FDA Approval for Ipilimumab
Brand name(s): Yervoy™
Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions.
On March 25, 2011, the U. S. Food and Drug Administration (FDA) approved ipilimumab injection (Yervoy, made by Bristol-Myers Squibb Company) for the treatment of unresectable or metastatic melanoma.
The approval was based on a randomized (3:1:1) double-blind double-dummy clinical trial (MDX010-20) in patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment for melanoma. Overall survival (OS) was the trial’s primary endpoint. Progression-free survival and best overall response rate were also assessed.
The clinical trial enrolled 676 patients with HLA-A2*0201 positive genotype. This HLA-A2*0201 genotype facilitated the immune presentation of the investigational tumor vaccine. Patients were randomly assigned to receive either ipilimumab, 3 mg/kg intravenously, in combination with the tumor vaccine (n=403); ipilimumab plus vaccine placebo (n=137); or tumor vaccine with placebo (n=136). The trial excluded patients with active autoimmune disease or those receiving systemic immunosuppression for organ transplantation.
The median age of patients was 57 years. Twenty-nine percent of patients were 65 years or older. More than half the patients were male, 71 percent had M1c stage, 12 percent had histories of previously treated brain metastases, 98 percent had ECOG performance status of either 0 or 1, and 23 percent had received prior aldesleukin (IL-2).
Overall survival was longer with ipilimumab alone compared with tumor vaccine [HR 0.66 (95 percent CI: 0.51, 0.87), p=0.0026]. Patients treated with ipilimumab alone had a median OS of 10 months. Patients treated with tumor vaccine had a median overall survival of 6 months. The trial also demonstrated a statistically significant improvement in OS for patients treated with the combination of ipilimumab plus tumor vaccine compared with patients treated with tumor vaccine alone [HR 0.68 (95 percent CI: 0.55, 0.85), p= 0.0004, log-rank test)]. Patients who received ipilimumab plus tumor vaccine had a median OS of 10 months. Patients treated with tumor vaccine alone had a median OS of 6 months. Patients treated with ipilimumab alone also had the best overall response rate (investigator assessed), of 10.9 percent (95 percent CI: 6.3 percent, 17.4 percent). Patients treated with the combination of ipilimumab plus vaccine arm had an overall response rate of 5.7 percent (95 percent CI: 3.7 percent, 8.4 percent). The patients treated with vaccine alone had an overall response rate of 1.5 percent (95 percent CI: 0.2 percent, 5.2 percent).
Safety data was evaluated in 511 patients who received ipilimumab alone or in combination with the tumor vaccine. The most common (at least 5 percent) adverse reactions (AEs) were manifestations of ipilimumab’s immunological mechanism of action leading to T-cell activation and proliferation. Such immune-mediated adverse reactions included diarrhea, pruritus, rash, and colitis. The most serious AEs were also immune-mediated adverse reactions. Ipilimumab was discontinued for adverse reactions in 10 percent of patients. Thirteen percent of ipilimumab-treated patients experienced a high grade immune-mediated AE. The most common of these involved the colon, liver, skin, endocrine system, and nervous system. Management of immune-mediated AEs may include discontinuation of ipilimumab and initiation of high dose corticosteroids.
The recommended dose and schedule for ipilimumab is 3 mg/kg as an intravenous infusion every 3 weeks for a total of four doses.
This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.
The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.