Yervoy - Drug Monograph

Introduction

Yervoy (ipilimumab) is a revolutionary monoclonal antibody that represents a paradigm shift in cancer immunotherapy. Developed by Bristol-Myers Squibb, it was the first immune checkpoint inhibitor approved by the FDA in 2011. Yervoy targets cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), effectively "releasing the brakes" on the immune system to enhance antitumor responses. This biologic medication has fundamentally changed the treatment landscape for advanced melanoma and other malignancies.

Mechanism of Action

Yervoy exerts its therapeutic effect through blockade of CTLA-4, a critical negative regulator of T-cell activation. Normally, CTLA-4 functions as an inhibitory receptor that dampens T-cell responses by competing with the costimulatory molecule CD28 for binding to B7 ligands on antigen-presenting cells. By inhibiting CTLA-4, ipilimumab enhances T-cell activation and proliferation, promotes memory T-cell development, and ultimately facilitates a more robust antitumor immune response. This mechanism represents a fundamentally different approach from traditional cytotoxic chemotherapy, targeting the immune system rather than directly attacking cancer cells.

Indications

Yervoy is FDA-approved for:

• Treatment of unresectable or metastatic melanoma in adults and pediatric patients (12 years and older)
• Adjuvant treatment of cutaneous melanoma with pathologic involvement of regional lymph nodes (>1 mm) after complete resection
• Advanced renal cell carcinoma in combination with nivolumab
• Metastatic colorectal cancer with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) in combination with nivolumab
• Hepatocellular carcinoma in combination with nivolumab
• Malignant pleural mesothelioma in combination with nivolumab
• Non-small cell lung cancer in combination with nivolumab (for patients with PD-L1 expression ≥1%)

Dosage and Administration

• Metastatic melanoma: 3 mg/kg IV every 3 weeks for 4 doses
• Adjuvant melanoma: 10 mg/kg IV every 3 weeks for 4 doses, then 10 mg/kg every 12 weeks for up to 3 years
• Combination therapy with nivolumab: 1 mg/kg IV every 3 weeks for 4 doses (with nivolumab 3 mg/kg), then continue nivolumab monotherapy

• Administer as an intravenous infusion over 90 minutes
• Premedication with antipyretics and antihistamines may be considered
• Dilute in 0.9% Sodium Chloride or 5% Dextrose injection to final concentration of 1-4 mg/mL

• Renal impairment: No dosage adjustment necessary
• Hepatic impairment: No dosage adjustment recommended for mild impairment; use with caution in moderate to severe impairment
• Elderly patients: No dosage adjustment required
• Pediatric patients: Safety established in patients 12 years and older

Pharmacokinetics

Contraindications

Yervoy is contraindicated in patients with:

• History of severe hypersensitivity reaction to ipilimumab or any of its excipients
• Autoimmune disorders that require immunosuppressive therapy (relative contraindication)
• Concurrent use with other immune checkpoint inhibitors not specifically approved in combination regimens

Warnings and Precautions

• Can cause severe and fatal immune-mediated reactions including enterocolitis, hepatitis, dermatitis, neuropathies, and endocrinopathies
• Permanently discontinue for severe immune-mediated reactions
• Requires prompt recognition and management with corticosteroids and/or other immunosuppressants

Drug Interactions

• Corticosteroids: May reduce efficacy of ipilimumab; use only for management of immune-mediated adverse reactions
• Other immunosuppressants: May interfere with therapeutic immune activation
• Live vaccines: Avoid concurrent administration due to risk of disseminated infection
• Other immune checkpoint inhibitors: Increased risk of immune-mediated adverse reactions when used in unapproved combinations

Adverse Effects

• Fatigue (41%)
• Diarrhea (32%)
• Pruritus (31%)
• Rash (29%)
• Colitis (8%)

• Enterocolitis (7-16%, may be fatal)
• Hepatitis (1-10%)
• Dermatitis (1-5%)
• Neuropathies (≤1%)
• Endocrinopathies (hypophysitis, thyroid disorders, adrenal insufficiency) (1-9%)

• Infusion reactions (1-2%)
• Ocular inflammation (uveitis, iritis) (<1%)
• Renal dysfunction (<1%)

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel (including liver function tests)
• Thyroid function tests
• Adrenal function assessment
• ECG for patients with cardiac risk factors

• Monitor for signs/symptoms of immune-mediated adverse reactions at each visit
• Liver function tests before each dose
• Thyroid function monthly
• Vigilant monitoring for diarrhea/colitis symptoms
• Neurologic assessment for new-onset weakness or sensory changes

• Continued monitoring for delayed immune-mediated reactions (can occur months after discontinuation)
• Long-term endocrine function monitoring

Patient Education

• Importance of immediately reporting new or worsening symptoms, especially diarrhea, abdominal pain, jaundice, skin rash, or neurological changes
• Understanding the delayed onset of immune-related adverse events (may occur after treatment completion)
• Need for regular monitoring and follow-up appointments
• Avoidance of live vaccines during treatment and until immune function recovers
• Reproductive considerations: Use effective contraception during and for 3 months after treatment
• Potential impact on ability to drive or operate machinery due to fatigue or neurological effects
• Management strategies for common side effects like fatigue and skin reactions

References

1. FDA Prescribing Information: Yervoy (ipilimumab). Revised 2023. 2. Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711-723. 3. Weber JS, et al. Safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma. J Clin Oncol. 2017;35(7):785-792. 4. Postow MA, et al. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974-1982. 5. NCCN Guidelines: Melanoma Version 3.2023. 6. Eggermont AMM, et al. Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma. Lancet Oncol. 2016;17(7):886-895. 7. Wolchok JD, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356.