FDA Accepts sBLA for Adjuvant Ipilimumab in Melanoma

Source: OncLive, March 2015

The FDA has accepted a supplemental Biologics License Application (sBLA) for ipilimumab (Yervoy) as an adjuvant treatment of patients with stage III melanoma at high risk of recurrence following complete resection, according to Bristol-Myers Squibb, the company developing the drug. The FDA is scheduled to make a decision on adjuvant ipilimumab by October 28, 2015.

The acceptance of the sBLA is based on results from the phase III EORTC 18071 trial, which was presented at the 2014 ASCO Annual Meeting. This study showed a 25% improvement in recurrence-free survival (RFS) in patients treated with ipilimumab versus placebo (HR = 0.75; 95% CI, 0.64–0.90).

“This is a promising treatment—we saw substantially fewer recurrences among patients who are at high risk of relapse,” Alexander Eggermont, MD, PhD, director general of the Gustave Roussy Cancer Campus Grand Paris in France, said in an 2014 ASCO Annual Meeting press release. “We’ve seen many impressive new treatments for advanced melanoma in recent years. 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.”

The FDA 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 of 10 months compared with 6.5 months with the experimental vaccine gp100. The FDA recommended dose for ipilimumab in the advanced setting is 3 mg/kg.

“Four years ago, Yervoy was approved for the treatment of unresectable or metastatic melanoma, the most advanced form of the disease,” Michael Giordano, MD, senior vice president, Head of Development, Oncology, Bristol-Myers Squibb, said in a statement. “Today’s announcement is a reflection of our commitment to investigate our immuno-oncology treatments for patients across lines of therapy and stages of the disease.”

In the EORTC 18071 trial, 951 adult patients were stratified by stage and region and randomized to receive ipilimumab at 10 mg/kg or placebo every 3 weeks for 4 doses then every 3 months for up to 3 years. Patients were treated until completion of therapy, disease recurrence, or unacceptable toxicity.

At a median follow-up of 2.7 years, ipilimumab had significantly improved RFS across all subgroups. The RFS rate was 46.5% and median RFS was 26.1 months among patients receiving ipilimumab and 34.8% and 17.1 months in the placebo arm (P = .0013).

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); 1.1% died (n = 5).

In the advanced melanoma setting, ipilimumab was approved with 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.

“The data that’s been presented on the adjuvant trial with Ipilimumab showed less than 50% of patients made it to the first maintenance dose,” Omid Hamid, MD, from The Angeles Clinic and Research Institute, said in an OncLive Peer Exchange discussion. “There is toxicity and the majority of patients don’t make it to the first maintenance dose. My opinion is that we will settle somewhere between 4 doses or a year of therapy.”

Another phase III trial, ECOG 1609, is examining two doses (10 mg/kg or 3 mg/kg) of adjuvant ipilimumab with high-dose interferon ?-2b. The primary endpoints on the trial are RFS and overall survival, with secondary endpoints focused on toxicity and quality of life. The trial is ongoing and recruiting participants (NCT01274338).