Formulary Drug Review: Ipilimumab (Yervoy)

Ipilimumab (Yervoy), manufactured by Bristol-Myers Squibb, is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody FDA approved for the treatment of unresectable or metastatic melanoma. CTLA-4 is a downregulator of T-cell activation pathways, which allows for enhanced T-cell activation and proliferation. Melanoma is an immunogenic cancer; ipilimumab works by indirectly mediating T-cell immune responses against tumors.^1,2

Melanoma is the leading cause of death from skin disease. According to the National Cancer Institute, an estimated 76,250 new cases of melanoma will be diagnosed in the United States this year, and an estimated 9180 people will die from the disease in 2012.³ Ipilimumab is the first agent ever proven to improve survival in advanced melanoma. Prior to approval of ipilimumab, no therapy was approved beyond the first-line therapy for metastatic melanoma, and enrollment in a clinical trial was the standard of care.

Pharmacokinetics

The mean volume of distribution of ipilimumab at steady state is 7.21 L. The half-life is 14.7 days and the rate of clearance is 15.3 mL/hr. Although not studied extensively, increased body weight, preexisting mild-to-moderate renal insufficiency (creatinine clearance >29 mL/min), or various degrees of hepatic dysfunction at baseline have not shown a clinically meaningful effect on ipilimumab’s pharmacokinetics; therefore, no dosage adjustment is currently recommended for these conditions.^1,4,5

Dosing

The current approved dosing schedule for ipilimumab is 3 mg/kg every 3 weeks for a total of 4 doses or up to 16 weeks from the first dose, whichever comes first. Each dose is administered intravenously over 90 minutes and does not require prophylactic antiemetics or premedications for infusion-related reactions. If the entire treatment cannot be completed within 16 weeks, ipilimumab should be permanently discontinued.^1,4

Dosing of ipilimumab should be withheld for patients with any moderate immune-related adverse reactions or for those with symptomatic endocrinopathy. Patients can restart ipilimumab if their immune-related adverse reactions have resolved to a Grade 0-1 and are receiving less than 7.5 mg of prednisone or equivalent daily. Ipilimumab should be resumed in these patients at the dose of 3 mg/kg every 3 weeks until all 4 planned doses have been given or 16 weeks from the first dose, whichever occurs first.^1-4

Clinical Efficacy

The efficacy and safety of ipilimumab have been confirmed in patients with advanced melanoma in 2 large randomized phase III trials. The first study by Hodi et al included 676 patients with unresectable stage III or IV melanoma whose disease had progressed after previous treatment. Patients were randomized in a 3:1:1 ratio to receive ipilimumab with the melanoma peptide vaccine gp100 (n = 403), ipilimumab with gp100 placebo (n = 137), or gp100 vaccine with ipilimumab placebo (n = 136). Ipilimumab was dosed at 3 mg/kg IV every 3 weeks for a total of 4 treatments with the vaccine administered immediately after each ipilimumab infusion.

The median overall survival at 20 months was 10, 10.1, or 6.4 months for patients treated with the combination, ipilimumab alone, or gp100 alone, respectively. Overall survival favoring both ipilimumab-containing regimens was statistically significant. The ipilimumab side effect profile was consistent with phase I/II experience, with grade III or IV immune-related adverse events observed in 10% to 15% of patients. The authors of this study concluded that ipilimumab may be useful as a treatment for patients with metastatic melanoma whose disease progressed after receiving 1 or more previous therapies.⁶

In a second phase III study by Robert et al, 502 treatment-naïve patients with unresectable stage III or IV melanoma were randomly assigned to receive either dacarbazine with ipilimumab (n = 250) or dacarbazine with placebo (n = 252). Ipilimumab was administered at 10 mg/kg for 4 doses followed by a maintenance phase. The addition of ipilimumab to dacarbazine significantly improved the primary outcome of overall survival compared with dacarbazine alone (11.2 vs 9.1 months; p <0.05). Similar to the previous study, most of the toxicities associated with the combination were immune-related adverse events; however, an increase in liver-function tests was observed more frequently than expected with the combination therapy. The authors concluded that there was a significant improvement in overall survival among patients with previously untreated metastatic melanoma who received ipilimumab plus dacarbazine compared with dacarbazine plus placebo.⁷

Medication Safety

Severe-to-fatal immune-related reactions were seen in 10% to 15% of patients treated with ipilimumab during clinical trials. Ipilimumab should be permanently discontinued for any of the following severe or lifethreatening adverse reactions: colitis; aspartate aminotransferase or alanine aminotransferase >5 times the upper limit of normal, or total bilirubin >3 times the upper limit of normal; Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis; severe immune-mediated reactions involving any organ system; and immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy.^1-4

Due to these unusual and severe adverse effects associated with ipilimumab, a risk evaluation and mitigation strategy (REMS) was developed in collaboration with the FDA, which is required to ensure that the benefits of ipilimumab outweigh the risks of severe and fatal immune-mediated adverse reactions.⁸ The ipilimumab REMS consists of a communication plan to inform health care professionals of the serious risks of ipilimumab and to facilitate early identification of these risks, and an overview of recommended management of patients with moderate or more severe immune-mediated adverse reactions.⁸

Product Availability and Cost

Ipilimumab is available as a 50-mg/10-mL vial, as well as a 200-mg/40-mL vial. It should be diluted with 0.9% sodium chloride or 5% dextrose to prepare a diluted solution with a final concentration ranging from 1 mg/mL to 2 mg/mL. The diluted solution should be stored for no more than 24 hours under refrigeration or at room temperature. Ipilimumab should not be mixed or administered with other medications and the IV line should be flushed with 0.9% sodium chloride or 5% dextrose after each infusion. The average wholesale price of ipilimumab (Yervoy) is $7308 per 50-mg vial and $29,232 per 200-mg vial. Health care professionals can access more information about ipilimumab (Yervoy), including complete prescribing information, at www.yervoy.com.

Ashley N. Lewis, PharmD, BCPS, is a drug information specialist at University of North Carolina Hospitals (UNCH). She completed her pharmacy training at Virginia Commonwealth University and went on to complete a general pharmacy practice residency followed by a drug information specialty at the Medical University of South Carolina. She is currently the pharmacy and therapeutics secretary at UNCH, manages the day-to-day operations of the Drug Information Center, and serves as a clinical assistant professor at the UNC Eshelman School of Pharmacy

References

1. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb; March 2011.

2. Patel S, Woodman S. Profile of ipilimumab and its role in the treatment of metastatic melanoma. Drug Des Devel Ther. 2011;5:489-495.

3. Melanoma. National Cancer Institute at the National Institutes of Health. www.cancer.gov/cancertopics/types/melanoma.

4. Ipilimumab. In: DRUGDEX System. Greenwood Village, CO: Thomson Reuters (Healthcare) Inc.

5. Trinh V, Hagen B. Ipilimumab for advanced melanoma: a pharmacologic perspective [published online]. J Oncol Pharm Pract. 2012:1-7.

6. Hodi F, O’Day S, McDermott D, et al. Improved survival with ipilimumab in patients with metastatic melanoma. NEJM. 2010;363:711-723.

7. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. NEJM. 2011;364:2517-2526.

8. Yervoy (ipilimumab): Risk Evaluation and Mitigation Strategy (REMS) - Severe Immune-Mediated Adverse Reactions: FDA Safety Information. FDA website. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm249770.htm. Updated April 6, 2011.