In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On October 28, 2015, ipilimumab (Yervoy) was approved for adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes > 1 mm who have undergone complete resection, including total lymphadenectomy.1,2
Supporting Efficacy Data
Approval was based on improvement in recurrence-free survival in a double-blind trial in which 945 patients with resected stage IIIA (lymph node > 1 mm), IIIB, and IIIC (with no in-transit metastases) cutaneous melanoma were randomly assigned to receive ipilimumab at 10 mg/kg (n = 471) or placebo (n = 474) via intravenous infusion for four doses every 3 weeks followed by 10 mg/kg every 12 weeks beginning at week 24 up to a maximum of 3 years.2,3
Overall, patients had a median age of 51 years (range = 18–84 years), 62% were male, 99% were white, and 94% had Eastern Cooperative Oncology Group performance status of 0. Disease stage was IIIA in 20%, IIIB in 44%, and IIIC in 36%. Ipilimumab-treated patients received a median of four doses (range = 1–16), and 36% received ipilimumab for > 6 months.
Median recurrence-free survival, the primary endpoint, was 26 months (95% confidence interval [CI] = 26–39 months) in the ipilimumab group vs 17 months (95% CI = 13–22 months) in the placebo group (hazard ratio = 0.75, P < .002).
How It Works
Ipilimumab is a monoclonal antibody that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands (CD80/CD86). CTLA-4 is a negative regulator of T-cell activity. Blockade of CTLA-4 increases T-cell activation and proliferation, including activation and proliferation of tumor-infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also reduce T-regulatory cell function, which may contribute to a general increase in T-cell responsiveness, including antitumor immune response.
How It Is Used
The recommended dose of ipilimumab in the new indication is 10 mg/kg given intravenously over 90 minutes every 3 weeks for 4 doses followed by 10 mg/kg every 12 weeks for up to 3 years. For toxicity, doses are omitted, not delayed.
Ipilimumab should be permanently discontinued and systemic high-dose corticosteroid therapy should be started for severe immune-mediated adverse reactions. Recommended treatment modifications for immune-mediated adverse reactions include withholding of treatment for symptomatic endocrinopathy and resuming treatment after complete or partial resolution to grade 0 or 1 in patients receiving < 7.5 mg/d of prednisone or its equivalent.
Treatment should be permanently discontinued for symptomatic reactions lasting ≥ 6 weeks and if the prednisone (or equivalent) dose cannot be reduced to ≤ 7.5 mg/d. Ipilimumab should be permanently discontinued for ophthalmologic grade 2 to 4 reactions that require systemic treatment or that do not improve to grade 1 within 2 weeks during topical therapy.
For other immune-mediated adverse reactions, treatment should be withheld for grade 2 adverse events and can be resumed after complete or partial resolution to grade 0 or 1 in patients receiving < 7.5 mg/d of prednisone/equivalent. It should be permanently discontinued for grade 2 reactions lasting ≥ 6 weeks, if prednisone/equivalent dose cannot be reduced to ≤ 7.5 mg/d, and for grade 3 or 4 adverse events.
Safety Profile
The most common adverse events of any grade in the ipilimumab group in the phase III trial were rash (50% vs 20% in placebo group), diarrhea (49% vs 30%), fatigue (46% vs 38%), pruritus (45% vs 15%), headache (33% vs 18%), and weight loss (32% vs 9%). The most common grade ≥ 3 adverse events were diarrhea (10% vs 2.1%) and colitis (8% vs 0.4%). The most common grade 3 or 4 laboratory abnormalities were increased alanine transaminase (10% vs 0%), increased aspartate transaminase (9% vs 0.2%), and increased lipase (9% vs 4.5%). Ipilimumab was discontinued due to adverse events in 52% of patients.
Grade 3 to 5 immune-mediated adverse events occurred in 41% of ipilimumab recipients, including enterocolitis in 16%, hepatitis in 11%, endocrinopathy in 8%, dermatitis in 4%, and neuropathy in 1.7%. The five treatment-related deaths in ipilimumab-treated patients were due to immune-mediated adverse reactions of enterocolitis in three patients, Guillain-Barré syndrome in one patient, and myocarditis in one patient.
Ipilimumab carries a boxed warning for immune-mediated adverse reactions, including fatal cases. These reactions may involve any organ system; however, the most common severe reactions are enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of reactions have onset during treatment; however, a minority occurred weeks to months after discontinuation of ipilimumab.
Patients should be routinely assessed for signs and symptoms of enterocolitis, dermatitis, neuropathy, and endocrinopathy and should undergo evaluation with clinical chemistries, including liver function tests, adrenocorticotropic hormone level, and thyroid function tests, before starting treatment and before each dose.
Ipilimumab also carries warnings/precautions for immune-mediated adverse reactions, immune-mediated hepatitis, immune-mediated endocrinopathies, and embryofetal toxicity. Women should discontinue breast-feeding during treatment. ■
References
1. U.S. Food and Drug Administration: Ipilimumab (Yervoy). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm470061.htm. Accessed November 4, 2015.
2. Yervoy (ipilimumab) injection for intravenous use prescribing information, Bristol-Myers Squibb, October 2015. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2015/125377s073lbl.pdf. Accessed November 4, 2015.
3. Eggermont AM, Chiarion-Sileni V, Grob JJ, et al: Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): A randomised, double-blind, phase 3 trial. Lancet Oncol 16:522-530, 2015.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088).
