Introduction
Keytruda (pembrolizumab) is a humanized monoclonal antibody and immune checkpoint inhibitor that represents a significant advancement in cancer immunotherapy. Developed by Merck & Co., it was first approved by the FDA in 2014 for advanced melanoma and has since revolutionized the treatment landscape for numerous malignancies. As a programmed death receptor-1 (PD-1) blocking antibody, Keytruda enhances the body's immune response against cancer cells by overcoming tumor immune evasion mechanisms.
Mechanism of Action
Keytruda binds to the PD-1 receptor on T-cells, blocking its interaction with programmed death-ligand 1 (PD-L1) and PD-L2 expressed on tumor cells and other immune cells. This interaction normally suppresses T-cell activation and proliferation, allowing tumors to evade immune surveillance. By inhibiting this checkpoint, Keytruda potentiates T-cell-mediated immune responses against tumor cells, leading to enhanced antitumor activity.
The drug specifically targets the immune checkpoint pathway rather than directly attacking cancer cells, making it fundamentally different from traditional chemotherapy. This mechanism enables the immune system to recognize and destroy cancer cells that might otherwise evade detection.
Indications
Keytruda is FDA-approved for multiple cancer types, including:
- Melanoma (unresectable or metastatic)
- Non-small cell lung cancer (NSCLC)
- Head and neck squamous cell cancer
- 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
- Renal cell carcinoma
- Endometrial carcinoma
- Tumor mutational burden-high (TMB-H) cancers
- Triple-negative breast cancer
- Cutaneous squamous cell carcinoma
Specific indications may vary based on line of therapy, biomarker status (e.g., PD-L1 expression), and combination regimens with other therapies.
Dosage and Administration
Standard dosing: 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes Dosing considerations:- Treatment continues until disease progression, unacceptable toxicity, or up to 24 months in patients without disease progression
- No dose reductions recommended; instead delay or discontinue for toxicity
- Premedication with antipyretics and antihistamines may be considered for infusion-related reactions
- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: No dosage adjustment necessary
- Pediatric patients: 2 mg/kg (up to 200 mg) every 3 weeks for approved indications
- Elderly: No dosage adjustment necessary
Pharmacokinetics
Absorption: Administered intravenously, resulting in complete bioavailability Distribution: Steady-state volume of distribution is approximately 8 L, with minimal extravascular distribution Metabolism: Cleared via proteolytic degradation into small peptides and amino acids, similar to endogenous IgG antibodies Elimination: Terminal half-life is approximately 22 days (range: 15-30 days)- Clearance: 0.22 L/day
- Linear pharmacokinetics observed at doses ≥2 mg/kg
- Age, gender, and mild renal/hepatic impairment do not significantly affect pharmacokinetics
- No formal studies in severe hepatic impairment
Contraindications
Keytruda is contraindicated in patients with:
- History of severe hypersensitivity to pembrolizumab or any of its excipients
- No other absolute contraindications exist, but careful risk-benefit assessment is required for patients with pre-existing autoimmune conditions
Warnings and Precautions
Immune-Mediated Adverse Reactions:Keytruda can cause severe and fatal immune-mediated reactions involving any organ system. These may include:
- Pneumonitis
- Colitis
- Hepatitis
- Endocrinopathies (hypophysitis, thyroid disorders, type 1 diabetes)
- Nephritis
- Dermatologic reactions
- Myocarditis
- Infusion-related reactions
- Complications of allogeneic hematopoietic stem cell transplantation
- Embryo-fetal toxicity
Most immune-mediated reactions are manageable with corticosteroids and treatment interruption or discontinuation. Permanent discontinuation is required for grade 4 reactions (except endocrinopathies that are controlled with hormone replacement).
Drug Interactions
No formal drug interaction studies have been conducted. However, consider potential interactions:
- Avoid concomitant use with other immunosuppressive agents (may enhance risk of infections)
- Use caution with corticosteroids for managing immune-mediated adverse reactions
- Theoretical increased risk of rejection with organ transplantation
- Live vaccines: Avoid during and after treatment (risk of infection)
Adverse Effects
Most common adverse reactions (≥20%):- Fatigue
- Musculoskeletal pain
- Decreased appetite
- Pruritus
- Diarrhea
- Nausea
- Rash
- Pyrexia
- Cough
- Constipation
- Dyspnea
- Immune-mediated pneumonitis (3.4%)
- Immune-mediated colitis (2.9%)
- Immune-mediated hepatitis (1.8%)
- Severe skin reactions (including SJS and TEN)
- Endocrinopathies
- Nephritis
- Myocarditis
- Anemia
- Lymphopenia
- Hyperglycemia
- Increased AST/ALT
- Hyponatremia
- Increased creatinine
Monitoring Parameters
Baseline assessment:- Complete blood count with differential
- Comprehensive metabolic panel (including liver and renal function)
- Thyroid function tests
- Baseline imaging
- Assessment of performance status
- Screening for symptoms of autoimmune disorders
- Monitor for signs/symptoms of immune-mediated adverse reactions at each visit
- Regular assessment of liver function (every 3-6 weeks)
- Thyroid function monitoring (periodically)
- Blood glucose monitoring
- Regular assessment of respiratory symptoms
- Diarrhea assessment (for colitis)
- Skin examination
- Tumor response assessment per standard guidelines (typically every 8-12 weeks)
Patient Education
Key points for patients:- Report any new or worsening symptoms immediately, especially:
- Shortness of breath or cough - Diarrhea or abdominal pain - Jaundice or dark urine - Severe skin reactions - Excessive fatigue or weakness - Changes in vision - Rapid heartbeat - Increased thirst or urination
- Understand that immune-related side effects can occur even after treatment discontinuation
- Keep all scheduled follow-up appointments and laboratory tests
- Inform all healthcare providers about Keytruda treatment
- Use effective contraception during and for at least 4 months after treatment
- Do not receive live vaccines during treatment
- Maintain hydration and nutrition
- Report any signs of infection promptly
References
1. Keytruda® (pembrolizumab) prescribing information. Merck & Co., Inc. 2023. 2. FDA Approval: Keytruda for multiple indications. FDA.gov. 3. Brahmer JR, et al. N Engl J Med. 2015;373(13):1234-1243. 4. Robert C, et al. N Engl J Med. 2015;372(26):2521-2532. 5. Reck M, et al. N Engl J Med. 2016;375(19):1823-1833. 6. NCCN Guidelines®: Various cancer types. National Comprehensive Cancer Network. 7. Postow MA, et al. N Engl J Med. 2018;378(17):1585-1596. 8. Schmid P, et al. N Engl J Med. 2018;379(22):2108-2121. 9. ClinicalTrials.gov: Various pembrolizumab trials.
This information is intended for educational purposes and should not replace clinical judgment. Always consult current prescribing information and clinical guidelines.