Introduction to Nivolumab

Nivolumab (trade name: Opdivo) is a human immunoglobulin G4 (IgG4) monoclonal antibody that belongs to a class of drugs known as immune checkpoint inhibitors. It was first approved by the FDA in 2014 for the treatment of melanoma and has since gained approval for various other cancers in adults and, more recently, in pediatric patients.

Mechanism of Action

Nivolumab works by targeting the programmed cell death protein 1 (PD-1) receptor found on T cells. Its mechanism involves:

• Binding to the PD-1 receptor, blocking its interaction with PD-L1 and PD-L2 ligands
• Preventing the inhibition of T cell activation and proliferation
• Enhancing T cell-mediated immune responses against tumor cells
• Restoring anti-tumor immune function that had been suppressed by the PD-1/PD-L1 pathway

This action effectively "takes the brakes off" the immune system, allowing it to recognize and attack cancer cells more effectively.

Indications

In pediatric oncology, nivolumab is approved for:

• Classical Hodgkin Lymphoma (cHL) in patients aged 12 years and older with relapsed or refractory disease after autologous stem cell transplant (ASCT) or after two or more prior multi-agent chemotherapy regimens in patients who did not have ASCT
• Metastatic colorectal cancer with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) in patients 12 years and older

In adults, nivolumab has broader indications, including:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hepatocellular carcinoma
• Head and neck squamous cell carcinoma
• Urothelial carcinoma

Administration

Nivolumab is administered as an intravenous infusion. The dosing regimen varies based on the indication and patient factors:

• For pediatric patients ≥12 years with cHL or MSI-H/dMMR colorectal cancer:
  • 240 mg every 2 weeks or 480 mg every 4 weeks
• Infusion time is typically 30 minutes
• Treatment is continued until disease progression or unacceptable toxicity

Dosing may be weight-based in some scenarios, particularly in clinical trials for pediatric patients.

Adverse Effects

Common adverse effects in pediatric patients include:

• Fatigue
• Rash
• Musculoskeletal pain
• Abdominal pain
• Cough
• Nausea
• Headache
• Decreased appetite

Serious immune-mediated adverse reactions can occur in any organ system, including:

• Pneumonitis
• Colitis
• Hepatitis
• Endocrinopathies (e.g., thyroid disorders, adrenal insufficiency)
• Nephritis and renal dysfunction
• Skin adverse reactions
• Encephalitis

Efficacy in Pediatrics

The efficacy of nivolumab in pediatric patients has been demonstrated in several studies:

• In relapsed/refractory classical Hodgkin lymphoma:
  • Overall response rate (ORR) of 64-69%
  • Complete remission rate of 21-29%
• In MSI-H/dMMR colorectal cancer:
  • ORR of 55% in pediatric and young adult patients
  • Durable responses observed, with many patients maintaining response for over 12 months

Ongoing clinical trials are evaluating nivolumab's efficacy in other pediatric cancers, including various solid tumors and brain tumors.

Monitoring and Management

Close monitoring is essential for patients receiving nivolumab:

• Regular assessment for signs and symptoms of immune-mediated adverse reactions
• Baseline and periodic monitoring of:
  • Liver function tests
  • Thyroid function tests
  • Renal function
  • Blood glucose levels
• Prompt evaluation of new or worsening respiratory symptoms for potential pneumonitis
• Vigilance for signs of colitis, hepatitis, nephritis, and endocrinopathies

Management of immune-mediated adverse reactions often involves:

• Withholding or permanently discontinuing nivolumab based on severity of the adverse reaction
• Administration of high-dose corticosteroids (e.g., prednisone 1-2 mg/kg/day or equivalent)
• Tapering of corticosteroids over at least 1 month upon improvement
• Use of additional immunosuppressive agents in corticosteroid-refractory cases