Introduction
Pembrolizumab is a programmed death receptor-1 (PD-1) blocking antibody that belongs to the class of immune checkpoint inhibitors. As a humanized monoclonal IgG4 antibody, it represents a groundbreaking approach in cancer immunotherapy by harnessing the body's immune system to fight malignancies. Approved by the FDA in 2014, pembrolizumab has revolutionized the treatment landscape for numerous cancers and continues to expand its therapeutic applications through ongoing clinical research.
Mechanism of Action
Pembrolizumab exerts its antitumor effects by binding to the PD-1 receptor on T-cells, thereby blocking its interaction with programmed death ligands PD-L1 and PD-L2. This interaction normally serves as an immune checkpoint that prevents excessive immune responses and maintains self-tolerance. By inhibiting this pathway, pembrolizumab prevents cancer cells from evading immune surveillance, allowing T-cells to recognize and attack tumor cells effectively. The drug essentially "releases the brakes" on the immune system, enabling enhanced antitumor immune responses.
Indications
Pembrolizumab has received FDA approval for multiple indications including:
- Melanoma (unresectable or metastatic)
- Non-small cell lung cancer (NSCLC)
- 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) cancers
- 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
Dosage and Administration
Standard dosing: 200 mg every 3 weeks OR 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes Special populations:- Renal impairment: No dosage adjustment recommended
- Hepatic impairment: No dosage adjustment recommended
- Pediatric patients: 2 mg/kg (up to 200 mg) every 3 weeks
- Elderly patients: No dosage adjustment recommended
Treatment should continue until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression.
Pharmacokinetics
Absorption: Administered intravenously, resulting in complete bioavailability Distribution: Steady-state volume of distribution approximately 8.2 L Metabolism: Undergoes proteolytic degradation like other immunoglobulin proteins Elimination: Half-life approximately 27 days; clearance approximately 0.22 L/day Time to steady state: Approximately 18 weeksContraindications
- History of severe hypersensitivity to pembrolizumab or any of its excipients
- No absolute contraindications based on organ function
Warnings and Precautions
Immune-mediated adverse reactions: Pembrolizumab can cause severe and fatal immune-mediated reactions including:- Pneumonitis
- Colitis
- Hepatitis
- Endocrinopathies (thyroid disorders, adrenal insufficiency, type 1 diabetes)
- Nephritis
- Dermatologic reactions
- Myocarditis
Drug Interactions
No formal drug interaction studies have been conducted. However:
- Immunosuppressive agents may diminish the therapeutic effect
- Live vaccines should be avoided during treatment
- Theoretical increased risk of adverse effects with other immunomodulatory agents
Adverse Effects
Common adverse reactions (≥20%):- Fatigue
- Musculoskeletal pain
- Decreased appetite
- Pruritus
- Diarrhea
- Nausea
- Rash
- Pyrexia
- Cough
- Constipation
- Dyspnea
- Severe immune-mediated reactions
- Severe infusion reactions
- Complications of allogeneic HSCT
Monitoring Parameters
Baseline and periodic monitoring:- Complete blood count with differential
- Comprehensive metabolic panel (including liver and renal function)
- Thyroid function tests
- Adrenal function assessment
- Pulmonary symptoms and imaging if indicated
- Cardiac monitoring if symptoms suggest myocarditis
- Blood glucose monitoring
- Assessment for signs/symptoms of colitis
- Tumor response assessment per RECIST criteria
Patient Education
- Report any new or worsening symptoms immediately, especially respiratory, gastrointestinal, endocrine, or dermatologic symptoms
- Understand the potential for delayed immune-mediated reactions
- Practice effective contraception during treatment and for 4 months after final dose
- Avoid live vaccines during treatment
- Keep all scheduled appointments for monitoring and treatment
- Carry patient wallet card identifying pembrolizumab treatment
- Report any signs of infection promptly
- Maintain adequate hydration and nutrition
- Understand that response assessment may take several treatment cycles
References
1. Keytruda® (pembrolizumab) prescribing information. Merck & Co., Inc. 2023. 2. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018;359(6382):1350-1355. 3. Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974-1982. 4. FDA Approval Documents: Keytruda (pembrolizumab). U.S. Food and Drug Administration. 5. NCCN Guidelines®: Various cancer-specific guidelines. National Comprehensive Cancer Network. 6. 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. 7. Schmid P, et al. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020;382(9):810-821. 8. Mok TSK, et al. Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer. Lancet. 2019;393(10183):1819-1830.
This monograph is intended for educational purposes only and should not replace clinical judgment. Always consult current prescribing information and clinical guidelines.