What is the treatment plan for a patient with unresectable esophageal cancer and a Combined Positive Score (CPS) of 5?

Treatment Plan for Unresectable Oesophageal Cancer with CPS 5

For a patient with unresectable oesophageal cancer and PD-L1 CPS of 5, the treatment approach depends critically on tumor histology (adenocarcinoma versus squamous cell carcinoma) and HER2 status, with immunotherapy plus chemotherapy recommended on a case-by-case basis for adenocarcinoma, while squamous cell carcinoma requires different PD-L1 thresholds for standard immunotherapy recommendations.

Initial Assessment Required

Before finalizing treatment, you must determine:

• Tumor histology: Adenocarcinoma (AC) versus squamous cell carcinoma (SCC) 1
• HER2 status: Critical for adenocarcinoma patients 1
• Exact tumor location: Esophageal versus gastroesophageal junction (GEJ) 1
• Performance status: ECOG 0-1 required for combination therapy 2
• MSI status: If available, as MSI-H tumors show exceptional responses to immunotherapy regardless of PD-L1 1, 3

Treatment Algorithm Based on Histology

If Esophageal or GEJ Adenocarcinoma (HER2-Negative)

With CPS 5, immunotherapy may be considered on a case-by-case basis but is not a strong standard recommendation:

• Nivolumab plus fluoropyrimidine- and platinum-based chemotherapy may be recommended on a case-by-case basis for patients with PD-L1 CPS 1-5 1
• Pembrolizumab plus chemotherapy may be recommended on a case-by-case basis for patients with PD-L1 CPS 1-10 1
• The evidence quality is low for these recommendations, as the CheckMate 649 trial showed a trend toward benefit (HR 0.73,95% CI 0.49-1.10 for esophageal AC with CPS ≥5) but did not reach statistical significance 1

Standard chemotherapy alone remains appropriate:

• Fluoropyrimidine- and platinum-based chemotherapy (cisplatin-5-FU or oxaliplatin-capecitabine) is the established standard if immunotherapy is not used 1

If Esophageal Squamous Cell Carcinoma

With CPS 5, standard chemotherapy is recommended, as immunotherapy requires higher PD-L1 thresholds:

• Pembrolizumab plus chemotherapy is NOT standard at CPS 5, as the KEYNOTE-590 trial showed benefit primarily in patients with CPS ≥10 (HR 0.57,95% CI 0.43-0.75), with post-hoc analysis suggesting no benefit at CPS <10 1, 2
• Nivolumab plus chemotherapy requires PD-L1 TPS ≥1% (not CPS), which is a different biomarker assessment 1
• Standard platinum-fluoropyrimidine chemotherapy (cisplatin-5-FU or oxaliplatin-capecitabine) is recommended 1

Specific Treatment Regimens

If Immunotherapy Is Used (Case-by-Case for AC with CPS 5)

Nivolumab-based regimen:

• Nivolumab 360 mg IV every 3 weeks (or 240 mg every 2 weeks) 4
• Plus FOLFOX (5-FU, leucovorin, oxaliplatin) or CAPOX (capecitabine, oxaliplatin) 1
• Continue until disease progression or unacceptable toxicity 4

Pembrolizumab-based regimen:

• Pembrolizumab 200 mg IV every 3 weeks 5, 2
• Plus cisplatin 80 mg/m² IV day 1 and 5-FU 800 mg/m²/day continuous infusion days 1-5, every 3 weeks 2
• Continue for up to 35 cycles (~2 years) 5, 2

If Chemotherapy Alone Is Used

Standard doublet chemotherapy:

• Cisplatin 80 mg/m² IV day 1 plus 5-FU 800 mg/m²/day continuous infusion days 1-5, every 3 weeks 1, 2
• OR oxaliplatin 130 mg/m² IV day 1 plus capecitabine 1000 mg/m² PO twice daily days 1-14, every 3 weeks 1

Critical Decision-Making Factors

Factors favoring immunotherapy addition (despite CPS 5):

• Younger age with good performance status 2
• Adenocarcinoma histology (where evidence exists for CPS 1-5 range) 1
• Patient preference for potentially improved progression-free survival despite uncertain overall survival benefit 1
• MSI-H status if known (dramatic benefit regardless of CPS) 1, 3

Factors favoring chemotherapy alone:

• Squamous cell carcinoma with CPS <10 (no proven benefit from pembrolizumab) 1, 2
• Concerns about immune-related adverse events 6, 7
• Older age or frailty (consider dose-reduced oxaliplatin-capecitabine) 1

Safety Monitoring

For immunotherapy combinations:

• Monitor for immune-related adverse events including colitis, hepatitis, pneumonitis, and endocrinopathies 6, 7
• Grade 3-4 treatment-related adverse events occur in approximately 72% with pembrolizumab plus chemotherapy versus 68% with chemotherapy alone 2
• Regular physical examinations and laboratory monitoring (including thyroid function, liver enzymes, creatinine) are essential 6, 7

For chemotherapy alone:

• Monitor for neutropenia, neuropathy (with oxaliplatin), and renal toxicity (with cisplatin) 7
• Dose modifications may be needed based on toxicity 1

Second-Line Options

If first-line treatment fails:

• For SCC: Nivolumab monotherapy is standard second-line treatment (HR 0.77 versus chemotherapy) 1
• For AC: Treatment should follow gastric cancer guidelines 1
• Taxane (paclitaxel or docetaxel) or irinotecan-based chemotherapy are alternatives 1

Important Caveats

• The optimal PD-L1 cutoff is unknown, and the CPS thresholds used in guidelines are based on subgroup analyses from clinical trials 1
• CPS 5 falls in a "gray zone" where evidence is weaker than for higher CPS values, particularly for adenocarcinoma 1
• For squamous cell carcinoma, CPS 5 is below the established benefit threshold of CPS ≥10 for pembrolizumab 1, 2
• HER2-positive adenocarcinoma requires different treatment with trastuzumab plus pembrolizumab plus chemotherapy regardless of CPS 1