Ipilimumab is now approved as an adjuvant treatment for patients who have undergone a complete resection of metastatic cutaneous melanoma.
The approval is based on data from a large study showing that ipilimumab, marketed as Yervoy by Bristol-Myers Squibb, improved recurrence-free survival, compared with placebo.
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“Today’s approval of Yervoy extends its use to patients who are at high risk of developing recurrence of melanoma after surgery,” Dr. Richard Pazdur, director of the office of hematology and oncology products in Food and Drug Administration’s Center for Drug Evaluation and Research, said in the FDA statement announcing the approval on Oct. 28. “This new use of the drug in earlier stages of the disease builds on our understanding of the immune system’s interaction with cancer.”
Ipilimumab, a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4), was initially approved in 2011 for the treatment of unresectable or metastatic melanoma.
The new indication is for the adjuvant treatment of patients “with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy.”
In the study of 951 patients, with resected Stage IIIA, IIIB, and IIIC cutaneous melanoma, the median recurrence-free survival was 26 months in the ipilimumab group vs. 17 months in the placebo group; 3-year recurrence-free survival was 46.5% vs. 34.8% (Lancet Oncol. 2015; 16[5]:522-30). The data on overall survival have not yet been analyzed.
The recommended dose and schedule for ipilimumab for adjuvant treatment is 10 mg/kg administered intravenously over 90 minutes every 3 weeks for four doses, followed by 10 mg/kg every 12 weeks for up to 3 years. Doses are omitted, not delayed, if toxicity occurs.
In the study, 52% of those treated with ipilimumab had to discontinue the drug because of adverse reactions. In addition, 41% experienced grade 3-5 immune mediated adverse reactions, including enterocolitis (16%), hepatitis (11%), endocrinopathy (8%), dermatitis (4%), and neuropathy (1.7%).
There were five treatment-related deaths in the study, from immune-mediated adverse reactions, which were enterocolitis (three), Guillain-Barré syndrome (one) and myocarditis (one).The prescribing information includes a boxed warning about the risk of immune-mediated adverse reactions.
In a statement, FDA officials cautioned physicians to carefully monitor patients taking the drug for signs of enterocolitis, dermatitis, neuropathy, and endocrinopathy. Liver function, adrenocorticotropic hormone level, and thyroid function should be measured at baseline and before each dose.
Among the most common reactions were rash, pruritus, diarrhea, nausea, colitis, vomiting, weight loss, fatigue, pyrexia, headache, decreased appetite, and insomnia.
CTLA-4 “may play a role in slowing down or turning off the body’s immune system, and affects its ability to fight off cancerous cells. Yervoy may work by allowing the body’s immune system to recognize, target and attack cells in melanoma tumors,” according to the FDA statement.
Serious adverse events associated with ipilimumab should be reported to the FDA’s MedWatch program or at 800-332-1088.
