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Pembrolizumab: Mechanism of Action, Adverse Effects, Contraindications and Dosage

Mechanism of Action of Pembrolizumab

Pembrolizumab is a monoclonal antibody directed against the programmed death-1 (PD-1) receptor. By inhibiting this immune checkpoint, pembrolizumab augments the T-cell–mediated antitumor immune response.

Treatment of Advanced Urothelial Carcinoma with Pembrolizumab

Pembrolizumab is approved as first-line therapy of metastatic urothelial (bladder) carcinoma in combination with Enfortumab vedotin.

• First-line therapy of metastatic urothelial (bladder) carcinoma with Enfortumab vedotin + pembrolizumab (EV+P): the combination EV+P was tested in a phase III trial (EV-302/KEYNOTE-A39) as first-line therapy against cisplatin-containing chemotherapy (Powles et al., 2024) with significantly better results: progression-free survival 12 vs. 6 months, overall survival 32 vs. 16 months, complete remission 29% vs. 13%, overall survival 32 vs. 16 months. Grade 3–5 adverse events were comparable, and the discontinuation rate due to adverse events was 35% vs. 19%.
• Monotherapy of metastatic urothelial (bladder) carcinoma with pembrolizumab as first-line or second-line options: is an option for patients not fit for enfortumab vedotin or platinum-based chemotherapy. In a phase III trial versus second-line chemotherapy, pembrolizumab improved objective response (21% vs. 11%) and overall survival (10 vs. 7 months) (Bellmunt et al., 2017). It received approval for second-line therapy and for first-line therapy in cisplatin-ineligible patients whose tumors express PD-L1 with a combined positive score (CPS) ≥ 10. The CPS (combined positive score) is an immunohistochemical assay that quantifies PD-L1 expression in solid tumors.

Treatment of Advanced Renal Cell Carcinoma with Pembrolizumab

Pembrolizumab is approved for first-line therapy of metastatic renal cell carcinoma in combination with axitinib or lenvatinib (all risk groups). It is also a adjuvant treatment option after nephrectomy for patients at high risk of recurrence.

• First-line therapy of metastatic renal cell carcinoma with pembrolizumab and axitinib: improved progression-free survival, response (complete response 6% vs. 2%, partial response 53% vs. 34%), and overall survival (HR 0.59; 1-year OS 90% vs. 79%) versus sunitinib, independent of IMDC risk category or PD-L1 expression (Rini et al., 2019).
• First-line therapy of metastatic renal cell carcinoma with pembrolizumab and lenvatinib: improved progression-free survival (24 vs. 9 months) and overall survival (HR 0.66) versus sunitinib (Motzer et al., 2021).
• Adjuvant pembrolizumab after nephrectomy: improved disease-free survival (HR 0.72) and overall survival (91% vs. 86% at four years) in patients at high risk of recurrence, including grade 4 tumors, pT3–4, node-positive disease, or after complete metastasectomy (Choueiri et al., 2024).

Pharmacokinetics of Pembrolizumab

Administer by intravenous infusion over 30 minutes. Terminal half-life is approximately 22 days. Clearance occurs via catabolic protein metabolism.

Adverse Effects of Pembrolizumab

Pembrolizumab is associated with immune-mediated adverse events that may occur up to five months after the last dose. Depending on severity, clinicians should hold or discontinue pembrolizumab and initiate corticosteroids (typically methylprednisolone 1–3 mg/kg/day), followed by an appropriate taper. See the section on adverse effects of immune checkpoint inhibition for each organ system.

Contraindications to Pembrolizumab

Loss of clinical benefit or unequivocal disease progression; grade 4 immune-mediated adverse events; persistent grade 2/3 adverse events despite treatment interruption and corticosteroids. Pregnancy and lactation.

Drug Interactions with Pembrolizumab

Systemic corticosteroids and other immunosuppressants may blunt pembrolizumab’s pharmacodynamic activity and should be avoided unless clinically necessary to manage immune-mediated toxicity. Live vaccines are generally not recommended during treatment.

There is a complex interplay between the gut microbiome and checkpoint inhibitor activity. Prior or early exposure to systemic antibiotics has been associated with reduced efficacy in observational studies.

Dosing of Pembrolizumab

As monotherapy or in combination with axitinib: 200 mg every 3 weeks as a 30-minute intravenous infusion. As monotherapy, pembrolizumab can also be dosed at 400 mg every 6 weeks as a 30-minute intravenous infusion.

Monitoring During Therapy with Pembrolizumab

Before each treatment cycle of pembrolizumab, assess for symptoms and laboratory abnormalities. Provide thorough patient education and perform targeted review of systems across all organ systems to ensure prompt diagnostics, treatment pause or discontinuation, and timely steroid initiation when indicated.

• Thorough medical history and physical examination: Inspect skin and oral mucosa; auscultate lungs; perform a focused neurologic examination; measure the blood pressure.
• Laboratory monitoring: Complete blood count with differential; electrolytes; liver function tests and bilirubin; lipase; creatine kinase and troponin; coagulation studies; blood glucose; creatinine; TSH and free T4; LDH; CRP.

References

J. Bellmunt et al., “Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.,” NEJM, vol. 376, no. 11, pp. 1015–1026, 2017, doi: 10.1056/NEJMoa1613683.

T. K. Choueiri et al., “Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.,” NEJM, vol. 390, no. 15, pp. 1359–1371, 2024, doi: 10.1056/NEJMoa2312695.

Brian I. Rini and Elizabeth R. Plimack and Viktor Stus and Keynote 426 Investigators, “Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.,” NEJM, vol. 380, no. 12, pp. 1116–1127, 2019, doi: 10.1056/NEJMoa1816714.

L. Heinzerling, E. N. de Toni, G. Schett, G. Hundorfean, and L. Zimmer “Checkpoint inhibitors - diagnosis and treatment of side effects,” Deutsches Arzteblatt international, vol. 116, no. 8, pp. 119–126, 2019.

R. Motzer et al., “Lenvatinib plus Pembrolizumab or Everolimus for Advanced Renal Cell Carcinoma.,” NEJM, vol. 384, no. 14, pp. 1289–1300, 2021, doi: 10.1056/NEJMoa2035716.

Powles et al., “Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer.,” NEJM, vol. 390, no. 10, pp. 875–888, 2024, doi: 10.1056/NEJMoa2312117.

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