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

Pembrolizumab: Recommended Use and Dosage for Cancer Treatment

Pembrolizumab is FDA-approved for multiple cancer types with specific dosing regimens: 200 mg IV every 3 weeks or 400 mg IV every 6 weeks until disease progression or unacceptable toxicity, with treatment selection guided by cancer type, biomarker status, and line of therapy. 1

Mechanism of Action

Pembrolizumab is a humanized monoclonal IgG4 antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response and restoring anti-tumor T-cell activity. 1

Standard Dosing Regimens

The FDA-approved dosing is 200 mg IV every 3 weeks or 400 mg IV every 6 weeks, with no clinically significant differences in efficacy or safety between these schedules. 1

• For pediatric patients (10 months to 17 years), weight-based dosing at 2 mg/kg every 3 weeks achieves comparable drug concentrations to adults. 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

Non-Small Cell Lung Cancer (NSCLC)

First-Line Treatment

For metastatic NSCLC with PD-L1 Tumor Proportion Score (TPS) ≥50% and no EGFR or ALK genomic aberrations, pembrolizumab monotherapy is the preferred first-line treatment (NCCN Category 1). 2, 3, 4

• In KEYNOTE-024, pembrolizumab 200 mg every 3 weeks demonstrated superior overall survival (OS) compared to chemotherapy (HR 0.60; 95% CI: 0.41-0.89; p=0.005) and progression-free survival (PFS) (HR 0.50; 95% CI: 0.37-0.68; p<0.001). 4
• PD-L1 testing using an FDA-approved companion diagnostic is mandatory before initiating first-line pembrolizumab. 2, 3

Second-Line Treatment

For metastatic NSCLC with PD-L1 expression ≥1% that has progressed after platinum-based chemotherapy, pembrolizumab is recommended as subsequent therapy (NCCN Category 1). 2, 3

• In KEYNOTE-010, pembrolizumab at both 2 mg/kg and 10 mg/kg every 3 weeks demonstrated superior OS compared to docetaxel: 2 mg/kg arm (median OS 10.4 months; HR 0.71; 95% CI: 0.58-0.88; p=0.0008) and 10 mg/kg arm (median OS 12.7 months; HR 0.61; 95% CI: 0.49-0.75; p<0.0001) versus docetaxel (median OS 8.5 months). 2
• For patients with PD-L1 expression ≥50%, the survival benefit was even more pronounced: 2 mg/kg arm (14.9 vs 8.2 months; HR 0.54; p=0.0002) and 10 mg/kg arm (17.3 vs 8.2 months; HR 0.50; p<0.0001). 2
• Patients with EGFR or ALK genomic aberrations should have disease progression on FDA-approved targeted therapy before receiving pembrolizumab. 4

Safety Profile in NSCLC

Grade 3-5 treatment-related adverse events occurred in 13% of patients receiving pembrolizumab 2 mg/kg and 16% receiving 10 mg/kg, compared to 35% with docetaxel. 2, 3

Melanoma

First-Line Treatment

Pembrolizumab is recommended as first-line therapy for unresectable or metastatic melanoma (NCCN Category 2A preferred). 2, 3, 5

• In KEYNOTE-006, pembrolizumab (10 mg/kg every 2 or 3 weeks) demonstrated superior response rate (37% and 36% vs 13%), 2-year PFS (31% and 28% vs 14%), and 2-year OS (55% and 55% vs 43%) compared to ipilimumab. 2
• Long-term follow-up (median 33.9 months) confirmed durable responses with pembrolizumab providing sustained improvement in PFS and OS compared to ipilimumab monotherapy. 2
• PD-L1 testing is not required for melanoma treatment decisions. 5

Neoadjuvant Setting for Resectable Stage III Melanoma

Pembrolizumab 200 mg every 3 weeks for 3 doses as neoadjuvant therapy followed by surgery and adjuvant pembrolizumab (15 additional doses) is preferred over adjuvant-only treatment (NCCN Category 2A). 2

• In SWOG 1801, neoadjuvant pembrolizumab followed by surgery and adjuvant therapy achieved 72% event-free survival at 2 years compared to 49% with adjuvant-only treatment (median follow-up 14.7 months). 2
• Grade ≥3 treatment-related adverse events occurred in 12% of neoadjuvant patients versus 14% in adjuvant-only patients. 2
• This approach is recommended for resectable stage III disease with clinically positive nodes, satellite/in-transit metastases, or nodal recurrence. 2

Safety Profile in Melanoma

Treatment-related adverse events of grade 3-4 severity occurred in approximately 17% of patients, with the most common immune-mediated reactions being hypothyroidism, pneumonitis, and hyperthyroidism. 5

Cervical Cancer

For persistent, recurrent, or metastatic cervical cancer, pembrolizumab 200 mg every 3 weeks is administered in combination with chemotherapy (paclitaxel plus cisplatin or carboplatin) with or without bevacizumab. 6

• In KEYNOTE-826, adding pembrolizumab to chemotherapy ± bevacizumab improved OS across all subgroups in patients with PD-L1 CPS ≥1 (HR 0.62-0.67 depending on bevacizumab use). 6
• Benefits were observed regardless of bevacizumab use, platinum choice (carboplatin vs cisplatin), prior chemoradiotherapy exposure, or histologic type (squamous vs nonsquamous). 6

