Nick Mulcahy

June 04, 2014

CHICAGO — For the first time, ipilimumab (Yervoy, Bristol-Myers Squibb) has been shown to be effective in an adjuvant setting for earlier-stage melanoma.

The drug is already approved for use in stage IV disease.

In a new study, known as EORTC 18071, more than 900 patients with stage III disease received ipilimumab (10 mg/kg) at a dose higher than the dose approved (3 mg/kg) for stage IV disease.

Results presented here at the 2014 Annual Meeting of the American Society of Clinical Oncology® show that ipilimumab significantly delayed recurrence, compared with placebo, in these stage III patients.

But experts say that these results are not strong enough to catapult the immunotherapy into the role of an important treatment option in this setting. And they cite the drug's toxicity as an ongoing concern, given the marginal benefit shown so far.

At 2 years, relapse-free survival, the study's primary end point, was 8% better with ipilimumab than with placebo (51.5% vs 43.8%). Overall, the drug decreased the relative risk for melanoma relapse by 25%, compared with placebo (hazard ratio, 0.75; P = .001)

Dr. Alexander Eggermont

Median relapse-free survival was also better with ipilimumab than with placebo (26.1 vs 17.1 months), reported lead investigator Alexander Eggermont, MD, PhD, from the Gustave Roussy Cancer Campus Grand Paris in France.

"The data are not robust enough to change practice," said Ryan Sullivan, MD, from the Massachusetts General Hospital Cancer Center in Boston, who was not involved in the study.

There is a "temptation" to use ipilimumab off-label, he acknowledged in an interview with Medscape Medical News. "I don't think that is appropriate, given these data."

What needs to be demonstrated before ipilimumab impresses in this setting?

Dr. Sullivan said that an overall survival benefit needs to be established, especially in patients with disease in the higher-risk stage III categories (IIIB and IIIC).

The data are not robust enough to change practice.

The very toxic effects of the drug were confirmed in this study. There were 5 treatment-related deaths (1.1%) in the trial; this rate is comparable to what has been seen in metastatic trials.

The other approved treatment for stage III melanoma is less toxic, Dr. Sullivan explained. "Interferon is a toxic drug, but it doesn't kill you."

Patrick O'Day, MD, who served as moderator of the press briefing during which this study was highlighted, is also concerned about the deaths and toxicity.

Furthermore, the rate of relapse-free survival seen with ipilimumab is "comparable" to that of interferon, which is already available to clinicians, said Dr. O'Day, who is from the University of Southern California Keck School of Medicine in Los Angeles.

But Dr. O'Day, who is also an ipilimumab investigator, believes it is "very important" to wait for the overall survival data to be released.

He explained that in the metastatic setting, the drug had an "underwhelming" effect on progression-free survival but "more accentuated effects" on overall survival.

These comments refer to the facts that ipilimumab, in metastatic disease, has had a low response rate (11% in its pivotal trial based on RECIST criteria), but that some responders receive great benefit and can be alive up to 7 to 10 years after treatment.

In short, ipilimumab does not work in many patients but, for the lucky ones, the benefit can be long-lasting.

Time and further clinical trial data will eventually reveal the value of ipilimumab in the stage III setting, said Dr. O'Day.

In this study, median follow-up was 2.7 years. "It's still early," said Jeffrey Gershenwald, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, about the follow-up and the potential to see an overall survival benefit. He acted as discussant of the study at the oral presentation.

Other forthcoming data will include results from a second phase 3 trial in the adjuvant setting, which compares ipilimumab (3 mg and 10 mg) with high-dose interferon.

Dr. Eggermont explained that his team used placebo — not interferon — because the latter is not used in Europe, and they were conducting an international trial.

Effective in Ulcerated Disease and Macroscopic Lymph Nodes

In the study, 951 patients with surgically treated stage III cutaneous melanoma were randomly assigned to receive ipilimumab 10 mg/kg or placebo.

Ipilimumab was given every 3 weeks for 4 doses, and the treatment was continued at 3-month intervals for up to 3 years.

The treatment period is very long, in contrast to the regimen currently approved, which is only 3 months long, Dr. Sullivan pointed out.

In the cohort, 20% had stage IIIA disease, 44% had stage IIIB disease, and 36% had stage IIIC disease. Other studies have established that 5-year relapse rates are 37% for stage IIIA disease, 68% for stage IIIB disease, and 89% for stage IIIC disease.

Recurrences occurred in 234 of the 475 patients (49.3%) in the ipilimumab group and in 294 of the 476 patients (61.8%) in the placebo group.

Some patients also had a strong likelihood of recurrence because the cancer had either spread to the lymph nodes and was palpable (58%) or the primary tumor was ulcerated (42%), Dr. Eggermont reported.

Nevertheless, the impact of ipilimumab on relapse-free survival was seen in patients with microscopic metastases (positive sentinel nodes on biopsy), macroscopic metastases (palpable lymph nodes), ulcerated primaries, and nonulcerated primaries.

Adverse effects were consistent with those observed in the treatment of metastatic melanoma.

Overall, 42% of ipilimumab-treated patients had grade 3/4 adverse events. The great majority of these serious events resolved with management.

However, grade 3/4 endocrine-related adverse effects are more difficult and resolve less easily, explained Dr. Eggermont. Some endocrine-related events, which include hypophysitis and hypothyroidism, "may require hormone-replacement therapy for years," he said.

The study was funded by Bristol-Myers Squibb. Dr. Eggermont reports being a consultant for or advisor to Bristol-Myers Squibb. Some of his coauthors are employees of and own stock in the company. Dr. O'Day has been an investigator of ipilimumab. Dr. Sullivan has disclosed no relevant financial relationships.

2014 Annual Meeting of the American Society of Clinical Oncology (ASCO): Abstract LBA9008. Presented June 2, 2014.


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