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

Keytruda (Pembrolizumab): Recommended Use and Dosage in Cancer Treatment

Pembrolizumab is a PD-1 checkpoint inhibitor with FDA approval across multiple cancer types, with dosing standardized at 200 mg IV every 3 weeks or 400 mg IV every 6 weeks for most adult indications, administered until disease progression, unacceptable toxicity, or up to 24 months. 1

Primary Indications and Patient Selection

Non-Small Cell Lung Cancer (NSCLC)

First-Line Therapy:

• Pembrolizumab monotherapy is recommended (Category 1) for metastatic NSCLC with PD-L1 Tumor Proportion Score (TPS) ≥50% and no EGFR mutations, ALK rearrangements, or ROS1 rearrangements 2, 3
• PD-L1 testing via FDA-approved companion diagnostic is mandatory before initiating first-line treatment 2
• Patients demonstrated superior overall survival (OS) compared to chemotherapy (44.8% vs 27.8% at 1 year) with fewer severe adverse events (26.6% vs 53.3%) 2

Second-Line Therapy:

• Recommended (Category 1) for patients with metastatic nonsquamous or squamous NSCLC with PD-L1 expression ≥1% who progressed after platinum-based chemotherapy 2, 3
• In KEYNOTE-010 trial, pembrolizumab demonstrated superior OS compared to docetaxel: 10.4 months (2 mg/kg dose) and 12.7 months (10 mg/kg dose) versus 8.5 months (HR 0.71 and 0.61 respectively, both P<0.001) 2
• For patients with PD-L1 ≥50%, OS benefit was even greater: 14.9-17.3 months versus 8.2 months with docetaxel 2

Neoadjuvant/Adjuvant Setting:

• For resectable NSCLC: 200 mg every 3 weeks for 12 weeks neoadjuvant with chemotherapy, followed by 39 weeks adjuvant monotherapy after surgery 1

Melanoma

Unresectable or Metastatic Disease:

• Pembrolizumab is recommended as first-line therapy for unresectable or metastatic melanoma 2, 3
• Demonstrated superior efficacy versus ipilimumab in KEYNOTE-006: improved OS (HR 0.63-0.69), progression-free survival, and response rates 2, 4
• Response rate of 45% in patients with PD-L1 ≥50%, with median duration of response 12.5 months 2

Adjuvant Therapy:

• Recommended for resected stage IIB-IIC melanoma: 200 mg every 3 weeks for up to 52 weeks 2
• For resected stage IIIA-D BRAF wild-type disease: pembrolizumab 200 mg every 3 weeks for 52 weeks 2

Neoadjuvant Setting:

• For clinical stage IIIB-IV resectable melanoma: maximum 3 courses of 200 mg every 3 weeks neoadjuvant, followed by resection and up to 15 courses adjuvant 2

Head and Neck Squamous Cell Carcinoma (HNSCC)

• Pembrolizumab is recommended (Category 2A) for recurrent or metastatic HNSCC with disease progression on or after platinum-based chemotherapy 2, 5
• KEYNOTE-012 demonstrated 18% overall response rate with durable responses (median follow-up 9 months) 2
• Response rate significantly higher in PD-L1-positive patients (≥1% expression): 22% versus 4% in PD-L1-negative (P=0.021) 2
• Well-tolerated with only 9% grade 3/4 toxicities 2

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

Colorectal Cancer:

• Recommended as first-line therapy for unresectable or metastatic MSI-H/dMMR colorectal cancer 3
• MSI or MMR status must be determined before initiating therapy 3
• NOT recommended for metastatic colorectal cancer with high tumor mutational burden (≥10 mutations/megabase) if mismatch repair is proficient 3

Other Solid Tumors:

• FDA-approved for MSI-H/dMMR solid tumors after progression on prior treatment 1
• Confirmation of MSI-H/dMMR status by FDA-approved test is recommended when feasible 1
• If confirmatory testing unavailable, TMB ≥10 mut/Mb by FDA-approved test may be used for patient selection 1

Additional Indications

Gastric/Gastroesophageal Junction Adenocarcinoma:

• HER2-positive: Combination with trastuzumab and chemotherapy for CPS ≥1 1
• HER2-negative: Combination with chemotherapy 1

Triple-Negative Breast Cancer (TNBC):

• High-risk early-stage: Neoadjuvant with chemotherapy for 24 weeks, followed by adjuvant monotherapy for 27 weeks 1
• Locally recurrent unresectable or metastatic: Combination with chemotherapy for CPS ≥10 1

Renal Cell Carcinoma:

• Combination with axitinib 5 mg orally twice daily or lenvatinib 20 mg orally once daily 1

Cervical Cancer:

• Persistent, recurrent, or metastatic disease with positive PD-L1 expression, in combination with chemotherapy with or without bevacizumab 1

Endometrial Carcinoma:

• pMMR/not MSI-H: Combination with lenvatinib 20 mg orally once daily 1
• dMMR/MSI-H: Combination with chemotherapy or lenvatinib 1

Other Approved Indications:

• High-risk BCG-unresponsive non-muscle invasive bladder cancer (NMIBC): 200 mg every 3 weeks for up to 24 months 1
• Cutaneous squamous cell carcinoma (recurrent/metastatic): 200 mg every 3 weeks demonstrated 34.3% objective response rate 6

Dosing and Administration

Standard Adult Dosing

• 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks 2, 1
• Administered as 30-minute IV infusion 1
• Continue until disease progression, unacceptable toxicity, or up to 24 months for most indications 1

