What is the first-line treatment for gastroesophageal junction (GEJ) cancer with high programmed death-ligand 1 (PD-L1) expression?

First-Line Treatment for Gastroesophageal Junction Cancer with PD-L1 >1

For patients with HER2-negative gastroesophageal junction (GEJ) cancer with PD-L1 CPS ≥5, nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy is the recommended first-line treatment. 1

Treatment Algorithm Based on PD-L1 Expression

For PD-L1 CPS ≥5:

• First choice: Nivolumab plus fluoropyrimidine- and platinum-based chemotherapy
  • Demonstrated trend toward OS benefit (HR 0.82,95% CI 0.58-1.16) 1
  • Significant improvements in PFS and ORR in the overall population with PD-L1 CPS ≥5 1

For PD-L1 CPS ≥10:

• Alternative option: Pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy
  • Showed significant PFS improvement (HR 0.49,95% CI 0.30-0.81) 1
  • OS trend favored combination but did not reach statistical significance (HR 0.83,95% CI 0.52-1.34) 1
  • FDA approved for esophageal/GEJ tumors with PD-L1 CPS ≥10 2

For PD-L1 CPS 1-5:

• Case-by-case consideration: Nivolumab plus fluoropyrimidine- and platinum-based chemotherapy 1
  • Less robust evidence for this subgroup
  • Consider patient factors including performance status and comorbidities

For PD-L1 CPS <1:

• Standard chemotherapy: Fluoropyrimidine- and platinum-based chemotherapy without immunotherapy 1
  • No demonstrated benefit of adding immunotherapy in this population

Evidence Quality and Considerations

Nivolumab Plus Chemotherapy (CheckMate 649)

• Fewer GEJ patients (170 patients, 16% of study population) compared to gastric cancer patients 1
• OS results for PD-L1 CPS ≥5 showed HR of 0.82 (95% CI 0.58-1.16) for GEJ patients 1
• Significant PFS and ORR improvements in overall population with PD-L1 CPS ≥5 1

Pembrolizumab Plus Chemotherapy (KEYNOTE-590)

• Subgroup analysis of 97 patients with esophageal or Siewert type 1 GEJ adenocarcinoma and PD-L1 CPS ≥10 1
• PFS benefit was significant (HR 0.49,95% CI 0.30-0.81) 1
• OS benefit showed trend but wide confidence interval (HR 0.83,95% CI 0.52-1.34) 1
• FDA approval for first-line treatment of locally advanced or metastatic esophageal/GEJ carcinoma in combination with platinum and fluoropyrimidine chemotherapy 2

Special Considerations

MSI-H Tumors

• Patients with MSI-H tumors show significant OS benefit with immunotherapy
• In CheckMate 649, MSI-H tumors (3% of patients) had HR 0.38 (95% CI 0.17-0.84) with nivolumab plus chemotherapy 1
• In KEYNOTE-062, MSI-H tumors (6.6% of patients) showed significant OS benefit with pembrolizumab alone or with chemotherapy 1
• Consider testing for MSI status to identify this highly responsive subgroup

Quality of Life Considerations

• Pembrolizumab maintained quality of life compared to chemotherapy alone 3
• Longer time to deterioration for nausea/vomiting with pembrolizumab versus chemotherapy (HR 0.61,95% CI 0.44-0.85) 3
• Grade 3-5 treatment-related adverse events were significantly lower with pembrolizumab monotherapy (17%) compared to chemotherapy (69%) 4

Common Pitfalls to Avoid

1. Not testing for PD-L1 expression: PD-L1 testing is essential for treatment selection as benefits vary significantly by CPS level
2. Overlooking MSI status: MSI-H tumors have exceptional response to immunotherapy regardless of PD-L1 status
3. Ignoring HER2 status: HER2 testing is mandatory as HER2-positive tumors have different first-line treatment recommendations
4. Using incorrect PD-L1 cutoffs: Different immunotherapy agents have different recommended PD-L1 cutoff values for optimal benefit

In summary, for GEJ cancer with PD-L1 CPS >1, the treatment approach should be stratified based on the exact PD-L1 CPS level, with nivolumab plus chemotherapy being the preferred option for CPS ≥5 and pembrolizumab plus chemotherapy being an alternative for CPS ≥10. For CPS 1-5, the decision to add immunotherapy should be made on a case-by-case basis, while standard chemotherapy remains appropriate for CPS <1.