How are Tumor Proportion Score (TPS) and Combined Positive Score (CPS) for Programmed death‑ligand 1 (PD‑L1) used to decide pembrolizumab therapy in advanced non‑small‑cell lung cancer (NSCLC) and head‑and‑neck squamous cell carcinoma (HNSCC)?

PD-L1 Scoring Methods: TPS and CPS in Pembrolizumab Therapy

Direct Answer

For advanced NSCLC, use Tumor Proportion Score (TPS) ≥1% to guide pembrolizumab monotherapy decisions, while for head and neck squamous cell carcinoma (HNSCC), use Combined Positive Score (CPS) ≥1 as the threshold for pembrolizumab-based treatment. 1

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Scoring Method Definitions

Tumor Proportion Score (TPS)

• TPS measures the percentage of viable tumor cells showing partial or complete PD-L1 membrane staining at any intensity 1
• Only tumor cells are counted in the numerator and denominator 1
• Used primarily in NSCLC for treatment decisions 1

Combined Positive Score (CPS)

• CPS is calculated as the total number of PD-L1-positive cells (tumor cells, lymphocytes, and macrophages) divided by the total number of viable tumor cells, multiplied by 100 1
• Includes immune cells in the numerator but only tumor cells in the denominator 1
• Preferred scoring method for HNSCC due to superior sensitivity 1, 2

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Clinical Application in NSCLC

Pembrolizumab Monotherapy

• TPS ≥1% is the FDA-approved threshold for pembrolizumab monotherapy in treatment-naïve, locally advanced/metastatic NSCLC without EGFR/ALK alterations 1
• Patients with TPS ≥50% derive the greatest benefit from monotherapy 1
• The 22C3 pharmDx assay is the validated companion diagnostic 1

Pembrolizumab Plus Chemotherapy

• Pembrolizumab combined with platinum-based chemotherapy is recommended regardless of PD-L1 expression level in NSCLC 1, 3, 4
• For non-squamous histology: pembrolizumab + pemetrexed + carboplatin 1, 4
• For squamous histology: pembrolizumab + carboplatin + paclitaxel (or nab-paclitaxel) 1, 3

TPS Thresholds in NSCLC

• TPS 1%-49%: Combination chemoimmunotherapy is preferred over monotherapy 1
• TPS ≥50%: Either monotherapy or combination therapy is appropriate, though combination yields higher response rates 1
• TPS <1%: Chemoimmunotherapy remains effective despite low PD-L1 expression 1

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Clinical Application in HNSCC

CPS as the Preferred Metric

• CPS is more sensitive than TPS at lower cutoffs (≥1) and is the recommended scoring method for HNSCC 1, 2
• Post hoc analysis from KEYNOTE-040 demonstrated that CPS ≥50 and TPS ≥50% perform equivalently at high thresholds, but CPS captures more responders at lower cutoffs 2
• CPS ≥1 is the validated threshold for pembrolizumab monotherapy or pembrolizumab-chemotherapy in recurrent/metastatic HNSCC 1, 5

Treatment Algorithms by CPS Score

CPS ≥20:

• Pembrolizumab monotherapy is appropriate for first-line treatment 1, 5
• Pembrolizumab + chemotherapy provides additional benefit 5

CPS 1-19:

• Pembrolizumab-chemotherapy combination is preferred over monotherapy 5
• Median OS with pembrolizumab-chemotherapy was 12.7 months versus 9.9 months with cetuximab-chemotherapy (HR 0.71) 5
• Pembrolizumab monotherapy showed median OS of 10.8 versus 10.1 months with cetuximab-chemotherapy (HR 0.86) 5

CPS <1:

• Pembrolizumab monotherapy is not recommended 5
• Pembrolizumab-chemotherapy showed limited benefit (median OS 11.3 vs 10.7 months, HR 1.21) 5
• Standard chemotherapy or clinical trial enrollment should be considered 5

Assay Selection for HNSCC

• The 22C3 pharmDx assay is the validated companion diagnostic for pembrolizumab in HNSCC 1
• SP263 assay tends to stain a higher percentage of cells, particularly with CPS scoring, and may not be interchangeable 6
• Concordance between assays is moderate to poor, especially at clinically relevant cutoffs 6

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Esophageal Cancer Context

Esophageal Squamous Cell Carcinoma (ESCC)

• Both TPS and CPS are used depending on the specific immunotherapy regimen 1
• Nivolumab ± ipilimumab: TPS ≥1% using 28-8 pharmDx assay 1
• Pembrolizumab + chemotherapy: CPS ≥10 using 22C3 assay 1
• For ESCC, 91% of patients had CPS ≥1, suggesting CPS ≥1 may substitute for TPS ≥1% when TPS is unavailable 1

Esophageal Adenocarcinoma

• CPS ≥5 is the threshold for nivolumab + chemotherapy in gastroesophageal junction adenocarcinoma 1
• CPS ≥10 for pembrolizumab + chemotherapy in esophageal adenocarcinoma 1

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Critical Pitfalls to Avoid

Assay Interchangeability

• Do not assume different PD-L1 assays are interchangeable without validation data 6
• The 22C3 and 28-8 assays show high analytical concordance in some tumor types, but conflicting data exist 1
• SP263 may overestimate PD-L1 positivity compared to 22C3, particularly with CPS scoring 6

Scoring Method Confusion

• Never use TPS cutoffs when CPS is the validated metric for the specific indication 1, 2
• In HNSCC, CPS identifies additional responders that TPS would miss at lower thresholds 2
• Recent research in NSCLC suggests CPS may better predict overall survival than TPS, particularly in the TPS-negative/CPS-positive subgroup 7

Cytology Specimens

• PD-L1 CPS evaluation is feasible on HNSCC cytology cell blocks with 76.2% concordance with histology 8
• Positive predictive value is 100% for both CPS and TPS, but negative predictive value is only 57.1% for CPS 8
• When cytology shows PD-L1 negativity, consider obtaining histologic confirmation if clinically feasible 8

Treatment Selection Errors

• Do not withhold pembrolizumab-chemotherapy based solely on low PD-L1 expression in NSCLC 1, 3, 4
• Combination therapy benefits patients across all PD-L1 expression levels 1, 4
• In HNSCC with CPS <1, pembrolizumab monotherapy should not be used, but combination therapy may still be considered on a case-by-case basis 5

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Quality Assurance Requirements

• Use a validated PD-L1 assay that is subject to a quality assurance program 1
• Ensure adequate tumor cellularity for accurate scoring (minimum 100 viable tumor cells recommended) 1
• Pathologists should be trained in the specific scoring methodology (TPS vs CPS) relevant to the clinical indication 1, 6