What is the recommended use and dosage of Pembrolizumab (pembrolizumab) in cancer treatment?

Pembrolizumab: Recommended Use and Dosing in Cancer Treatment

Pembrolizumab is a PD-1 blocking antibody administered at 200 mg intravenously every 3 weeks until disease progression, unacceptable toxicity, or up to 24 months of treatment, with FDA approval across multiple cancer types including melanoma, non-small cell lung cancer, head and neck cancer, and urothelial carcinoma. 1

Mechanism of Action

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

Standard Dosing Regimen

The FDA-approved dose is 200 mg intravenously every 3 weeks, which has replaced the previous weight-based dosing of 2 mg/kg every 3 weeks. 1 This fixed-dose regimen achieves equivalent pharmacokinetic exposure and clinical outcomes compared to weight-based dosing. 1

• 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. 1
• Treatment continues until disease progression, unacceptable toxicity, or up to 24 months (35 cycles). 1, 2

Cancer-Specific Indications and Dosing

Melanoma

For resectable stage IIIB-IV cutaneous melanoma, neoadjuvant pembrolizumab (200 mg every 3 weeks for maximum 3 courses) followed by resection and adjuvant pembrolizumab (200 mg every 3 weeks for maximum 15 courses) should be offered. 3, 4 This approach demonstrated 72% 2-year event-free survival versus 49% with adjuvant therapy alone, with only 12% grade ≥3 adverse events. 4

For resected stage IIB-IIC melanoma, adjuvant pembrolizumab should be offered for 52 weeks. 3

For resected stage IIIA-D BRAF wild-type disease, adjuvant pembrolizumab for 52 weeks is recommended. 3

For unresectable or metastatic melanoma, pembrolizumab is recommended as first-line therapy. 3, 5 In the KEYNOTE-006 trial, pembrolizumab demonstrated superior response rate (36-37% vs 13%), progression-free survival (31-28% 2-year rate vs 14%), and overall survival (55% 2-year rate vs 43%) compared to ipilimumab. 3

Non-Small Cell Lung Cancer (NSCLC)

For first-line treatment of metastatic NSCLC with PD-L1 Tumor Proportion Score ≥50% and no EGFR or ALK genomic aberrations, pembrolizumab 200 mg every 3 weeks is recommended. 5, 6 The KEYNOTE-024 trial demonstrated significant improvements in overall survival (HR 0.60, p=0.005) and progression-free survival (HR 0.50, p<0.001) compared to chemotherapy. 6

For second-line treatment after platinum-based chemotherapy in patients with PD-L1 expression ≥1%, pembrolizumab is recommended. 3, 5 The KEYNOTE-010 trial showed median overall survival of 10.4-12.7 months with pembrolizumab versus 8.5 months with docetaxel (HR 0.61-0.71, p<0.001). 3

• For patients with PD-L1 ≥50%, overall survival was 14.9-17.3 months with pembrolizumab versus 8.2 months with docetaxel (HR 0.50-0.54, p<0.001). 3
• Grade 3-5 treatment-related adverse events occurred in 13-16% with pembrolizumab versus 35% with docetaxel. 3, 5

Head and Neck Squamous Cell Carcinoma

For recurrent or metastatic squamous cell head and neck cancer that has progressed on or after platinum-based chemotherapy, pembrolizumab 200 mg every 3 weeks is recommended. 3 This is a category 2A recommendation based on nonrandomized trials showing 18% overall response rate with durable responses and only 9% grade 3/4 toxicities. 3

• PD-L1 expression (≥1%) was associated with better response rates (22% vs 4%, p=0.021). 3

Cutaneous Squamous Cell Carcinoma

For locally advanced or recurrent/metastatic cutaneous squamous cell carcinoma, pembrolizumab 200 mg every 3 weeks for up to 35 cycles is recommended. 7 The KEYNOTE-629 trial demonstrated objective response rates of 50% in locally advanced disease and 35.2% in recurrent/metastatic disease, with median duration of response not reached. 7

Biomarker Testing Requirements

PD-L1 testing should be performed at diagnosis to inform pembrolizumab use in NSCLC. 3, 5 The FDA has approved a companion diagnostic biomarker test for assessing PD-L1 expression. 3

For colorectal cancer, microsatellite instability (MSI) or mismatch repair (MMR) status should be determined before initiating therapy. 5

Important Caveats About PD-L1 Testing

• PD-L1 expression is continuously variable and dynamic; cutoff values are artificial. 3
• Patients with PD-L1 levels just below and above 50% will likely have similar responses. 3
• Unique anti-PD-L1 IHC assays exist for different immune checkpoint inhibitors, and definitions of positive results vary by assay. 3
• Higher PD-L1 expression is generally associated with better response, but unselected patients may still benefit compared to chemotherapy. 5

Response Assessment and Duration of Therapy

Median time to response is approximately 3 months, coinciding with first assessment at 12 weeks. 5

Late responses can occur more than a year after starting treatment, and initial partial responses may become complete responses with time. 5

Complete responses are highly durable, with 88% persisting after median follow-up of 30 months. 5

Pseudoprogression Consideration

Progressive disease may be observed initially before response (pseudoprogression), requiring careful clinical assessment before discontinuing therapy. 5 In MSI-H or dMMR colorectal cancer, initial progressive disease occurred in 29% of cases despite overall survival benefit. 5

Treatment Duration Considerations

Although FDA labeling indicates treatment until disease progression or unacceptable toxicity, the KEYNOTE-002 trial administered pembrolizumab for a maximum of 24 months. 3 Discontinuation rates of 45-77% have been observed in trials with median follow-up <2 years. 3 Further studies are needed to determine whether treatment beyond 2 years is necessary to maintain disease control. 3

Safety Profile

Grade 3-5 treatment-related adverse events occur in approximately 13-16% of patients receiving pembrolizumab monotherapy. 5 This compares favorably to 35% with chemotherapy. 5

The most common immune-mediated adverse reactions (≥2%) are hypothyroidism, pneumonitis, and hyperthyroidism. 8

Treatment-related adverse events of any grade occur in 63-73% of patients, but most are manageable. 3, 2

Special Populations

Elderly Patients

No overall differences in safety or effectiveness are observed between elderly patients (≥65 years) and younger patients. 1, 5 Immunotherapy should be considered for elderly patients with metastatic NSCLC. 5

However, patients ≥75 years treated with pembrolizumab in combination with enfortumab vedotin experienced higher incidence of fatal adverse reactions (7% vs 4% in younger patients). 1

Pediatric Patients

Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (10 months to 17 years) are comparable to those of adults at the same dose. 1

Renal and Hepatic Impairment

No dose adjustment is required for renal impairment (eGFR ≥15 mL/min/1.73 m²) or mild to moderate hepatic impairment (total bilirubin ≤3 times ULN and any AST). 1 The impact of severe hepatic impairment on pembrolizumab pharmacokinetics is unknown. 1

Common Pitfalls to Avoid

• Do not delay treatment waiting for "perfect" PD-L1 testing results. If biopsy risk is high and genetic alteration testing is not feasible, it is appropriate to test for PD-L1 expression levels. 3
• Do not automatically discontinue therapy at first sign of progression. Pseudoprogression can occur, requiring careful clinical assessment. 5
• Do not assume lack of early response means treatment failure. Late responses beyond one year have been documented. 5
• Do not use pembrolizumab in NSCLC patients with EGFR or ALK genomic aberrations without prior progression on targeted therapy. 6