Nivolumab - Drug Monograph

Introduction

Nivolumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that functions as an immune checkpoint inhibitor. It represents a significant advancement in cancer immunotherapy, specifically targeting the programmed death-1 (PD-1) receptor. Approved by the FDA in 2014, nivolumab has revolutionized the treatment landscape for multiple malignancies by harnessing the body's immune system to fight cancer cells.

Mechanism of Action

Nivolumab binds selectively to the PD-1 receptor on activated T-cells, blocking its interaction with programmed death-ligand 1 (PD-L1) and PD-L2. This interaction normally serves as an "off switch" that prevents T-cells from attacking other cells in the body. By inhibiting this checkpoint, nivolumab enhances T-cell-mediated immune responses against tumor cells, effectively "releasing the brakes" on the immune system. This mechanism allows for restored anti-tumor activity and enhanced immune surveillance against malignant cells.

Indications

Nivolumab is FDA-approved for:

• Unresectable or metastatic melanoma
• Metastatic non-small cell lung cancer (NSCLC)
• Advanced renal cell carcinoma
• Classical Hodgkin lymphoma
• Recurrent or metastatic squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma
• Malignant pleural mesothelioma
• Gastric, gastroesophageal junction, and esophageal adenocarcinoma

Dosage and Administration

• Renal impairment: No dosage adjustment required
• Hepatic impairment: No dosage adjustment required
• Elderly patients: No dosage adjustment required
• Pediatric patients: 3 mg/kg every 2 weeks for patients ≥12 years with MSI-H cancers

Dosage modifications may be required for immune-mediated adverse reactions. Infusion should be interrupted or discontinued for severe infusion reactions.

Pharmacokinetics

• Absorption: Administered intravenously, achieving complete bioavailability
• Distribution: Steady-state volume of distribution approximately 8.0 L
• Metabolism: Degraded via proteolytic enzymes throughout the body
• Elimination: Terminal half-life approximately 25 days; clearance approximately 8.2 mL/hour
• Special populations: No clinically significant differences based on age, gender, race, renal impairment, or mild hepatic impairment

Contraindications

• History of severe hypersensitivity to nivolumab or any of its excipients
• No absolute contraindications based on organ function, but requires careful consideration in patients with active autoimmune diseases

Warnings and Precautions

• Pneumonitis
• Colitis
• Hepatitis
• Endocrinopathies (thyroid disorders, adrenal insufficiency, type 1 diabetes)
• Nephritis
• Skin reactions
• Neurologic toxicities

Drug Interactions

• No formal drug interaction studies conducted
• Theoretical increased risk of immune-mediated adverse reactions when combined with other immunomodulatory drugs
• Caution advised with corticosteroids and other immunosuppressive agents, which may reduce efficacy
• Live vaccines should be avoided during treatment

Adverse Effects

• Fatigue
• Rash
• Musculoskeletal pain
• Pruritus
• Diarrhea
• Nausea
• Decreased appetite
• Constipation
• Cough
• Dyspnea

• Immune-mediated pneumonitis (1.3-6.4%)
• Immune-mediated colitis (1.2-8.6%)
• Immune-mediated hepatitis (1.1-10%)
• Immune-mediated endocrinopathies (thyroid disorders 4.6-16%, adrenal insufficiency 0.6-1.3%)
• Severe infusion reactions (0.3-1.5%)

Monitoring Parameters

• Complete blood count with differential
• Comprehensive metabolic panel including liver function tests
• Thyroid function tests
• Cortisol levels
• Lipase/amylase
• Baseline imaging

• Regular assessment for signs/symptoms of immune-mediated adverse reactions
• Liver function tests every 3-6 weeks
• Thyroid function every 4-6 weeks
• Regular imaging assessments per treatment protocol
• Blood glucose monitoring
• Respiratory symptoms assessment

Patient Education

• Report any new or worsening symptoms immediately, including respiratory difficulties, diarrhea, abdominal pain, rash, fatigue, or endocrine symptoms
• Understand the potential for delayed immune-related adverse events
• Avoid live vaccines during treatment and consult healthcare provider before any vaccinations
• Use effective contraception during treatment and for at least 5 months after final dose
• Keep all scheduled appointments for monitoring and laboratory tests
• Carry patient wallet card identifying nivolumab treatment
• Report any infusion-related symptoms during or after treatment

References

1. Topalian SL, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-2454. 2. Brahmer JR, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373(2):123-135. 3. Weber JS, et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015;16(4):375-384. 4. Opdivo® (nivolumab) prescribing information. Bristol-Myers Squibb Company; 2023. 5. NCCN Guidelines®. Various cancer types. Version 2023. 6. Postow MA, et al. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(16):1585-1586. 7. FDA.gov: Nivolumab approval documents and safety communications.