high likelihood of recurrence because the cancer had spread to the lymph nodes. Ipilimumab (10 mg/kg) was given every 3 weeks for 4 doses, and then the treatment continued at 3-month intervals for up to 3 years. Patients in the control arm were given placebo on the same treatment and maintenance schedules.

At a median follow-up of 2.7 years, ipilimumab had substantially reduced the risk of melanoma recurrence. There were 294 recurrences in the placebo group compared to 234 in the ipilimumab group. The 3-year RFS rates were 34.8% and 46.5% in the placebo and ipilimumab groups, respectively. Overall, ipilimumab reduced the relative risk of recurrence by 25% compared to placebo (hazard ratio 0.75, P = .0013).

“We also looked at absolute differences in the recurrence-free survival rates at 2 years and 3 years; those numbers are much simpler to explain to patients,” Eggermont said. “The difference at 2 years is 8% and at 3 years is 12%, favoring the ipilimumab treatment arm.”

“Grade 3 and 4 events were experienced by 42% of patients,” Eggermont said. “Here you must make the split between grade 3 events, which are immune-related and will discontinue treatment, which totaled 36.5%, and grade 4 immune-related adverse events, the really serious ones, which totaled 5.5%,” he said. More than 90% of these side effects are manageable via treatment, Eggermont said, but added that “adverse events that may linger on for a very long time are the endocrine adverse events,” such as the shutdown of the pituary and adrenal glands, “because patients may require hormone replacement therapy for years.”

Researchers will continue following patients on this study to evaluate OS and distant metastasis-free survival.

A separate, ongoing phase III study (ECOG1609) is comparing two different doses (3 mg/kg and 10 mg/kg) of adjuvant ipilimumab with high-dose interferon.

This research was supported by Bristol-Myers Squibb Company.

References

1. Eggermont AM, Chiarion-Seleni V, Grob JJ, et al. Ipilimumab versus placebo after complete resection of stage III melanoma: initial efficacy and safety results from the EORTC 18071 phase III trial. Presented at: the 2014 Annual Meeting of the American Society of Clinical Oncology; May 30-June 2, 2014; Chicago, IL. Abstract LBA9008.
2. National Cancer Institute. Stage III Melanoma. National Cancer Institute at the National Institutes of Health website. http://tinyurl.com/lnvy3bo. Updated March 19, 2014. Accessed June 2, 2014.

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