Pembrolizumab

Pembrolizumab is a humanized IgG4 monoclonal antibody that binds to the programmed death receptor-1 (PD-1) and blocks its interaction with the ligands PD-L1 and PD-L2. It is an immune checkpoint inhibitor that enhances the body’s immune response against cancer cells.

Mechanism of Action

PD-1 is an inhibitory receptor expressed on activated T cells. Many tumors express PD-L1 to evade immune detection — the PD-1/PD-L1 interaction suppresses T-cell activity and allows cancer cells to escape immune surveillance.

Pembrolizumab binds to PD-1 and prevents its engagement with PD-L1 and PD-L2, restoring T-cell function and reactivating anti-tumor immunity. The result is tumor regression in responsive cancers, often with durable responses and the potential for long-term disease control through immune memory.

Pharmacokinetics

Pembrolizumab follows non-linear, time-varying pharmacokinetics typical of large-molecule IgG4 antibodies. The values below are from population PK analyses of IV administration:

• Volume of distribution: approximately 6 L at steady state (central compartment) — consistent with restricted distribution to plasma and interstitial space.
• Protein binding: not expected to bind non-specifically to plasma proteins (IgG antibody, binds specifically to PD-1).
• Metabolism: degraded by general protein catabolism pathways; not metabolized by CYP enzymes.
• Half-life: approximately 22 days.
• Clearance: 195 mL/day at steady state (vs 252 mL/day at first dose) — time-varying clearance that decreases by approximately 21% over the course of treatment, likely due to target-mediated drug disposition.
• Steady state: achieved after approximately 16 weeks (4 months) of repeated dosing.
• Excretion: degraded to peptide fragments and amino acids; not renally excreted as intact antibody.

Subcutaneous formulation (Keytruda QLEX): approved September 2025. Administered as a fixed 460 mg SC dose every 6 weeks. Absolute bioavailability ~61%; median Tmax approximately 4 days. Delivers non-inferior systemic exposure to IV pembrolizumab at approved doses.

Pembrolizumab has demonstrated efficacy across a wide range of solid tumors and hematologic malignancies in numerous registrational clinical trials, with significant improvements in overall survival, progression-free survival, and durable response rates compared to standard chemotherapy in many indications. Many patients achieve long-lasting responses, and a subset maintain response after discontinuation.

Pembrolizumab is indicated for the treatment of multiple cancer types. Specific approved indications, line of therapy, and biomarker requirements vary by country. Major indications include:

Solid tumors: melanoma (adjuvant and metastatic); non-small cell lung cancer; head and neck squamous cell carcinoma; urothelial carcinoma; gastric and gastroesophageal junction adenocarcinoma; colorectal cancer (MSI-H/dMMR); renal cell carcinoma; hepatocellular carcinoma; esophageal carcinoma; cervical cancer; endometrial carcinoma; cutaneous squamous cell carcinoma; triple-negative breast cancer; biliary tract cancer.

Hematologic malignancies: classical Hodgkin lymphoma; primary mediastinal large B-cell lymphoma.

Biomarker-selected: tumor mutational burden-high (TMB-H) solid tumors; microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) solid tumors (tissue-agnostic indication).

Many indications require biomarker testing (PD-L1 expression, MSI-H/dMMR status, or TMB-H). Consult current prescribing information for detailed eligibility criteria.

• Severe hypersensitivity to pembrolizumab or any of the excipients.

Use with caution / special precautions:

• Active autoimmune disease (may worsen).
• Organ transplant recipients (risk of allograft rejection).
• Severe active infections.
• Pregnancy and breastfeeding.

Pembrolizumab causes immune-related adverse events (irAEs) due to the enhanced immune system activity it produces.

Very Common (>10%): fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, abdominal pain.

Immune-Related Adverse Events:

• Skin: rash, pruritus, vitiligo; severe cutaneous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) are rare but serious.
• Endocrine: hypothyroidism (most common, 8–10%), hyperthyroidism, adrenal insufficiency, hypophysitis, type 1 diabetes mellitus.
• Gastrointestinal: colitis, diarrhea, hepatitis (with elevated transaminases).
• Pulmonary: pneumonitis (potentially serious or fatal).
• Renal: nephritis with renal dysfunction.
• Cardiac: myocarditis (rare but can be fatal).
• Neurologic: encephalitis, myasthenia gravis, Guillain-Barré syndrome, peripheral neuropathy.
• Other: pancreatitis, uveitis, myositis.

