What is programmed death‑ligand 1 (PD‑L1) and how do we determine if a patient is eligible for PD‑1/PD‑L1 inhibitor therapy?

What is PD-L1 and How to Determine Patient Eligibility for PD-1/PD-L1 Inhibitor Therapy

PD-L1 is a cell surface protein that tumor cells exploit to suppress T-cell immune responses, and patients are selected for PD-1/PD-L1 inhibitor therapy based on PD-L1 expression testing using FDA-approved companion diagnostic assays with specific scoring thresholds that vary by cancer type. 1, 2

Understanding PD-L1 Biology

What PD-L1 Is:

• PD-L1 (programmed death-ligand 1) is a co-regulatory molecule expressed on tumor cells and antigen-presenting cells that binds to PD-1 receptors on T-cells 1, 2, 3
• When PD-L1 binds to PD-1, it delivers an inhibitory signal that suppresses T-cell activation, proliferation, and cytotoxic function 1, 2, 4
• Under normal conditions, this pathway prevents excessive immune responses and autoimmunity, but tumor cells hijack this mechanism to evade immune destruction 4, 5

Why It Matters:

• Tumor cells frequently overexpress PD-L1 to facilitate immune evasion and tumor growth 1, 6
• Checkpoint inhibitor antibodies block the PD-1/PD-L1 interaction, thereby restoring T-cell antitumor activity 1, 2, 3

Determining Patient Eligibility: Testing Requirements

Step 1: Obtain Appropriate Tissue Sample

• Testing requires formalin-fixed paraffin-embedded (FFPE) tumor tissue 1, 7
• A minimum of 100 viable tumor cells must be present in the PD-L1-stained slide for adequate evaluation 1, 7
• Testing must be performed in a CLIA-approved laboratory using FDA-approved companion diagnostic assays 1, 7

Step 2: Use Cancer-Specific Scoring Systems

Combined Positive Score (CPS) - Used for Gastric Cancer:

• CPS = (number of PD-L1-staining cells [tumor cells, lymphocytes, macrophages] / total viable tumor cells) × 100 1, 7
• A specimen is considered PD-L1-positive if CPS ≥1 1
• Stronger evidence for benefit exists at CPS ≥5 and CPS ≥10 thresholds 7

Tumor Proportion Score (TPS) - Used for Lung Cancer:

• TPS measures the percentage of tumor cells with membranous PD-L1 staining 1, 2, 8
• For first-line pembrolizumab monotherapy in NSCLC: requires TPS ≥50% 1
• For second-line pembrolizumab in NSCLC: requires TPS ≥1% 1
• For adjuvant atezolizumab in NSCLC: requires PD-L1 expression on ≥1% of tumor cells 8

Step 3: Apply Cancer-Specific Treatment Algorithms

Non-Small Cell Lung Cancer (NSCLC):

• PD-L1 testing is recommended for all patients with newly diagnosed advanced NSCLC 2, 3
• First-line pembrolizumab monotherapy: TPS ≥50% required 1
• Second-line pembrolizumab: TPS ≥1% required 1
• Combination therapy with chemotherapy ± bevacizumab: PD-L1 testing guides but may not exclude treatment 8

Gastric/Gastroesophageal Junction Adenocarcinoma:

• For HER2-negative disease, test PD-L1 using FDA-approved companion diagnostic (22C3 pharmDx) 7
• CPS ≥5: strongest evidence (Category 1) for pembrolizumab plus chemotherapy 7
• CPS ≥1: demonstrated survival benefit (median OS 13 vs 11.4 months, HR 0.74) 7
• CPS ≥10: most pronounced benefit (median OS 15.7 vs 11.8 months, HR 0.65) 7

Critical Exception - MSI-H/dMMR Tumors:

• PD-L1 testing is NOT required for microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors 7
• These patients qualify for pembrolizumab monotherapy regardless of PD-L1 status 7
• Universal MSI/MMR testing should be performed first for all newly diagnosed gastric cancers 7

Important Clinical Pitfalls and Caveats

Testing Variability:

• Various antibody clones exist for PD-L1 IHC, and while several show relative equivalence, some do not 1
• The definition of positive/negative testing depends on the individual antibody, platform, and specific checkpoint inhibitor being considered 1
• Different FDA-approved companion diagnostics are paired with specific immunotherapy agents 1, 7

Biomarker Limitations:

• PD-L1 is not a perfect biomarker: less than half of biomarker-selected patients benefit from treatment 2
• Some responses occur in "biomarker-negative" cohorts, meaning PD-L1-negative patients may still respond 2
• PD-L1 expression can be heterogeneous within tumors, creating sampling challenges 1

Prognostic vs. Predictive Value:

• The prognostic significance of PD-L1 expression remains unclear and varies by cancer type 1, 2
• Some studies suggest favorable survival associations while others show unfavorable or no relationship 1
• PD-L1 expression is frequently associated with MSI-H and Epstein-Barr virus positivity in gastric tumors 1

Practical Testing Algorithm

1. Confirm adequate tissue: Verify ≥100 viable tumor cells available 1, 7
2. Check MSI/MMR status first (especially for gastric cancer): If MSI-H/dMMR, PD-L1 testing unnecessary 7
3. Select appropriate FDA-approved companion diagnostic based on intended immunotherapy agent 1, 7
4. Apply cancer-specific scoring system: CPS for gastric cancer, TPS for lung cancer 1, 7
5. Use appropriate threshold: Match cutoff to specific drug and line of therapy 1, 7
6. Ensure CLIA-approved laboratory performs testing 1, 7