The approval is based on results from the phase 3 EORTC 18071 trial, in which adjuvant Yervoy reduced the risk of recurrence by 25 percent versus placebo.
The FDA expanded the approval of Yervoy (ipilimumab) in melanoma to include adjuvant treatment of patients with stage 3 melanoma at high risk of recurrence following complete resection.
The approval is based on results from the phase 3 EORTC 18071 trial, in which adjuvant Yervoy reduced the risk of recurrence by 25 percent versus placebo. In the trial, Yervoy was administered at 10 mg/kg, which is higher than the FDA-recommended dose of 3 mg/kg.
To help provide access to all patients at this dose and in this setting, Bristol-Myers Squibb, the manufacturer of the drug, is offering an assistance program. Through the program, all patients, whether insured or uninsured, will be able to receive Yervoy at 10 mg/kg free of charge for the duration of treatment.
"Treatment for stage 3 patients has historically been challenging, with fewer options available. A stage 3 diagnosis means that melanoma cells have been found in lymph nodes," Tim Turnham, executive director, Melanoma Research Foundation, said in a statement. "It is difficult to predict whether these cells will remain dormant indefinitely or if they will spread and form new tumors."
"Today's approval marks the first new FDA approved adjuvant option in 20 years."
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." A guide will also be provided to patients, according to the FDA, to inform them about the drug's potential side effects.
The international, double-blind phase 3 EORTC 18071 trial included 951 patients with stage 3 cutaneous melanoma who had adequate resection of lymph nodes. Patients were randomized in a one-to-one ratio to receive Yervoy at 10 mg/kg (intravenous) or placebo every three weeks for four doses, then every three months for up to three years.
Patients received treatment until completion of therapy, disease recurrence, or unacceptable toxicity. The primary endpoint was recurrence-free survival, with overall survival as a secondary outcome measure.
At a median follow-up of 2.74 years, there were 528 recurrence-free survival events, comprising 234 and 294 events in the Yervoy and placebo arms, respectively. The median recurrence-free survival was 26.1 versus 17.1 months with Yervoy versus placebo, respectively. The three-year recurrence-free survival rate was 46.5 percent in the Yervoy arm compared with 34.8 percent in the placebo group.
The most common grade 3/4 immune-related adverse events observed in the Yervoy and placebo groups were gastrointestinal (15.9 percent vs 0.8 percent), hepatic (10.6 percent vs 0.2 percent) and endocrine (8.5 percent vs 0 percent). Most events were managed with established regimens. In total, 52 percent of patients (245 patients) who started Yervoy discontinued treatment due to adverse events — 38.6 percent within 12 weeks (182 patients). There were five patient deaths linked to drug-related adverse events in the Yervoy arm.
The FDA first approved Yervoy as a treatment for patients with unresectable or metastatic melanoma in March 2011. The approval was based on findings from the phase 3 MDX010-20 trial, which demonstrated a median overall survival with Yervoy 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 Yervoy have survived for at least 10 years.
The initial approval of Yervoy 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.
In an interview with CURE, Jeffrey Weber, 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 Yervoy in EORTC 18071.
“When this trial started in 2008, Yervoy 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 3 ECOG 1609 trial is comparing the two doses of adjuvant Yervoy (10 mg/kg or 3 mg/kg) with high-dose interferon α-2b. The primary endpoints on the trial are recurrence-free survival and OS, with secondary endpoints focused on toxicity and quality of life. The trial is ongoing and recruiting participants,and results are not expected for two to three years, according to Weber.
Yervoy is also approved in combination with the PD-1 inhibitor Opdivo (nivolumab) 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.