Introduction to Pembrolizumab

Pembrolizumab (trade name: Keytruda) is a humanized monoclonal antibody that belongs to the class of immune checkpoint inhibitors. It was first approved by the FDA in 2014 for the treatment of advanced melanoma and has since gained approval for various other cancers in adults and, more recently, in pediatric patients. Pembrolizumab has become a cornerstone in cancer immunotherapy, revolutionizing treatment approaches in oncology.

Mechanism of Action

Pembrolizumab targets 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

By blocking the PD-1 pathway, pembrolizumab reactivates the immune system's ability to recognize and attack cancer cells. This mechanism is particularly effective in tumors that express PD-L1, although responses can be seen in PD-L1 negative tumors as well.

Indications

In pediatric oncology, pembrolizumab is approved for:

• Refractory classical Hodgkin lymphoma (cHL) in patients aged 3 years and older
• Recurrent locally advanced or metastatic Merkel cell carcinoma in pediatric patients 6 months of age and older
• Unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase] solid tumors in pediatric patients aged 12 years and older who have progressed following prior treatment
• Recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by surgery or radiation in patients 6 months of age and older

In adults, pembrolizumab has broader indications, including:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Classical Hodgkin lymphoma
• Primary mediastinal large B-cell lymphoma
• Urothelial carcinoma
• Microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors
• Gastric cancer
• Esophageal cancer
• Cervical cancer
• Hepatocellular carcinoma
• Merkel cell carcinoma
• Renal cell carcinoma
• Endometrial carcinoma
• Tumor mutational burden-high (TMB-H) solid tumors
• Cutaneous squamous cell carcinoma
• Triple-negative breast cancer

Administration

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

• For pediatric patients with cHL, Merkel cell carcinoma, or TMB-H solid tumors:
  • 2 mg/kg (up to a maximum of 200 mg) every 3 weeks
• For cutaneous squamous cell carcinoma:
  • Patients weighing ≥30 kg: 200 mg every 3 weeks or 400 mg every 6 weeks
  • Patients weighing <30 kg: 2 mg/kg every 3 weeks
• Infusion time is typically 30 minutes
• Treatment is continued until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression

Adverse Effects

Common adverse effects in pediatric patients include:

• Fatigue
• Pyrexia (fever)
• Nausea
• Vomiting
• Constipation
• Diarrhea
• Abdominal pain
• Rash
• Headache
• Cough
• Dyspnea (shortness of breath)

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

• Pneumonitis
• Colitis
• Hepatitis
• Endocrinopathies (e.g., hypophysitis, thyroid disorders, adrenal insufficiency, type 1 diabetes)
• Nephritis and renal dysfunction
• Severe skin reactions
• Encephalitis
• Myocarditis

Pembrolizumab can also cause severe or life-threatening infusion-related reactions.

Efficacy in Pediatrics

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

• In refractory classical Hodgkin lymphoma:
  • Overall response rate (ORR) of 66% in pediatric patients
  • Complete remission rate of 22%
• In Merkel cell carcinoma:
  • ORR of 60% in adult patients, with similar efficacy expected in pediatric patients
• In TMB-H solid tumors:
  • ORR of 29% across multiple tumor types in adults, with responses observed in pediatric patients as well

Ongoing clinical trials are evaluating pembrolizumab's efficacy in other pediatric cancers, including various solid tumors and hematologic malignancies.

Monitoring and Management

Close monitoring is essential for patients receiving pembrolizumab:

• 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 pembrolizumab 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
• Hormone replacement therapy for endocrinopathies

Patient and family education about potential side effects and the importance of prompt reporting of new symptoms is crucial.