What is the PD-L1 (Programmed Death-Ligand 1) expression cutoff for a patient with gastric cancer to be considered for treatment with Keytruda (pembrolizumab)?

PD-L1 Cutoff for Pembrolizumab in Gastric Cancer

For gastric cancer, pembrolizumab requires a PD-L1 Combined Positive Score (CPS) ≥1 as the minimum threshold, with CPS ≥5 representing the strongest evidence for benefit and Category 1 recommendation status.

HER2-Negative Gastric Cancer

First-Line Treatment Thresholds

Pembrolizumab combined with fluoropyrimidine- and platinum-based chemotherapy is the standard approach, with treatment recommendations stratified by PD-L1 CPS level 1:

• CPS ≥5: Category 1 preferred option (strongest recommendation) 1
• CPS ≥1: Preferred option, though evidence is less robust than CPS ≥5 1
• CPS 0: Pembrolizumab is NOT recommended; use chemotherapy alone 1

The KEYNOTE-859 trial demonstrated that in HER2-negative gastric/GEJ cancer with CPS ≥10, median OS was 15.7 months with pembrolizumab versus 11.8 months with placebo (HR 0.65, P <0.0001) 1. For CPS ≥1, median OS was 13 months versus 11.4 months (HR 0.74, P <0.0001) 1.

Evidence Quality by CPS Level

The survival benefit becomes progressively stronger at higher CPS thresholds 1, 2:

• CPS ≥10: Objective response rate 23-25% with pembrolizumab monotherapy 2, 3
• CPS ≥5: Objective response rate 20% 3
• CPS ≥1: Objective response rate 13% 3
• CPS <1: Objective response rate only 3% 3

HER2-Positive Gastric Cancer

For HER2-positive gastric or GEJ adenocarcinoma, pembrolizumab combined with trastuzumab and fluoropyrimidine/platinum chemotherapy requires CPS ≥1 1, 4. This is a Category 1 preferred first-line therapy option 1.

The FDA modified approval in 2023 specifically for patients with PD-L1 CPS ≥1 in this setting 1.

MSI-H/dMMR Gastric Cancer

Pembrolizumab monotherapy is approved regardless of PD-L1 expression for MSI-H or dMMR gastric cancer 1, 4. Among 42 gastric cancer patients with MSI-H tumors in KEYNOTE-158, the objective response rate was 31% 1. In KEYNOTE-059,4 of 7 MSI-H patients achieved objective responses (ORR 57.1%) 1.

PD-L1 Testing Requirements

Companion Diagnostic Specifications

PD-L1 testing must be performed using FDA-approved companion diagnostic assays in CLIA-approved laboratories 1:

• Approved assays: 22C3 pharmDx or SP263 assay 1, 5
• Scoring method: Combined Positive Score (CPS) 1
• CPS calculation: (Number of PD-L1-stained cells [tumor cells, lymphocytes, macrophages] ÷ total viable tumor cells) × 100 1
• Minimum requirement: At least 100 tumor cells must be present for adequate evaluation 1
• Positive threshold: CPS ≥1 1

The two FDA-approved assays (22C3 and SP263) show high concordance, with overall percent agreement >90% at CPS ≥1 and 99.2% at CPS ≥10 5.

Critical Clinical Caveats

Tissue Sampling Considerations

Fresh tumor specimens are preferred if archival tissue shows PD-L1 negativity 6. The FDA approval for pembrolizumab in gastric cancer specifically recommends obtaining fresh biopsy if archival specimens are PD-L1-negative 6.

Geographic Variation in Approval

While the NCCN and FDA use CPS ≥1 as the minimum threshold 1, 4, ASCO guidelines provide more nuanced recommendations 1:

• Strong recommendation: CPS ≥10 for esophageal/GEJ adenocarcinoma 1
• Case-by-case consideration: CPS 1-10 1

Optimal Cutoff Uncertainty

The optimal PD-L1 cutoff remains uncertain, but efficacy clearly increases with higher PD-L1 expression levels 1. The interaction between treatment effect and PD-L1 expression was significant at CPS ≥5 in CheckMate 649 1, supporting the Category 1 designation at this threshold 1.

Interobserver Variability

Pathologist interpretation variability exceeds assay variability 5. Agreement between pathologists is higher at CPS ≥10 (99.2%) compared to CPS ≥1 (94.7%) 5, making higher cutoffs more reliable for clinical decision-making.

Treatment Algorithm Summary

1. Test all advanced gastric cancer for PD-L1 CPS using FDA-approved assay 1
2. If HER2-positive and CPS ≥1: Pembrolizumab + trastuzumab + chemotherapy 1
3. If HER2-negative and CPS ≥5: Pembrolizumab + chemotherapy (Category 1) 1
4. If HER2-negative and CPS 1-4: Consider pembrolizumab + chemotherapy on case-by-case basis 1
5. If CPS 0: Chemotherapy alone without pembrolizumab 1
6. If MSI-H/dMMR: Pembrolizumab monotherapy regardless of PD-L1 status 1, 4