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Melanoma: First Use of Adjuvant Ipilimumab Extends Recurrence-Free Survival in High-Risk Stage III Patients, but Big Questions about Toxicity

Fuerst, Mark

doi: 10.1097/01.COT.0000452085.09862.8e


CHICAGO—Adjuvant therapy with ipilimumab for patients with high-risk, lymph-node positive stage III melanoma decreases the relative risk of cancer recurrence by roughly 25 percent compared with placebo, according to the final analysis of a randomized Phase III study reported here at the ASCO Annual Meeting (Abstract LBA9008). However, the side effects of the drug, which was used at a dose higher than that approved for metastatic melanoma, are considerable.

“This is the first adjuvant trial with a drug, ipilimumab, that has demonstrated an overall survival benefit in advanced melanoma,” said the study's lead author, Alexander Eggermont, MD, PhD, Director General of the Gustave Roussy Cancer Campus Grand Paris in France.

“This is a promising treatment. We saw substantially fewer recurrences among patients who are at high risk of relapse. We have seen many impressive new treatments for advanced melanoma in recent years, but 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.”

Asked for his perspective for this article, Jedd Wolchok, MD, PhD, Chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan-Kettering Cancer Center, said: “Ipilimumab has activity in the post-surgical setting. This is a different, higher dose and schedule than has previously been used in the metastatic melanoma setting. We don't know the value of the 3 mg/kg versus 10 mg/kg dose. In this heterogeneous population, some patients are cured by surgery alone. This study is a strong call for more precise risk stratification in this population. If we offer regimens with significant toxicity, we need to put them in the proper risk/benefit context.”



In an ASCO news conference highlighting abstracts illustrating progress in immunotherapy, Eggermont said that ipilimumab could be a third effective adjuvant treatment for these patients, who currently have five-year relapse rates that range between 37 and 89 percent. Two other therapies already approved in this setting include interferon alfa-2a and pegylated interferon (peginterferon) alfa-2b. “But there is still an unmet need, because interferon has modest impact, and leads to only an eight to 14 percent relative risk reduction,” he said.

Ipilimumab is currently approved for the treatment of patients with inoperable stage IV melanoma, at a dose of 3 mg/kg for four doses. The drug increased overall survival in two randomized, controlled Phase III trials in advanced melanoma, with long-term survival in a some of the patients. “The demonstrated efficacy of ipilimumab in advanced disease supported its evaluation in earlier stages of melanoma when tumor burden is low,” Eggermont explained.

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Study Details

The study—EORTC 18071—included 951 patients with a median age of 51, with surgically treated stage III cutaneous melanoma who were randomly assigned 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 at 10 mg/kg was given every three weeks for four doses, and the treatment continued at three-month intervals for up to three years. Patient characteristics were well-balanced between the two arms.



Eggermont reported that at a median follow-up of 2.7 years, ipilimumab substantially reduced the risk of melanoma recurrence, with 294 recurrences in the placebo group compared with 234 in the patients receiving ipilimumab. The three-year recurrence-free survival (RFS) rates were 46.5 percent in the ipilimumab patients and 34.8 percent in the placebo patients. At three years, the RFS rates were 26.1 percent in the ipilimumab group and 17.1 percent in the placebo group.

“We also looked at absolute differences in RFS at two and three years,” he said. “Those numbers are much simpler to explain to patient: The difference at two years is eight percent and at three years is 12 percent, favoring the ipilimumab treatment arm.” Disease progression was about half as much with ipilimumab (28%) as placebo (58%).

Overall, ipilimumab reduced the relative risk of recurrence by 25 percent compared with placebo. Higher-risk patients with stages IIIB and IIIC disease showed the most prominent improvement, he said. The RFS benefit of ipilimumab was consistent in both ulcerated and non-ulcerated primary melanomas. Subgroup analysis showed a 33 percent risk reduction among patients with microscopic disease in lymph nodes and a 17 percent reduction among patients with macroscopic disease.



Both high-dose interferon alpha2b and peginterferon-alpha2b are approved by the FDA as a post-surgery treatment for patients with stage III melanoma who are at a high risk of relapse. The EORTC 18991 trial that resulted in the approval of peginterferon-alpha2b did not show an appreciable effect in patients with macroscopic metastases in lymph nodes.

