FDA Approves Ipilimumab for Earlier Stage Melanoma

Ipilimumab (Yervoy, Bristol Myers Squibb) is now approved by the US Food and Drug Administration (FDA) as an adjuvant therapy for stage III melanoma patients.¹ In this setting, the immunotherapy is used following surgery to lower the risk of relapse. Ipilimumab is already FDA-approved for the treatment of metastatic, stage IV melanoma.

The monoclonal antibody, first approved in 2011, blocks the cytotoxic T-lymphocyte antigen 4 (CTLA-4) which can slow down the ability of a patient’s immune system to fight tumor cells. Ipilimumab blocks this antigen, facilitating the immune system’s ability to recognize melanoma cells as foreign and to mount an immune response against these tumor cells.

Ipilimumab was the first immune checkpoint antibody to be approved for 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 in a statement released by the FDA. “This new use of the drug in earlier stages of the disease builds on our understanding of the immune system’s interaction with cancer.”

According to a statement by the Melanoma Research Foundation, the approval is the first by the FDA in 20 years for an adjuvant melanoma therapy. Another available adjvuvant option for stage III patients is interferon. 

The FDA approval is based on the EORTC 18071 phase III randomized, double blind clinical trial of 951 patients with high-risk stage III melanoma. All patients had complete lymph node dissection prior to starting the trial. Patients were randomized one to one to either 10 mg/kg ipilimumab or placebo infusions every 3 weeks for 4 doses, and then every 3 months for up to 3 years or to placebo.

The results were published online May 2015, in The Lancet Oncology.²

The most common reported side effects on trial were rash, diarrhea, fatigue, itching, headache, weight loss, and nausea. The most common high-grade immune-related adverse events in the ipilimumab treatment arm were gastrointestinal (16% of patients compared to <1% in the placebo arm), hepatic (11% compared to <1% in the placebo arm, and endocrine (8% compared to zero in the placebo arm).

Adverse events resulted in 52% (245 patients) of patients discontinuing treatment. Five patients (1%) died due to a drug-related adverse event in the ipilimumab treatment arm. Three patients died from colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure due to Guillain-Barré syndrome.

The median recurrence-free survival was 26.1 months in the ipilimumab study arm compared to 17.1 months in the placebo arm (hazard ratio of 0.75; P = .0013). The 3-year recurrence-free survival was 46.5% in the ipilimumab arm compared to 34.8% in the placebo arm.

“Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma,” concluded the trial study authors. “The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk-benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value.”

References:

• U.S. Department of Health and Human Services. (2015). FDA approves Yervoy to reduce the risk of melanoma returning after surgery. U.S. Food and Drug Administration.
• Eggermont AMM, Chiarion-Sileni V, Grob JJ, et al. (2015). Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial. The Lancet Oncology, May;16(5):522-30. doi: 10.1016/S1470-2045(15)70122-1.