Ipilimumab: Unleashing the power of T-cells in advanced melanoma

Ipilimumab (Yervoy, Bristol-Myers Squibb) is a recombinant, human monoclonal antibody which binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). CTLA-4 functions as a negative regulator of T-cell activation, and, when bound to a specific receptor on antigen-presenting cells, sends inhibitory signals that downregulate T-cell activation. Ipilimumab is an IgG1 kappa immunoglobulin which blocks the inhibitory signal of CTLA-4, allowing T-cell activation and proliferation to persist.

Clinical Activity

Ipilimumab was approved by the US Food and Drug Administration (FDA) in March 2011, based on the results of a phase 3 study by Hodi and colleagues in 676 patients with unresectable Stage III or IV melanoma, who were previously treated with one or more regimens. Patients were randomized to receive ipilimumab 3 mg/kg plus a gp100 peptide vaccine; ipilimumab plus a gp100 placebo; or gp100 plus ipilimumab placebo once every 3 weeks for four treatments. The primary endpoint of median OS was 10 months in the ipilimumab plus gp100 group as compared to 6.4 months with the gp100-alone group (hazard ratio [HR] for death, 0.68; P<0.001). Median OS in the ipilimumab-alone group was 10.1 months (HR for death in comparison to the gp100-alone group, 0.66; P=0.003). These results support ipilimumab as the first agent to improve OS in patients with metastatic melanoma.

Jaime E. Anderson

More recently, another phase 3 study by Robert and colleagues was conducted in 502 patients with previously untreated metastatic melanoma. Patients were randomized to receive ipilimumab 10 mg/kg plus dacarbazine 850 mg/m2 or dacarbazine 850 mg/m2 plus ipilimumab placebo, administered on weeks 1, 4, 7, and 10. This was followed by dacarbazine treatment alone every 3 weeks through week 22. The primary endpoint of median overall survival in the ipilimumab plus dacarbazine group was 11.2 months as compared with 9.1 months in the dacarbazine alone group (HR=0.72, P< 0.001). Although this higher dosage of ipilimumab in combination with dacarbazine demonstrated improved efficacy over dacarbazine alone in this trial, this dose and schedule has not been approved by the FDA, is not likely to be reimbursed nor covered via the patient assistance program, and imparts additional risks of serious toxicities.

Toxicity and adverse effects

Stimulating the immune system to fight cancerous cells also brings with it significant risk for serious and potentially fatal adverse effects. Incorporated into the FDA-approval was a boxed warning for severe and life-threatening immune-related adverse events (IrAE), which have the potential to affect any organ system. Combining ipilimumab with chemotherapy adds another dimension to the adverse events, with the potential to add chemotherapy-related adverse events to the immune-related adverse events and further complicate therapy.

The most common adverse effects for patients using the 3 mg/kg dose (ipi-3), as noted in the study by Hodi and colleagues, were fatigue (41%, Grade 3-5 = 7%); diarrhea (32%, Grade 3-5 = 5%); pruritis (31%); rash (29%, Grade 3-5 = 2%); and colitis (8%, Grade 3-5 = 5%). Overall, the incidence of any severe, life-threatening, or fatal IrAE was 10% to 15%. (See Table 1 for details regarding criteria for characterizing and managing selected adverse events experienced with ipilimumab to left). Based on data from the Robert trial with an increased dose of ipilimumab (ipi-10) in combination with dacarbazine, this approach to dosing imparts a greater incidence of serious adverse events compared with dacarbazine alone (56% vs 28%), likely representing the combined chemotherapy-related and immune-related toxicities. When comparing the ipi-10 plus dacarbazine to the ipi-3 alone, the incidence of hepatic toxicity appears to be higher with the combination therapy. Due to the limited amount of available data and concerns regarding adverse events, this high-dose, combination regimen should not be utilized outside the context of a clinical trial.

