Is Pembrolizumab (pembrolizumab) + CapeOx (capecitabine and oxaliplatin) a viable treatment option for unresectable esophageal squamous cell carcinoma?

Pembrolizumab + CapeOx for Unresectable Esophageal Squamous Cell Carcinoma

Pembrolizumab combined with capecitabine and oxaliplatin (CapeOx) is a viable and guideline-recommended first-line treatment option for unresectable esophageal squamous cell carcinoma, with the greatest benefit seen in patients with PD-L1 CPS ≥10. 1

Treatment Recommendation by PD-L1 Status

For PD-L1 CPS ≥10 (Preferred Population)

• Pembrolizumab plus platinum-fluoropyrimidine chemotherapy (including oxaliplatin-capecitabine) is a Level I, Grade A recommendation with an ESMO-MCBS score of 4 1
• The FDA approves this combination irrespective of PD-L1 expression, while the EMA approval is specifically for tumors with PD-L1 CPS ≥10 1
• This represents one of the highest-quality evidence recommendations for first-line treatment of advanced esophageal SCC 1

For PD-L1 CPS <10

• Pembrolizumab plus chemotherapy can still be used based on FDA approval, though the benefit is less pronounced than in the CPS ≥10 population 1
• Standard platinum-fluoropyrimidine chemotherapy alone remains an acceptable alternative (Level II, Grade A) 1

Specific Regimen Details

Dosing Considerations

• Dose-reduced oxaliplatin-capecitabine (CapeOx) is explicitly mentioned as an alternative option for patients unsuitable for full-dose chemotherapy (Level I, Grade A) 1
• This makes the pembrolizumab + CapeOx combination particularly valuable for patients with borderline performance status or comorbidities 1

Administration

• Pembrolizumab is typically given at 200 mg IV every 3 weeks when combined with chemotherapy 2
• The combination should continue until disease progression, unacceptable toxicity, or completion of planned therapy 1

Comparative Context with Other Immunotherapy Options

Alternative First-Line Regimens

• Nivolumab plus chemotherapy is recommended for patients with PD-L1 TPS ≥1% (Level I, Grade A; ESMO-MCBS score 4) 1
• Nivolumab-ipilimumab can be given but has a lower radiological response rate and increased risk of early progression and death compared to immunotherapy-chemotherapy combinations (Level I, Grade B) 1

Why Pembrolizumab + CapeOx is Viable

• The guideline explicitly states that platinum-fluoropyrimidine combinations (which includes oxaliplatin-capecitabine) are standard chemotherapy backbones for combination with pembrolizumab 1
• CapeOx offers the advantage of oral capecitabine administration, potentially improving quality of life compared to infusional 5-FU regimens 1

Evidence Quality and Clinical Trial Support

• The recommendation is based on the KEYNOTE-590 trial, which demonstrated superiority of pembrolizumab plus chemotherapy over chemotherapy alone for advanced esophageal cancer 3, 4
• The combination achieved improved overall survival and progression-free survival compared to chemotherapy alone 4
• This represents the highest level of evidence (Level I) with the strongest grade of recommendation (Grade A) 1

Safety Considerations

Immune-Related Adverse Events

• Immune-related adverse events (irAEs) may occur and are potentially fatal, requiring treatment with steroids or immunosuppressive drugs 3
• Regular physical and laboratory examinations, including hormone level measurements, are needed during and after pembrolizumab-containing therapy 3
• Despite these risks, pembrolizumab-containing therapies are generally tolerable as first-line treatment 3

Chemotherapy Toxicity

• The safety profile of pembrolizumab plus chemotherapy is manageable, with common adverse events including diarrhea, nausea, and anemia 1
• The dose-reduced CapeOx option specifically addresses tolerability concerns in less fit patients 1

Critical Pitfalls to Avoid

• Do not use pembrolizumab monotherapy in the first-line setting - the evidence supports combination with chemotherapy, not monotherapy 1, 4
• Do not assume all platinum-fluoropyrimidine regimens are equivalent - while guidelines support the class, individual patient factors should guide specific agent selection 1
• Do not neglect PD-L1 testing - while FDA approval is irrespective of PD-L1 status, the greatest benefit is in CPS ≥10 patients, and this information guides treatment discussions 1
• Do not overlook the need for early palliative care referral and nutritional support, which are Level I, Grade A recommendations for all patients with advanced esophageal cancer 1

Second-Line Options if First-Line Fails

• Nivolumab monotherapy is the standard second-line option for esophageal SCC previously treated with platinum-fluoropyrimidine (Level I, Grade A; ESMO-MCBS score 3) 1
• Taxane or irinotecan-based chemotherapy can be considered in fit patients who have progressed on platinum-fluoropyrimidine and/or immunotherapy (Level II, Grade B) 1