Pembrolizumab: PD 1 Antibody and Oncology

Pembrolizumab (trade name Keytruda) is a humanized monoclonal antibody of the immunoglobulin G4 class directed against the programmed cell death protein 1 (PD 1) receptor on T lymphocytes. It belongs to the group of immune checkpoint inhibitors and has fundamentally changed oncology since its first approval in the USA in 2014 and in Europe in 2015. Pembrolizumab is used in numerous solid and hematologic tumor entities, often in combination with chemotherapy or targeted agents. The list of indications is among the most comprehensive in modern oncology and continues to expand.

The therapy has the potential to achieve long-lasting remissions or even cures in previously difficult-to-treat tumors. At the same time, it is associated with a characteristic spectrum of immune-mediated adverse effects that can affect any organ system. Successful treatment requires structured patient education, early recognition of typical adverse effects, and multidisciplinary care in centers with immunooncology expertise.

Mechanism of Action

Under physiological conditions, the PD 1 receptor on activated T cells inhibits the immune response once it binds to its ligands PD L1 or PD L2. Tumor cells frequently express PD L1 on their surface and exploit this mechanism to evade immune defenses. Pembrolizumab binds with high affinity to PD 1 and prevents interaction with PD L1 and PD L2. The T cell remains activated, recognizes tumor antigens, and can kill tumor cells.

Clinically, tumors with high PD L1 expression, high tumor mutation burden (TMB), or microsatellite instability (MSI H) and mismatch repair deficiency (dMMR) respond particularly well to pembrolizumab. These biomarkers have become integral to treatment decisions and are determined before therapy begins. Pembrolizumab can also be effective in tumors without classical PD L1 expression in certain scenarios, particularly in combination therapy.

The half-life is approximately 22 days. Pembrolizumab is metabolized via the reticuloendothelial system, with no significant metabolism via CYP enzymes or renal elimination. Therefore, classical pharmacokinetic interactions with other medications are minimal.

Indications

• Malignant melanoma in adjuvant and metastatic settings
• Non-small cell lung cancer (NSCLC) with high PD L1 expression as monotherapy or in combination with chemotherapy
• Classical Hodgkin lymphoma following failure of prior therapy lines
• Urothelial carcinoma in first and second line
• Tumors with MSI H or dMMR status independent of tumor origin (so-called agnostic approval)
• Squamous cell carcinomas of the head and neck
• Gastric, esophageal, and colorectal carcinoma in specific constellations
• Triple negative breast cancer in combination therapy
• Renal cell carcinoma in combination with tyrosine kinase inhibitors or other antibodies
• Endometrial, cervical, and hepatocellular carcinoma in defined lines

Indications are continuously expanded through studies. The current prescribing information and recommendations from oncologic guidelines are decisive for prescription.

Dosage and Administration

Standard adult dosage: 200 mg intravenously as a 30-minute infusion every three weeks. Alternatively, 400 mg intravenously every six weeks, which simplifies treatment intervals for patient and clinic.

Pediatrics: for defined indications, 2 mg per kg body weight (maximum 200 mg) every three weeks.

Duration of therapy: in the adjuvant setting typically one year, in the metastatic setting up to a maximum duration of 24 months or until disease progression or unacceptable adverse effects, depending on study and indication.

Administration: exclusively intravenously as slow infusion. Administration occurs in an oncology center or outpatient day clinic with experienced staff and emergency equipment.

Renal and hepatic insufficiency: typically no dose adjustment required because no relevant renal or hepatic elimination occurs. In very advanced hepatic insufficiency, individualized decision-making is necessary.

Therapy interruption or pause: in case of moderate to severe immune-mediated adverse effects, therapy is interrupted and, depending on toxicity and response, either resumed after resolution or permanently discontinued.

Adverse Effects

Pembrolizumab can theoretically affect any organ system because the immune system can develop inflammatory reactions at various sites. The most important immune-mediated adverse effects are:

Endocrine: hypothyroidism (frequent), hyperthyroidism, hypophysitis, adrenal insufficiency, autoimmune diabetes with risk for diabetic ketoacidosis.