In addition, patients and caregivers should be carefully educated on the potential IrAEs and instructed to report any signs of such reactions to their oncologist immediately. The proper management of IrAEs and initiation of corticosteroids as noted in Table 1 is critical to minimizing morbidity and mortality associated with ipilimumab.

Administration and Dose Modifications

The FDA-approved dosing for ipilimumab is 3 mg/kg (actual body weight) administered as a 90-minute outpatient intravenous infusion, given every 3 weeks for a total of four doses. Several trials have designated this as an induction phase for 12 weeks, using either 3 mg/kg or 10 mg/kg doses, which are then followed by ipilimumab dosing every 12 weeks thereafter as the maintenance phase for stable disease or better. It is important to note that neither the 10 mg/kg dosing nor the maintenance phase has been approved by the FDA at the present time.

Laura Boehnke Michaud

The infusion schedule of ipilimumab allows for convenient outpatient administration. This is similar to infusion schedules of other melanoma regimens, such as dacarbazine or carboplatin plus paclitaxel. It does offer an advantage over regimens including high-dose interleukin-2 or biochemotherapy, which require week-long inpatient hospitalizations in medical centers trained and equipped to manage toxicities. The prepared product of ipilimumab should be administered through an intravenous line containing a sterile, pyrogenic, low-protein-binding in-line filter. Although it does contain polysorbate 80, the reported incidence of infusion-related reactions in clinical trials has been very low (approximately 1%). Pre-medication with acetaminophen or diphenhydramine is not standard, unless such reactions occur.

REMS Program and Sponsored Assistance Programs

Due to the risk for severe IrAE associated with use, Bristol-Myers Squibb and the FDA collaborated to develop a risk evaluation and mitigation strategy (REMS) for ipilimumab. The required REMS includes a Communication Plan to educate prescribers of potential IrAE, assist in identifying early manifestations of such, and provide recommendations for management of moderate to severe reactions.

Ipilimumab is available solely through McKesson Specialty Care, as part of a closed distribution model. Once an order has been placed with the company, a representative from Bristol-Myers Squibb will contact each prescriber to ensure the REMS Communication Plan has been discussed.

One of the more controversial issues with ipilimumab is the cost for a full treatment course. For an 80-kg patient, the average wholesale price of four doses of ipilimumab 3 mg/kg would be approximately $144,000 for the drug alone. Not to be forgotten is consideration of associated costs with infusion center preparation and administration, and cost of management and possible hospitalization should severe IrAEs occur. For qualifying patients, financial assistance programs for access are also available.

Conclusion

Ipilimumab is a first-in-class monoclonal antibody which blocks CTLA-4, augmenting T-cell activation and proliferation. It is the first agent to demonstrate an overall survival advantage in both previously-treated and treatment-naïve advanced melanoma patients. This status is reflected in the NCCN’s designation of ipilimumab as a category 1 recommendation for initial management of advanced melanoma.

Despite cost being a potentially prohibitive factor, the most important consideration in treatment planning is the likelihood of severe and life-threatening IrAE. These may take weeks to occur, so patients must be educated to report early symptoms to their oncologists, who in turn must be quick to initiate appropriate management.

For more information:

• Hodi FS, et al. N Engl J Med. 2010; 363:711-23.
• NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 4.2011. www.nccn.org. Accessed Aug. XX, 2011.
• Robert C, Ghiringhelli F. The Oncologist. 2009; 14:848-861.
• Robert C, et al. N Engl J Med. 2011. Epub June 6, 2011.
• US Food and Drug Administration Website. Ipilimumab. www.fda.gov/AboutFDA/CentersOffices/CDER/ucm248478.htm. Accessed July 29, 2011.
• Yervoy [package insert]. Princeton, NJ; Bristol-Myers Squibb Company; March 2011.
• Yervoy (ipilimumab): Risk Evaluation and Mitigation Strategy (REMS) – Severe Immune-Mediated Adverse Reactions. US Food and Drug Administration Website. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm249770.htm. Accessed July 29, 2011.