Head and Neck Squamous Cell Carcinoma

First-Line Treatment

For metastatic head and neck squamous cell carcinoma with PD-L1 CPS ≥1, pembrolizumab combined with platinum and 5-FU is recommended; for CPS ≥20, pembrolizumab monotherapy is an alternative for patients not requiring rapid tumor reduction. 7

• For PD-L1 CPS ≥20, pembrolizumab monotherapy achieved median OS of 14.9 months versus 10.7 months with cetuximab-chemotherapy (HR 0.61; p=0.0007). 7
• For PD-L1 CPS 1-19, pembrolizumab plus platinum plus 5-FU achieved median OS of 12.3 months versus 10.3 months with cetuximab-chemotherapy (HR 0.78; p=0.0086). 7

Second-Line Treatment

For disease progression within 6 months of platinum-based chemotherapy, pembrolizumab monotherapy is recommended regardless of PD-L1 status. 7

• Pembrolizumab demonstrated median OS of 8.4 months in KEYNOTE-040 with significantly lower grade 3-4 adverse events (9%) compared to chemotherapy (35.1%). 7

Biomarker Testing Requirements

PD-L1 Testing

PD-L1 testing using FDA-approved companion diagnostics is required for NSCLC and recommended for head and neck cancer to guide pembrolizumab use. 2, 3, 7

• For NSCLC, TPS ≥50% is required for first-line monotherapy; TPS ≥1% is required for second-line therapy. 2, 3
• For head and neck cancer, Combined Positive Score (CPS) ≥1 guides combination therapy decisions; CPS ≥20 supports monotherapy. 7
• PD-L1 expression is continuously variable and dynamic; cutoff values are artificial, and patients with levels just below and above thresholds likely have similar responses. 2

Molecular Testing Priority

In NSCLC, EGFR mutation, ALK rearrangement, and ROS1 rearrangement testing should be completed before PD-L1 testing when feasible. 2

• If biopsy risk is high and molecular testing is not feasible, PD-L1 testing alone is appropriate. 2
• Blood assays for EGFR and ALK are available but less sensitive than tissue assays. 2

Treatment Duration and Response Assessment

Pembrolizumab is administered until disease progression or unacceptable toxicity, with no prespecified maximum duration in most indications. 2, 3, 1

• Median time to response is approximately 3 months, coinciding with first radiographic assessment at 12 weeks. 3
• Late responses can occur more than one year after starting treatment. 3
• Initial partial responses may become complete responses with continued treatment. 3
• Complete responses are highly durable, with 88% persisting after median follow-up of 30 months. 3

Pseudoprogression Consideration

Initial progressive disease may occur before response (pseudoprogression), requiring careful clinical assessment before discontinuing therapy. 3

• In MSI-H/dMMR colorectal cancer, initial progressive disease occurred in 29% of patients despite overall survival benefit. 3
• Treatment beyond progression may be appropriate in patients with clinical benefit and acceptable toxicity. 2

Special Populations

Elderly Patients

No dose adjustments are required for elderly patients, with equivalent efficacy and no difference in toxicity compared to younger patients. 3, 1

• Patients ≥75 years treated with pembrolizumab plus enfortumab vedotin experienced higher incidence of fatal adverse reactions (7%) compared to younger patients (4%). 1

Renal and Hepatic Impairment

No dose adjustments are required for patients with 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 (total bilirubin >3 times ULN and any AST) on pembrolizumab pharmacokinetics is unknown. 1

Brain Metastases

Pembrolizumab demonstrates activity in untreated brain metastases from melanoma and NSCLC with acceptable safety profile. 8

• In a phase 2 trial, brain metastasis response was achieved in 22% of melanoma patients and 33% of NSCLC patients with PD-L1-positive tumors. 8
• Responses were durable, with most patients showing ongoing response at data analysis. 8
• Patients must have at least one untreated or progressive brain metastasis 5-20 mm in diameter without neurological symptoms or need for corticosteroids. 8

Critical Safety Monitoring

Grade 3-5 treatment-related adverse events occur in 13-17% of patients across cancer types, significantly lower than chemotherapy (35%). 2, 3

• Common immune-mediated adverse reactions include hypothyroidism, pneumonitis, and hyperthyroidism. 5
• Treatment-related deaths are rare, occurring in approximately 1% of patients. 2
• New adverse events can develop throughout the treatment period, not just during initial cycles. 2

Common Pitfalls to Avoid

Do not use pembrolizumab in NSCLC patients with untreated EGFR mutations or ALK rearrangements; these patients should receive targeted therapy first. 2, 4

Do not assume PD-L1 negativity excludes benefit in all cancer types; melanoma does not require PD-L1 testing, and second-line head and neck cancer benefits regardless of PD-L1 status. 7, 5

Do not discontinue pembrolizumab at first radiographic progression without clinical correlation; pseudoprogression can occur and treatment beyond progression may be appropriate in select patients. 2, 3