Pediatric Dosing

• 2 mg/kg every 3 weeks (maximum 200 mg) for classical Hodgkin lymphoma, primary mediastinal B-cell lymphoma, MSI-H/dMMR cancers, Merkel cell carcinoma, or TMB-H cancers 1
• For adjuvant melanoma (≥12 years): 2 mg/kg every 3 weeks (maximum 200 mg) for up to 12 months 1

Combination Therapy Considerations

• When combined with chemotherapy: administer pembrolizumab PRIOR to chemotherapy on the same day 1
• When combined with enfortumab vedotin: administer pembrolizumab AFTER enfortumab vedotin 1
• When combined with trastuzumab: administer pembrolizumab prior to trastuzumab and chemotherapy 1

Biomarker Testing Requirements

PD-L1 Testing

• Mandatory for NSCLC first-line and second-line therapy decisions 2, 3
• Required for HER2-positive gastric cancer (CPS ≥1), cervical cancer, and TNBC combination therapy 1
• FDA-approved companion diagnostic test required for patient selection 2
• Important caveat: PD-L1 expression is continuously variable and dynamic; cutoff values are artificial, and patients just below/above thresholds likely have similar responses 2

MSI-H/dMMR Testing

• Required for colorectal cancer and other solid tumors when considering pembrolizumab monotherapy 3, 1
• Confirmation by FDA-approved test recommended when feasible 1
• For high-grade gliomas: test primary tumor specimens obtained BEFORE temozolomide initiation, as subclonal dMMR mutations may arise during temozolomide therapy 1

Genetic Alteration Testing Priority

• For NSCLC: establish EGFR, ALK, and ROS1 status BEFORE PD-L1 testing 2
• Blood assays available for EGFR/ALK but less sensitive than tissue assays 2
• If biopsy risk is high and genetic testing not feasible, PD-L1 testing is appropriate 2

Response Assessment and Monitoring

Expected Response Patterns

• Median time to response: approximately 3 months (coinciding with first assessment at 12 weeks) 3
• Late responses can occur more than 1 year after starting treatment 3
• Initial partial responses may evolve to complete responses over time 3
• Complete responses are highly durable: 88% persist after median follow-up of 30 months 3

Critical Pitfall: Pseudoprogression

• Progressive disease may be observed initially before response (pseudoprogression) 3
• Requires careful clinical assessment before discontinuing therapy 3
• In MSI-H/dMMR colorectal cancer, initial progressive disease occurs in 29% despite overall survival benefit 3

Safety Profile and Dose Modifications

Common Adverse Events

• Grade 3-5 treatment-related adverse events: 13-16% of patients 2, 3
• Significantly fewer severe adverse events compared to chemotherapy: 13% versus 35% 3
• Most common: pruritus (14.3%), asthenia (13.3%), fatigue (12.4%) 6
• Less than 10% of patients experience serious toxicity grade ≥3 2

Immune-Related Adverse Events

• Pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus 5, 4
• Thyroid disorders (hypothyroidism, hyperthyroidism): occur in 5-10% of patients 7
• Skin toxicity, myositis 5, 4

Dose Modification Guidelines

• No dose reduction recommended 1
• Withhold for severe (Grade 3) immune-mediated adverse reactions 1
• Permanently discontinue for:
  • Life-threatening (Grade 4) immune-mediated reactions 1
  • Recurrent severe (Grade 3) reactions requiring systemic immunosuppression 1
  • Inability to reduce corticosteroid to ≤10 mg prednisone equivalent daily within 12 weeks 1

Thyroid Dysfunction Management

• Monitor TSH and free T4 every 4-6 weeks during therapy 7
• Normal TSH does not rule out pembrolizumab-induced thyroiditis 7
• Pembrolizumab can generally be continued during management of thyroid dysfunction 7
• Treat hyperthyroidism with beta-blockers for symptoms; hypothyroidism with thyroid hormone replacement (usually long-lasting) 7

Special Populations

Elderly Patients

• Elderly patients (>65 years) show equivalent efficacy and no difference in toxicity compared to younger patients 3
• Immunotherapy should be considered for elderly patients with metastatic NSCLC 3

Duration of Therapy Considerations

• Treatment may be prolonged if disease is controlled and toxicity is acceptable 3
• Most trials allowed treatment up to 24 months 2, 1
• KEYNOTE-002 limited pembrolizumab to maximum 24 months 2
• Discontinuation rates of 45-77% observed in anti-PD-1 trials with median follow-up <2 years 2

Key Clinical Pearls

Biomarker Interpretation

• Higher PD-L1 expression generally associated with better response, but unselected patients may still benefit compared to chemotherapy 3
• PD-L1 expression levels just below and above 50% likely have similar responses 2
• Unique anti-PD-L1 IHC assays exist for different checkpoint inhibitors; definition of positive result varies by assay 2

Treatment Sequencing

• For patients progressing after first-line pembrolizumab: platinum-based chemotherapy recommended as second-line 3
• Patients who experience disease progression or unacceptable toxicity with neoadjuvant pembrolizumab should not receive adjuvant single-agent pembrolizumab 1

Comparative Efficacy

• Pembrolizumab demonstrated fewer treatment-related deaths compared to docetaxel (6 versus 5 in KEYNOTE-010) 2
• Superior to ipilimumab in treatment-naive melanoma patients with improved OS, PFS, and response rates 2, 4