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Side Effects Problematic

Eggermont noted that side effects remain considerable, however, and are consistent with those observed in treatment of stage IV melanoma—colitis, thyroid and pituitary gland abnormalities, and skin rash. Nearly half of the patients (48%) had adverse events related to ipilimumab. Patients receiving seven or more doses discontinued treatment more from the adverse events than from disease progression, he said.

More than 90 percent of patients on ipilimumab had immune-related adverse events, more than one-third of which were grade 3. Gastrointestinal events occurred in 15 percent of patients, and eight percent had endocrine events. “Most events occurred during the first four or five doses, and then reached a plateau. After that, there were little additional events,” Eggermont said.

Virtually all of the skin and GI immune-related adverse events were resolved. Endocrine-related adverse events may linger, though, he explained, such as the shutdown of the pituitary and adrenal glands, because patients may require hormone-replacement therapy for years.

“Still, the toxicity was nothing that we did not know about before,” he said. “The endocrine toxicity was more common than expected. It may be these are healthier patients with more robust immune systems. They may have a narrower window of pharmacokinetics before we see toxicities.”

There have been five treatment-related deaths in the ipilimumab group—three patients with colitis, one with myocarditis, and one with Guillain-Barre syndrome.

In conclusion, Eggermont said: “The study met its primary endpoint of a significant improvement in RFS with 10 mg/kg ipilimumab versus placebo. Results from pre-specified subgroup and sensitivity analyses show a consistent pattern with hazard ratios favoring ipilimumab relative to placebo.”

He said he and his co-researchers will continue to follow these patients to evaluate overall survival and distant metastasis-free survival.

He added that an ongoing second Phase III study (E1609) is evaluating adjuvant ipilimumab at 3 or 10 mg/kg versus high-dose interferon. That trial has dual primary endpoints of overall survival and recurrence-free survival, and completion of accrual of about 1,500 patients is anticipated by the end of this summer.

The moderator of the news briefing, Steven O'Day, MD, Clinical Associate Professor of Medicine at the University of Southern California Keck School of Medicine, called the study important and said the results are promising.

“This is the first randomized global study to show activity in the adjuvant setting. Ipilimumab is an effective treatment in stage IV melanoma, and this is the first study to demonstrate its clinical benefit 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.”

He added: “For this class of drug, it is important to wait for overall survival data and the direct comparison with interferon before we conclude that ipilimumab has a role in the salvage setting.” He noted that the drug produced long-term survival, and a cure for this disease is difficult in the adjuvant setting.

In answer to a question at the news briefing, Eggermont said: “Survival is what we are all looking for. We are still hopeful for an overall survival benefit. We saw an impact of RFS despite so many patients coming off treatment after four or five doses. The longer patients stayed on, the better they got.”

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Cautions from Discussant

The Discussant for the study, Jeffrey Gershenwald, MD, Professor in the Departments of Surgical Oncology and Cancer Biology and Medical Director of Melanoma and Skin Center at the University of Texas MD Anderson Cancer Center, said the 2.7 years follow-up is still early, and he also emphasized the “significant fraction” of patients who had to discontinue therapy after a median of four doses due to toxicity.



He questioned whether the significant toxicity was acceptable in the adjuvant arena when not all patients will necessarily have disease recurrence. “We can also treat at relapse,” he said. “This adds to our decision-making process. Who is actually benefiting? The amount of disease burden may play a role.”

He also wondered whether the researchers adequately explored the concept of maintenance immunotherapy in the trial, pointing out that the median number of doses was four, and that only 29 percent of patients received treatment for one year.

Other factors to consider, Gershenwald said, are the cost of therapy, which is “a significant unknown,” and “will the tail of the survival curve be sustained with longer follow-up.”

In addition, 80 percent of melanoma patients have only microscopic evidence of disease. There is limited disease burden at stage III disease. Is there a minimum threshold of occult non-regional lymph node metastatic disease sufficient to induce a therapeutic immune response? Not all patients considered for adjuvant therapy are similar risk, even in the sentinel node era.”

At MD Anderson, he said, the median tumor burden is less than 1 mm, meaning that half of those patients would not be represented in the cohort of this study.

© 2014 by Lippincott Williams & Wilkins, Inc.
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