Is pembrolizumab (pembrolizumab) plus CapeOx (capecitabine (capecitabine) + oxaliplatin (oxaliplatin)) recommended for unresectable esophageal squamous cell carcinoma with a Combined Positive Score (CPS) as low as 5 according to the 2026 National Comprehensive Cancer Network (NCCN) guidelines?

Pembrolizumab Plus CapeOx for Esophageal SCC with CPS 5

Yes, pembrolizumab plus capecitabine-oxaliplatin (CapeOx) is recommended for unresectable esophageal squamous cell carcinoma with PD-L1 CPS as low as 5, though it achieves Category 1 status only at CPS ≥5 according to the 2025 NCCN guidelines. 1

Guideline-Based Recommendations

NCCN 2025 Position on CPS Thresholds

The 2025 NCCN guidelines for gastric cancer (which include esophageal cancer treatment algorithms) explicitly state:

• Pembrolizumab plus fluoropyrimidine-oxaliplatin is approved for PD-L1 CPS ≥1 1
• Category 1 evidence (highest level) applies specifically when CPS ≥5 1
• The guidelines mandate: "A checkpoint inhibitor should be added to first-line chemotherapy for patients with advanced disease with PD-L1 CPS ≥1" 1

Regulatory Context

• FDA approval is irrespective of PD-L1 expression for esophageal squamous cell carcinoma 1
• EMA approval requires PD-L1 CPS ≥10 1
• This creates a practical treatment window where CPS 5 falls into FDA-approved territory but achieves NCCN Category 1 designation 1

Evidence Supporting CPS 5 as a Threshold

KEYNOTE-590 Trial Data

The pivotal KEYNOTE-590 trial demonstrated:

• Significant OS benefit in all patients with ESCC (HR 0.72; p=0.0006) 2
• Greatest benefit in PD-L1 CPS ≥10 (HR 0.57; p<0.0001) 1, 2
• Significant interaction effect at CPS cutoff of 10 for both OS (p=0.02) and PFS (p=0.007) 1
• However, benefit was observed across the entire CPS ≥1 population 2

ASCO Guideline Interpretation

The 2023 ASCO guidelines provide nuanced guidance:

• Pembrolizumab plus chemotherapy is recommended for ESCC with PD-L1 CPS ≥10 (strong recommendation) 1
• For CPS 1-10, pembrolizumab may be considered on a case-by-case basis 1
• The guidelines acknowledge that while CPS ≥10 shows the strongest benefit, the FDA approval covers all PD-L1 levels 1

Clinical Decision Algorithm for CPS 5

Treatment Selection Based on CPS Level

For CPS 5 specifically:

1. Pembrolizumab plus CapeOx is appropriate and guideline-supported 1, 3
2. Alternative: Nivolumab plus chemotherapy (also Category 1 for CPS ≥5) 1
3. Oxaliplatin is preferred over cisplatin due to lower toxicity 1

Regimen specifics:

• Pembrolizumab 200 mg IV every 3 weeks 2
• Capecitabine plus oxaliplatin (CapeOx) 3
• Continue until disease progression, unacceptable toxicity, or completion of 35 cycles 2

Comparative Options at Different CPS Levels

CPS ≥10:

• Pembrolizumab plus chemotherapy is the preferred option with strongest evidence 1, 3, 2

CPS 5-9:

• Pembrolizumab plus chemotherapy is recommended (Category 1 per NCCN) 1
• Nivolumab plus chemotherapy is an equivalent alternative 1

CPS 1-4:

• Immunotherapy plus chemotherapy may be considered but evidence is weaker 1
• Chemotherapy alone remains a reasonable option 1

CPS 0:

• Chemotherapy alone without immunotherapy is recommended 1

Critical Caveats for CPS 5

Evidence Strength Considerations

• The survival benefit at CPS 5 is driven by the higher CPS subgroups 1
• The interaction test was significant at CPS 10, not at lower thresholds 1
• NCCN upgraded to Category 1 at CPS ≥5 based on aggregate data, not a specific CPS 5 analysis 1

Practical Implementation

Do not:

• Withhold immunotherapy at CPS 5 based on the CPS 10 threshold from KEYNOTE-590 1
• Use pembrolizumab monotherapy in first-line setting (combination with chemotherapy is required) 3, 2
• Confuse CPS with TPS (tumor proportion score)—guidelines specify different thresholds for different tests 1, 4

Do:

• Confirm PD-L1 testing methodology (CPS vs TPS) before treatment selection 1, 4
• Consider patient fitness for combination therapy—dose-reduced CapeOx is an option for less fit patients 3
• Monitor for immune-related adverse events, which occur in approximately 12-14% of patients 2, 5

Safety Profile at CPS 5

The safety data from KEYNOTE-590 showed:

• Grade 3-5 treatment-related adverse events: 72% with pembrolizumab plus chemotherapy vs 68% with chemotherapy alone 2
• Treatment discontinuation due to adverse events: 4.1% 6
• Immune-related adverse events are manageable but require vigilance 5
• Common toxicities include diarrhea, nausea, and anemia 1, 2

Summary of 2025 NCCN Position

The 2025 NCCN guidelines explicitly support pembrolizumab plus CapeOx for esophageal SCC with CPS 5, designating this as Category 1 evidence when CPS ≥5. 1 This represents a practical threshold that balances the strongest evidence (CPS ≥10) with the broader FDA approval and aggregate trial data showing benefit across the CPS ≥1 population. 1, 2