FDA Approves New Adjuvant Option for Patients with Melanoma

October 29, 2015
Jason M. Broderick

The FDA has expanded the approval of Yervoy (ipilimumab) to include adjuvant treatment of fully resected stage III melanoma. The treatment will apply to patients with pathologic involvement of regional lymph nodes >1 mm.

The FDA has expanded the approval of Yervoy (ipilimumab) to include adjuvant treatment of fully resected stage III melanoma. The treatment will apply to patients with pathologic involvement of regional lymph nodes >1 mm.

The approval is based on results from the phase III EORTC 18071 trial, in which adjuvant ipilimumab at a 10 mg/kg dose reduced the risk of recurrence by 25% versus placebo (HR, 0.75; 95% CI, 0.64-0.90; P = .0013). The approval of adjuvant ipilimumab is for the 10 mg/kg dose, which is higher than the 3 mg/kg dose the FDA recommended in ipilimumab's initial approval for advanced melanoma.

“This approval of Yervoy extends its use to patients who are at high risk of developing recurrence of melanoma after surgery,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in FDA’s Center for Drug Evaluation and Research. “This new use of the drug in earlier stages of the disease builds on our understanding of the immune system’s interaction with cancer.”

Bristol-Myers Squibb, the manufacturer of the drug, is offering an assistance program to patients prescribed the 10 mg/kg dose. Through the Adjuvant Patient Program for Melanoma, patients prescribed the 10 mg/kg dose can receive the drug free of charge for the duration of treatment, regardless of their insurance status.

The international, double-blind phase III EORTC 18071 trial included 951 patients with stage III cutaneous melanoma who had adequate resection of lymph nodes. Patients were randomized in a 1:1 ratio to receive ipilimumab at 10 mg/kg (IV) or placebo every 3 weeks for 4 doses, then every 3 months for up to 3 years.

Patients received treatment until completion of therapy, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival (RFS), with overall survival (OS) as a secondary outcome measure.

At a median follow-up of 2.74 years, there were 528 RFS events, comprising 234 and 294 events in the ipilimumab and placebo arms, respectively. The median RFS was 26.1 versus 17.1 months with ipilimumab versus placebo, respectively. The 3-year RFS rate was 46.5% in the ipilimumab arm compared with 34.8% in the placebo group.

Adverse Events With Yervoy

The most common grade 3/4 immune-related adverse events observed in the ipilimumab and placebo groups were gastrointestinal (15.9% vs 0.8%), hepatic (10.6% vs 0.2%), and endocrine (8.5% vs 0%). Most events were managed with established regimens. In total, 52% of patients (n = 245) who started ipilimumab discontinued treatment due to adverse events—38.6% within 12 weeks (n = 182). There were 5 patient deaths linked to drug-related adverse events in the ipilimumab arm.

A boxed warning was included by the FDA with the label for adjuvant ipilimumab, due to the potential for fatal immune-mediated adverse events and "unusual severe side effects," according to the regulatory agency.

“Although some patients might encounter adverse reactions to the treatment, it is important to note that this approval represents another option for people fighting this deadly cancer,” Turnham said.

The FDA first approved ipilimumab as a treatment for patients with unresectable or metastatic melanoma in March 2011. The approval was based on findings from the phase III MDX010-20 trial, which demonstrated a median OS with ipilimumab (3 mg/kg) of 10 months compared with 6.5 months with the experimental vaccine gp100. Results from a pooled analysis of 12 studies presented at the 2013 European Cancer Congress demonstrated that some melanoma patients treated with ipilimumab have survived for at least 10 years.

The initial approval of ipilimumab included a Risk Evaluation and Mitigation Strategy (REMS) to address serious adverse events associated with the drug. The REMS focuses on immune-related adverse events, namely gastrointestinal perforation, hepatic failure, toxic epidermal necrolysis, neuropathies, and endocrinopathies.

Ipilimumab 10 mg Dosing

In an interview with OncLive, Jeffrey Weber, MD, PhD, the incoming deputy director of the NYU Langone Medical Center’s Laura and Isaac Perlmutter Cancer Center, discussed the use of a 10 mg/kg dose of ipilimumab in EORTC 18071.

“When this trial started in 2008, ipilimumab was not an approved drug and there was data suggesting that 10 mg/kg was better than 3 mg/kg. Data suggested that the response rate and the progression-free survival were clearly better in metastatic disease when you use 10 mg over 3 mg. In those days, everyone agreed that 10 mg was a better option than 3 mg, which is why it was used. However, it is more toxic across the board.”

The ongoing phase III ECOG 1609 trial is comparing the two doses of adjuvant ipilimumab (10 mg/kg or 3 mg/kg) with high-dose interferon α-2b. The primary endpoints on the trial are RFS and OS, with secondary endpoints focused on toxicity and quality of life. The trial is ongoing and recruiting participants (NCT01274338), and results are not expected for 2 to 3 years, according to Weber.

Ipilimumab is also approved in combination with the PD-1 inhibitor nivolumab (Opdivo) as a treatment for patients with BRAF V600 wild-type unresectable or metastatic melanoma.

Eggermont AM, Chiarion-Sileni V, Grob JJ et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2015;16(5):522-530.