FDA Approves Adjuvant Ipilimumab in Melanoma

Richard Pazdur, MD

The FDA expanded the approval of ipilimumab (Yervoy) in melanoma to include adjuvant treatment of patients with stage III melanoma with pathologic involvement of regional lymph nodes >1 mm who have undergone complete resection including total lymphadenectomy.

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 <.002). The drug was approved at this 10 mg/kg dose, which is higher than the 3 mg/kg dose the FDA recommended in ipilimumab's initial approval for advanced melanoma.

“Today’s 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.”

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 in the ipilimumab arm received a median of 4 doses (range, 1-16), with 36% remaining on the drug for >6 months.

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.

The most frequently reported adverse events in the ipilimumab arm included rash, pruritus, diarrhea, nausea, colitis, vomiting, weight loss, fatigue, pyrexia, headache, decreased appetite, and insomnia, according to the FDA.

Grade 3 to 5 adverse events occurred in 41% of patients receiving ipilimumab. The most common grade 3/4 immune-related adverse events observed in the ipilimumab and placebo groups, respectively, 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.

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.

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.

"Today’s [adjuvant] approval is an important step in our commitment to bring our immuno-oncology pipeline to earlier lines of cancer treatment and to make new options available quickly while we continue to build upon our scientific understanding and develop even better solutions,” Michael Giordano, MD, senior vice president, head of Development, Oncology, at Bristol-Myers Squibb, the developer of ipilimumab, said in a statement. “Bristol-Myers Squibb has broad development programs in the adjuvant setting across multiple tumors, including the ongoing studies of Opdivo and of Yervoy in adjuvant 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.