Skin: pruritus, maculopapular rash, vitiligo (may correlate with better tumor response in melanoma), severe reactions such as Stevens Johnson syndrome are rare.

Gastrointestinal: diarrhea, colitis, with risk of perforation in severe cases.

Hepatitis: increase in liver transaminases and bilirubin, in severe cases with hepatic insufficiency.

Pneumonitis: cough, dyspnea, new oxygen requirement, typical changes on computed tomography. Immediate clarification and possible glucocorticoid therapy required.

Nephritis: increase in creatinine and new-onset proteinuria.

Neurological: myasthenia, Guillain Barré syndrome, encephalitis, neuropathies, all relatively rare but potentially serious.

Cardiac: myocarditis, a rare but potentially fatal complication, early diagnosis with troponin and MRI.

Hematological: autoimmune cytopenias, thrombocytopenia, anemia.

General: fatigue, fever, nausea, loss of appetite, joint pain.

Early detection is crucial: symptoms often appear weeks to months after therapy initiation and can begin mildly. Patients receive an emergency card and are trained to report new complaints immediately.

Drug Interactions

• Glucocorticoids: indispensable for treating immune-mediated adverse effects, but as concomitant medication at therapy start without clear indication potentially worsens therapeutic response. Studies show that a daily dose exceeding 10 mg prednisolone equivalent at therapy initiation can reduce therapeutic response.
• Other immunosuppressants such as tacrolimus, cyclosporine, methotrexate: theoretically unfavorable before therapy start, individualized assessment required.
• Live vaccines: not recommended during pembrolizumab therapy due to insufficient data.
• Antibiotics in the immediate period before therapy start: some observational studies show reduced response, possibly through alteration of gut microbiota.
• Other immune checkpoint inhibitors such as ipilimumab or nivolumab: combinations are more potent but also significantly increase toxicity. Use only in approved regimens.
• Biologics for autoimmune diseases such as TNF antagonists: caution in active autoimmune disease, individualized treatment planning required.

Special Precautions

Pregnancy: Pembrolizumab is contraindicated in pregnancy because placental passage increases from the second trimester onward and severe fetal damage is possible. Women of childbearing age require reliable contraception during therapy and for at least four months thereafter. Breastfeeding: Breastfeeding during therapy and for at least four months after therapy completion is not recommended.

Preexisting autoimmune diseases: Patients with active autoimmune diseases were excluded from many studies because disease flare is very likely. In clinical practice, careful benefit-risk assessment with the treating rheumatologist or endocrinologist is required.

Before therapy start: detailed history regarding autoimmune diseases and prior radiation, comprehensive laboratory diagnostics (TSH, free T4, cortisol, ACTH, glucose, lipase, liver function tests, creatinine, differential blood count), if necessary lung function and baseline cardiac diagnostics. Training on warning symptoms.

Concomitant therapies: classical chemotherapy, targeted agents, and radiation therapy can be combined, which often increases efficacy. Treatment plan and sequence must be coordinated interdisciplinarily.

Emergency plan: Patients receive an emergency card so that treating emergency physicians are aware of ongoing immunotherapy and consider immune-mediated adverse effects early in unclear complaints.

Therapy response assessment: some patients show very long remissions, others do not respond initially. Response assessment follows iRECIST criteria. Pseudoprogression with initially seemingly growing tumor and later response is possible but rare.

You May Also Be Interested In

• Rituximab, Anti CD20 antibody in lymphomas and autoimmune diseases
• Dupilumab, Anti IL 4 and IL 13 in atopic dermatitis
• Methotrexate, classical cytostatic and immunosuppressive agent
• Cisplatin, platinum compound in many combination therapies
• Oxaliplatin, platinum compound in gastrointestinal oncology

Frequently Asked Questions

Sources

• EMA, Keytruda (Pembrolizumab) EPAR
• Gelbe Liste, Pembrolizumab Active Substance Profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Oncologic Guidelines
• ESMO, European Society for Medical Oncology