What is Pembrolizumab (pembrolizumab)?

What is Pembrolizumab?

Pembrolizumab is a humanized monoclonal IgG4 antibody that blocks the programmed death receptor-1 (PD-1) immune checkpoint, thereby restoring anti-tumor T-cell immune responses. 1

Mechanism of Action

Pembrolizumab binds to the PD-1 receptor on T cells and blocks its interaction with PD-L1 and PD-L2 ligands, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. 1

• The drug has an approximate molecular weight of 149 kDa and is produced in recombinant Chinese hamster ovary (CHO) cells. 1
• When PD-1 ligands bind to PD-1 receptors under normal circumstances, they inhibit T-cell proliferation and cytokine production—a pathway that tumors exploit to evade immune surveillance. 1
• In preclinical syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth. 1

Pharmacokinetics and Dosing

The standard dosing regimen is 200 mg intravenously every 3 weeks or 400 mg every 6 weeks, with treatment continued until disease progression, unacceptable toxicity, or up to 24 months. 2

• Steady-state concentrations are reached by 16 weeks of repeated dosing with systemic accumulation of 2.1-fold. 1
• The terminal half-life is 22 days, with a volume of distribution at steady state of 6.0 L. 1
• Pembrolizumab clearance is approximately 23% lower at steady state compared to after the first dose, though this decrease is not clinically important. 1
• No dose adjustments are required based on age (15-94 years), sex, race, renal impairment (eGFR ≥15 mL/min/1.73 m²), or mild to moderate hepatic impairment. 1
• The impact of severe hepatic impairment (total bilirubin >3 times ULN and any AST) on pembrolizumab pharmacokinetics is unknown. 1

FDA-Approved Indications

Non-Small Cell Lung Cancer (NSCLC)

Pembrolizumab is FDA-approved as first-line monotherapy for metastatic NSCLC with PD-L1 Tumor Proportion Score ≥50% and no EGFR or ALK genomic aberrations. 3, 4

• The KEYNOTE-024 trial demonstrated superior outcomes with pembrolizumab versus chemotherapy: objective response rate 45% vs 28%, progression-free survival HR 0.5 (95% CI 0.37-0.68, P<0.001), and overall survival HR 0.6 (95% CI 0.41-0.89, P=0.005). 3
• Median overall survival was doubled with pembrolizumab (30 months) compared to chemotherapy (14 months). 3
• Pembrolizumab is also approved for subsequent therapy after platinum-based chemotherapy in patients with PD-L1 expression ≥1%. 3, 4

Urothelial Carcinoma

Pembrolizumab received Category 1 recommendation from NCCN as second-line therapy for locally advanced or metastatic urothelial carcinoma that progressed during or after platinum-based chemotherapy. 3, 5

• The phase III KEYNOTE-045 trial showed superior median overall survival of 10.3 months versus 7.4 months with chemotherapy (P=0.002), with significantly fewer grade 3-5 adverse events (15.0% vs 49.4%). 3, 5
• As first-line therapy, pembrolizumab is approved for cisplatin-ineligible patients whose tumors express PD-L1 (combined positive score ≥10). 3, 5
• The KEYNOTE-052 trial demonstrated an overall response rate of 29% with 7% complete responses in cisplatin-ineligible patients. 3, 5

Melanoma

Pembrolizumab is recommended as first-line therapy for unresectable or metastatic melanoma, demonstrating improved response rate, progression-free survival, and overall survival compared with ipilimumab. 6, 7

Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Solid Tumors

Pembrolizumab received FDA approval for unresectable or metastatic MSI-H or dMMR solid tumors that have progressed after prior treatment with no satisfactory alternative options—the first tissue-agnostic cancer indication. 3, 4

• The overall response rate was 39.6% across tumor types, with 78% of responders maintaining response for ≥6 months. 5
• In colorectal cancer specifically, pembrolizumab is a Category 1 first-line recommendation for MSI-H/dMMR tumors. 4, 6
• The KEYNOTE-158 study of noncolorectal MSI-H/dMMR tumors reported an overall response rate of 34.3%, with median progression-free survival of 4.1 months and median overall survival of 23.5 months. 5

Breast Cancer

Pembrolizumab is an option for recurrent or stage IV breast cancer with MSI-H/dMMR mutations that have progressed after prior treatments with no satisfactory alternatives. 3

• Pembrolizumab demonstrated anti-tumor activity in heavily pretreated metastatic breast cancer patients with high tumor mutation burden (≥9 mutations/megabase). 3

Cervical Cancer

Adding pembrolizumab to chemotherapy with or without bevacizumab significantly improved outcomes in persistent, recurrent, or metastatic cervical cancer, with median progression-free survival of 10.4 months versus 8.2 months with placebo (HR 0.62, p<0.001). 5

Biomarker Testing Requirements

PD-L1 expression is the primary biomarker for pembrolizumab response, with companion diagnostic tests FDA-approved for measurement. 3, 4

• In NSCLC, PD-L1 expression levels ≥50% are required for first-line pembrolizumab monotherapy. 3
• Higher PD-L1 expression generally correlates with better response rates (22% in PD-L1 positive vs 4% in PD-L1 negative tumors, p=0.021). 4
• MSI-H/dMMR status is predictive of response across tumor types, with immune-related objective response rates of 40% in dMMR colorectal cancer compared to 0% in MMR-proficient disease. 4
• Tumor mutational burden (TMB) is associated with better response, with higher response rates in TMB-high tumors compared to non-TMB high tumors (29% vs 6%). 4

Safety Profile

Pembrolizumab is generally well-tolerated with grade 3-5 treatment-related adverse events occurring in 9-18% of patients, significantly lower than chemotherapy (15.0% vs 49.4%). 3, 5, 6

Common Adverse Events

• Fatigue, rash, itching, and diarrhea are the most frequent side effects. 7
• Grade 3/4 toxicities are observed in <10% of cases. 8

Immune-Related Adverse Events (irAEs)

Less frequent but more serious immune-related adverse events include pneumonitis, colitis, hepatitis, endocrinopathies (particularly hypothyroidism), nephritis, and skin reactions. 4, 5, 7

• These irAEs may require treatment cessation and are critical to recognize for appropriate management. 8, 9
• Patients 75 years or older treated with pembrolizumab in combination with enfortumab vedotin experienced higher incidence of fatal adverse reactions (7%) compared to younger patients (4%). 1

Clinical Considerations

Response Assessment

Median time to response is approximately 3 months, coinciding with first assessment at 12 weeks. 6

• Late responses can occur more than a year after starting treatment. 6
• Initial partial responses may become complete responses with time. 6
• Complete responses are highly durable, with 88% persisting after median follow-up of 30 months. 6
• Pseudoprogression may occur—initial progressive disease before response—requiring careful clinical assessment before discontinuing therapy. 6

Special Populations

Elderly patients (>65 years) show equivalent efficacy and no difference in toxicity compared to younger patients, making immunotherapy appropriate for elderly patients with metastatic disease. 6, 1

Common Pitfalls

• In patients with MSI-H or dMMR colorectal cancer, initial progressive disease may occur in 29% of cases despite overall survival benefit. 6
• Higher PD-L1 expression is generally associated with better response, but unselected patients may still benefit compared to chemotherapy. 6
• Proper biomarker testing (PD-L1, MSI/MMR status, or TMB) should be performed before initiating pembrolizumab therapy, as response varies based on biomarker status. 4