Is PD-L1 (Programmed Death-Ligand 1) testing required before initiating Keytruda (pembrolizumab) treatment in a patient with stage 4 gastric adenocarcinoma?

PD-L1 Testing for Pembrolizumab in Stage 4 Gastric Adenocarcinoma

PD-L1 testing is not strictly required before initiating pembrolizumab (Keytruda) in stage 4 gastric adenocarcinoma, but it is strongly recommended to guide optimal treatment selection and maximize survival benefit. 1, 2

Testing Requirements Based on Clinical Context

First-Line Treatment Setting

For HER2-negative gastric/GEJ adenocarcinoma:

• PD-L1 testing should be performed using an FDA-approved companion diagnostic test (22C3 pharmDx) in a CLIA-approved laboratory 1, 2
• Pembrolizumab combined with fluoropyrimidine- and platinum-based chemotherapy is FDA-approved for first-line treatment without a specific PD-L1 threshold requirement 2
• However, the strongest evidence (Category 1 recommendation) exists for patients with PD-L1 CPS ≥5, where pembrolizumab plus chemotherapy demonstrated superior overall survival 3
• For patients with CPS ≥1, pembrolizumab plus chemotherapy showed median OS of 13 months versus 11.4 months with chemotherapy alone (HR 0.74, P <0.0001) 3
• For patients with CPS ≥10, the survival benefit is most pronounced with median OS of 15.7 months versus 11.8 months (HR 0.65, P <0.0001) 3

For HER2-positive gastric/GEJ adenocarcinoma:

• PD-L1 testing IS required with a minimum threshold of CPS ≥1 2
• Pembrolizumab combined with trastuzumab and fluoropyrimidine/platinum chemotherapy is approved only for PD-L1 CPS ≥1 tumors 3, 2
• This indication received accelerated approval and requires PD-L1 expression documentation 2

Second-Line or Later Treatment Setting

PD-L1 testing IS required for pembrolizumab monotherapy in recurrent/metastatic disease after prior therapy 2, 4

• FDA approval mandates PD-L1 CPS ≥1 for pembrolizumab monotherapy after progression on fluoropyrimidine- and platinum-containing chemotherapy 2, 4
• Among PD-L1-positive patients (CPS ≥1), the confirmed overall response rate was 13.3% with durable responses 4

Important Exception: MSI-H/dMMR Tumors

PD-L1 testing is NOT required for MSI-H or dMMR gastric cancers 1, 2

• Pembrolizumab monotherapy is approved regardless of PD-L1 status for MSI-H/dMMR tumors 3, 2
• Universal MSI/MMR testing should be performed for all newly diagnosed gastric cancers 1
• MSI-H tumors showed 31% objective response rate to pembrolizumab in KEYNOTE-158 3

Technical Requirements for PD-L1 Testing

Specimen requirements:

• Minimum of 100 viable tumor cells must be present in the PD-L1-stained slide for adequate evaluation 1, 3
• Testing should be performed on formalin-fixed paraffin-embedded (FFPE) tissue 1
• Fresh tumor specimens are recommended if archival tissue shows no PD-L1 expression, as PD-L1 expression can be heterogeneous 4

Scoring methodology:

• Combined Positive Score (CPS) is calculated as: (number of PD-L1-staining cells [tumor cells, lymphocytes, macrophages] / total viable tumor cells) × 100 1
• A specimen is considered PD-L1-positive if CPS ≥1 1
• Only FDA-approved companion diagnostic assays (22C3 or SP263) should be used, which show >90% concordance at CPS ≥1 and 99.2% at CPS ≥10 3

Clinical Pitfalls and Caveats

PD-L1 is an imperfect biomarker:

• Some PD-L1-negative tumors (CPS <1) still respond to pembrolizumab, though at lower rates 5, 6
• In one analysis, 5.2% of PD-L1-negative tumors had high tumor mutational burden or MSI-H that could predict benefit from immunotherapy 5
• Primary tumors have higher rates of high TMB (8.8% vs 3.9%) and MSI-H (8.5% vs 3.9%) compared to metastases, suggesting primary tumor biopsy may be preferable when feasible 5

Testing limitations:

• Pre-analytical factors (electrocauterization, inadequate fixation) can cause false-negative results 7
• PD-L1 expression is more frequently observed in intestinal-type gastric cancer and is associated with MSI-H and EBV-positivity 1, 8
• The prognostic significance of PD-L1 in gastric cancer remains unclear, with conflicting data on survival associations 1

Practical Algorithm for Stage 4 Gastric Adenocarcinoma

1. Perform universal MSI/MMR testing first 1

   • If MSI-H/dMMR: Consider pembrolizumab monotherapy regardless of PD-L1 status 3, 2

2. Perform HER2 testing 1

3. Perform PD-L1 testing using FDA-approved companion diagnostic 1, 3

4. Treatment selection based on biomarkers:

   • HER2-positive + PD-L1 CPS ≥1: Pembrolizumab + trastuzumab + chemotherapy (Category 1) 3, 2
   • HER2-negative + PD-L1 CPS ≥5: Pembrolizumab + chemotherapy (Category 1, strongest evidence) 3
   • HER2-negative + PD-L1 CPS 1-4: Pembrolizumab + chemotherapy (FDA-approved, moderate evidence) 3, 2
   • HER2-negative + PD-L1 CPS <1: Pembrolizumab + chemotherapy (Category 2B, weaker evidence) 1

Bottom line: While pembrolizumab can be administered without PD-L1 testing in the first-line HER2-negative setting, performing PD-L1 testing allows for evidence-based treatment stratification and helps identify patients most likely to benefit, particularly those with CPS ≥5 who have the strongest survival advantage. 1, 3