Infusion-related reactions: generally mild (fever, chills, flushing); severe reactions are rare.

Laboratory abnormalities: increased liver enzymes, anemia, lymphopenia, hyponatremia, increased creatinine, hyperglycemia.

Most irAEs are manageable with corticosteroids; endocrinopathies typically require permanent hormone replacement. Severe events may require permanent discontinuation. Early recognition and treatment are critical.

Pembrolizumab does not undergo hepatic metabolism, and no formal drug interaction studies have been conducted.

• Systemic immunosuppressants and high-dose corticosteroids: avoid except when needed to treat irAEs (may reduce efficacy).
• Live vaccines: avoid during treatment.

Pembrolizumab is administered as an intravenous infusion by qualified healthcare professionals.

Dosing Regimens

Intravenous — standard adult fixed-dose regimens (with equivalent efficacy and safety):

• 200 mg every 3 weeks, or
• 400 mg every 6 weeks.

Subcutaneous (Keytruda QLEX) — approved September 2025 for adults with any indication for IV pembrolizumab:

• 460 mg every 6 weeks (single fixed dose; no dose selection required).

Weight-based pediatric IV dosing: 2 mg/kg (up to 200 mg) every 3 weeks.

Preparation and Infusion

• Dilute in 0.9% sodium chloride or 5% dextrose to a final concentration of 1–10 mg/mL.
• Mix gently — do not shake.
• Administer over 30 minutes through a sterile, non-pyrogenic, low-protein-binding in-line filter.
• Do not administer as IV push or bolus. Do not co-infuse with other drugs.

Treatment Duration

Continue until disease progression, unacceptable toxicity, or up to 24 months in some indications.

Dose Modifications

Dose reductions are not recommended; instead, dose is withheld or permanently discontinued based on the type and severity of adverse reactions. Withhold for most Grade 2–3 irAEs; permanently discontinue for Grade 3–4 pneumonitis, Grade 4 colitis or hepatitis, myocarditis, severe cutaneous reactions, Grade 4 infusion reactions, and other life-threatening events. Discontinue if corticosteroids cannot be reduced to ≤10 mg prednisone equivalent per day within 12 weeks.

Patient Education and Monitoring

• Educate patients on signs and symptoms of irAEs and provide a contact for immediate reporting.
• Before each infusion, check liver function tests, renal function, thyroid function, blood glucose, and complete blood count.
• Monitor for new or worsening symptoms throughout treatment and after discontinuation (irAEs can occur late).

Endocrine Disorders

Endocrinopathies often require lifelong hormone replacement: levothyroxine for hypothyroidism, hydrocortisone or prednisone for adrenal insufficiency, insulin for new-onset type 1 diabetes. Medical-alert identification is recommended.

Pregnancy and Breastfeeding

Pembrolizumab may cause fetal harm. Effective contraception is required during treatment and for 4 months after the last dose. Discontinue breastfeeding during treatment.

Special Populations

• Elderly: no dose adjustment required.
• Renal/hepatic impairment: no dose adjustment for mild to moderate impairment; limited data in severe impairment.
• Pediatric: approved for selected pediatric cancers; growth and development monitoring recommended.

Immunization

Avoid live vaccines during treatment. Inactivated vaccines may be administered, though immune response may be impaired. Where possible, vaccinate before initiating therapy.

Unopened vials: store in a refrigerator at 2–8°C, protected from light, in the original carton. Do not freeze.

After dilution for infusion: use immediately. If needed, the prepared infusion may be stored at room temperature (up to 25°C) for up to 24 hours, or refrigerated (2–8°C) for up to 96 hours from the time of preparation (including infusion time). Do not freeze. Protect from light. Discard partially used vials.

36 months when stored properly. Do not use after the expiry date.

Prescription required. For hospital and oncology-clinic use only. Must be administered by qualified healthcare professionals in settings equipped to manage severe adverse reactions.