Ipilimumab, interferon debated as standard adjuvant therapy for high-risk disease

Issue: April 25, 2016

NEW YORK — Two speakers at HemOnc Today Melanoma and Cutaneous Malignancies debated whether ipilimumab has replaced interferon as the standard of care for patients with high-risk melanoma.

Approved drugs in the United States for the adjuvant treatment of stage III melanoma include high-dose interferon and pegylated interferon.

“However, there is clearly an unmet need,” Antonio C. Buzaid, MD, chairman of the oncology center at Hospital São José da Beneficencia Portuguesa in São Paulo, Brazil, said during his presentation. “We know that interferon doesn’t do a great job, with only a 10% reduction in the risk for death. It has a very low impact, and we need to improve upon this.”

Axel Hauschild, MD

Ipilimumab

Researchers conducted the EORTC 18071 trial to compare ipilimumab (Yervoy, Bristol-Myers Squibb) with placebo in patients with stage III disease, and results of the trial were the first to show an OS benefit for advanced melanoma with adjuvant therapy.

Patients who received ipilimumab experienced significantly prolonged RFS, the study’s primary endpoint (median, 26.1 months vs. 17.1 months; HR = 0.75; 95% CI, 0.64-0.9).

Results of prespecified subgroup analyses showed a significant RFS benefit with ipilimumab in patients with microscopic disease (HR = 0.68; 95% CI, 0.47-0.99) and ulceration (HR = 0.67; 95% CI, 0.48-0.93).

Although more patients in the placebo arm discontinued therapy due to disease progression (57.6% vs. 28%), more patients in the ipilimumab arm discontinued due to adverse events (48.8% vs. 1.7%). Further, five patients died due to ipilimumab-related adverse events.

When looking at these data, it is important to remember this trial began in 2008, and ipilimumab was not approved until 2011, Buzaid said.

“This probably would not happen with ipilimumab in any center today, because we are much more aware of how to manage the side effects,” he said.

“Considering the toxicity, which today would have been much more easily managed, I would discuss adjuvant ipilimumab particularly in patients with microscopic nodal disease and ulcerated primary,” Buzaid added.

Interferon

Interferon demonstrated activity in three trials — ECOG 1684, ECOG 1690 and ECOG 1694 — with significant DFS improvements and a trend toward OS improvement, Axel Hauschild, MD, professor of dermatology at University Hospital in Kiel, Germany, said during his presentation.

Further, RFS benefits appear similar, ranging from HRs of 0.8 to 0.82, for low-dose, intermediate-dose, high-dose and pegylated interferon, Hauschild said.

“Ipilimumab was the door-opener of checkpoint inhibition, and it was the first drug to improve overall survival at all in advanced melanoma,” Hauschild said. “However, it is used in a curious scheme that is not scientifically based.”

The approved dose of ipilimumab is 3 mg for 3 months. However, the EORTC 18071 trial evaluated 10-mg/kg ipilimumab for 3 years.

“I believe this is a maximum tolerated-dose approach in a maximum duration of time,” Hauschild said. “It reminds me of the pegylated story, where the maximum tolerated dose of pegylated interferon was used in the trial that bought it to market in the United States.”

Further, the toxicity with ipilimumab should be given consideration, especially since 18.3% of patients experienced hypophysitis on EORTC 18071, Hauschild said.

“This is the only adverse event where you can suffer for the rest of your life,” he said. “These are patients who were potentially cured when they entered the clinical trial — half of the patients in the observation arm survived without any treatment.”

Researchers await results of the phase 3 intergroup E1609 trial, which is evaluating high-dose interferon vs. 3-mg/kg ipilimumab vs. 10-mg/kg ipilimumab.

“This trial will tell us the truth of the benefits of ipilimumab over existing standards of care, like high-dose interferon,” Hauschild said. “If prior HRs are replicated, we will need to treat over 3,000 patients to demonstrate statistically significant differences to prove superiority of ipilimumab. So, it will be negative trial in that sense.”

However, the trial could show 3-mg/kg ipilimumab is as good as the 10-mg/kg dose, Hauschild said.

“Then we have a different story completely, with less toxicity and less cost,” he said. – by Alexandra Todak

Reference:

Buzaid AC and Hauschild A. Adjuvant therapy for high-risk melanoma: What’s a clinician to do in 2016? Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 18-19, 2016; New York.

Disclosure: Buzaid reports consultant fees from Astellas, AstraZeneca, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Roche and Sanofi. Hauschild reports consultant roles with and speaker fees from Almirall Hermal, Bristol-Myers Squibb, Celgene, Delcath, Eisai, Galderma, GlaxoSmithKline, MedImmune, MelaSciences, Merck, Novartis, Oncosec, Roche and SciBase.