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 must be performed before treatment initiation using an FDA-approved companion diagnostic test. 2, 3
• 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% grade 3-5). 2

Second-Line Therapy:

• Pembrolizumab is recommended (Category 1) for patients with metastatic nonsquamous or squamous NSCLC with PD-L1 expression ≥1% who have progressed after platinum-based chemotherapy. 2, 3
• In the 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 for docetaxel (HR 0.71 and 0.61, respectively; both P<0.001). 2
• For patients with PD-L1 TPS ≥50%, OS benefit was even greater: 14.9-17.3 months versus 8.2 months with docetaxel. 2

Melanoma

Unresectable or Metastatic Disease:

• Pembrolizumab is recommended as first-line therapy for unresectable or metastatic melanoma, demonstrating improved response rate, progression-free survival, and overall survival compared to ipilimumab. 2, 3
• In KEYNOTE-006, pembrolizumab showed superior OS compared to ipilimumab in treatment-naïve patients (HR 0.63-0.69; P<0.004). 2, 4
• Response rates were 33-34% with median duration of response of 12.5 months. 2

Adjuvant Therapy:

• Pembrolizumab 200 mg every 3 weeks for 52 weeks is recommended for resected stage IIB-IIC and stage IIIA-D melanoma. 2
• For stage IIIA-D BRAF wild-type disease, pembrolizumab and nivolumab are equally recommended options. 2

Neoadjuvant Therapy:

• Pembrolizumab should be offered for clinical stage IIIB-IV resectable melanoma: 3 doses neoadjuvant (200 mg every 3 weeks) followed by resection, then 15 doses adjuvant (200 mg every 3 weeks). 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
• Objective response rate was 18% with durable responses (median follow-up 9 months). 2
• PD-L1 expression ≥1% was associated with significantly higher response rates (22% vs 4%; P=0.021). 2
• Pembrolizumab demonstrated 59% OS rate at 6 months with only 9% grade 3/4 toxicities. 2

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

• Pembrolizumab is recommended as first-line therapy for unresectable or metastatic MSI-H or dMMR colorectal cancer. 3, 1
• MSI or MMR status must be determined before initiating therapy. 3, 1
• For non-colorectal MSI-H/dMMR solid tumors, confirmation by FDA-approved test is recommended; if unavailable, TMB ≥10 mutations/megabase may be used for patient selection. 1

Other Approved Indications

Renal Cell Carcinoma:

• Pembrolizumab 200 mg every 3 weeks in combination with axitinib 5 mg orally twice daily or lenvatinib 20 mg orally once daily until disease progression or up to 24 months. 1

Endometrial Carcinoma:

• For proficient MMR (pMMR)/not MSI-H disease: pembrolizumab in combination with lenvatinib 20 mg orally once daily. 1
• For dMMR/MSI-H disease: pembrolizumab with or without chemotherapy. 1

Triple-Negative Breast Cancer (TNBC):

• High-risk early-stage: neoadjuvant pembrolizumab with chemotherapy for 24 weeks, followed by adjuvant pembrolizumab for 27 weeks. 1
• Locally recurrent unresectable or metastatic: pembrolizumab with chemotherapy for PD-L1-positive tumors. 1

Dosing Specifications

Standard Adult Dosing

The FDA-approved dosing is 200 mg IV every 3 weeks OR 400 mg IV every 6 weeks, administered as a 30-minute infusion. 1

Pediatric Dosing

• For patients with cHL, PMBCL, MSI-H/dMMR cancer, MCC, or TMB-H cancer: 2 mg/kg every 3 weeks (maximum 200 mg). 1
• For adjuvant melanoma in patients ≥12 years: 2 mg/kg every 3 weeks (maximum 200 mg). 1

Duration of Therapy

• Continue until disease progression, unacceptable toxicity, or up to 24 months for most indications. 1
• Adjuvant melanoma: 12 months. 2, 1
• High-risk BCG-unresponsive NMIBC: up to 24 months. 1

Response Assessment and Monitoring

Timing of Response

• Median time to response is approximately 3 months, coinciding with first assessment at 12 weeks. 3
• Late responses can occur more than one year after starting treatment. 3
• Initial partial responses may evolve into complete responses over time. 3

Pseudoprogression Considerations

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

Durability of Response

• Complete responses are highly durable, with 88% persisting after median follow-up of 30 months. 3
• In NSCLC, median duration of response was 12.5 months. 2

Safety Profile and Dose Modifications

Common Adverse Events

• Grade 3-5 treatment-related adverse events occur in approximately 13-16% of patients, significantly lower than chemotherapy (35%). 2
• Most common adverse events: pruritus (14.3%), asthenia (13.3%), fatigue (12.4%). 5

Immune-Related Adverse Events

Clinically significant immune-mediated reactions include: 1, 6

• Pneumonitis
• Colitis
• Hepatitis
• Thyroid disorders (hypothyroidism, hyperthyroidism)
• Adrenal insufficiency
• Diabetes mellitus
• Skin toxicity
• Myositis

Thyroid Dysfunction Management

• Thyroid dysfunction occurs in approximately 5-10% of patients receiving pembrolizumab. 7
• Monitor TSH and free T4 every 4-6 weeks during therapy. 7
• Pembrolizumab can generally be continued during management of thyroid dysfunction with appropriate hormone replacement or beta-blockers for symptoms. 7
• Normal TSH does not rule out pembrolizumab-induced thyroiditis initially. 7

Dose Modification Guidelines

• No dose reduction is recommended; withhold for severe (Grade 3) immune-mediated adverse reactions. 1
• Permanently discontinue for life-threatening (Grade 4) reactions, recurrent severe (Grade 3) reactions requiring systemic immunosuppression, or inability to reduce corticosteroids to ≤10 mg prednisone equivalent daily within 12 weeks. 1

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

Critical Clinical Considerations

Biomarker Testing Nuances

• PD-L1 expression is continuously variable and dynamic; cutoff values are artificial, and patients just below and above 50% likely have similar responses. 2
• Higher PD-L1 expression is generally associated with better response, but unselected patients may still benefit compared to chemotherapy. 3
• Each immune checkpoint inhibitor has unique PD-L1 IHC assays with different definitions of positivity. 2

Genetic Testing Priority

• Every effort must be made to establish EGFR, ALK, and ROS1 status before initiating pembrolizumab in NSCLC. 2
• Blood assays for EGFR and ALK are available but less sensitive than tissue assays. 2
• PD-L1 testing should only proceed if genetic alteration testing is not feasible due to high biopsy risk. 2

Combination Therapy Timing

• When pembrolizumab is given with chemotherapy, administer pembrolizumab prior to chemotherapy on the same day. 1
• When given with enfortumab vedotin, administer pembrolizumab after enfortumab vedotin on the same day. 1

Treatment Beyond Progression

• Treatment may be prolonged if disease is controlled and toxicity is acceptable. 3
• Studies allowed treatment beyond progression in patients with clinical benefit without substantial adverse events. 2