What is the recommended first-line treatment for a patient with squamous cell carcinoma and a Combined Positive Score (CPS) of 5?

First-Line Treatment for Squamous Cell Carcinoma with CPS 5

For squamous cell carcinoma with CPS 5, pembrolizumab plus chemotherapy (platinum/5-FU) is the recommended first-line treatment, particularly when rapid tumor shrinkage is needed or the patient is symptomatic. 1

Primary Treatment Recommendation

Head and Neck Squamous Cell Carcinoma (HNSCC)

Pembrolizumab combined with platinum-based chemotherapy (cisplatin or carboplatin) plus 5-FU is the preferred first-line option for CPS ≥1, which includes your patient with CPS 5. 1 This combination demonstrated superior overall survival (13.0 vs 10.7 months, p=0.0034) compared to the EXTREME regimen (platinum/5-FU/cetuximab), with similar response rates (35.6% vs 36.3%) and progression-free survival (5.1 vs 4.9 months). 1

• The FDA approved pembrolizumab plus chemotherapy as first-line treatment regardless of PD-L1 expression. 1
• The EMA approved pembrolizumab with or without chemotherapy only for patients with CPS ≥1, making this patient eligible under both regulatory frameworks. 1

Alternative Monotherapy Approach

Pembrolizumab monotherapy can be considered for CPS ≥1 patients when rapid tumor shrinkage is not urgently needed and the patient is asymptomatic. 1 However, this approach has significant limitations at CPS 5:

• Pembrolizumab monotherapy improved overall survival in the CPS ≥1 subgroup (12.3 vs 10.3 months) but demonstrated inferior progression-free survival (3.2 vs 5.0 months) and lower response rates (19.1% vs 34.9%) compared to EXTREME. 1
• Monotherapy is better tolerated (grade 3-5 adverse events 54.7% vs 83.3%) but should be reserved for patients where chemotherapy toxicity is a major concern. 1

Esophageal Squamous Cell Carcinoma

For esophageal squamous cell carcinoma with CPS 5, pembrolizumab plus platinum and fluoropyrimidine chemotherapy is recommended as first-line treatment. 2, 3

• The KEYNOTE-590 trial demonstrated improved overall survival (12.4 vs 9.8 months, HR 0.73, p<0.0001) and progression-free survival (6.3 vs 5.8 months, HR 0.65, p<0.0001) in all patients regardless of PD-L1 status. 3
• Pembrolizumab monotherapy is FDA-approved only for esophageal squamous cell carcinoma with CPS ≥10 after prior systemic therapy, making it inappropriate for first-line treatment at CPS 5. 2

Alternative Nivolumab-Based Regimens

Nivolumab plus chemotherapy or nivolumab plus ipilimumab are alternative first-line options for esophageal squamous cell carcinoma. 4

• Nivolumab plus chemotherapy demonstrated OS benefit (HR 0.78,95% CI 0.65-0.93) in the overall population with improved PFS in PD-L1 ≥1% patients (HR 0.67). 4
• Nivolumab plus ipilimumab showed OS benefit (HR 0.77,95% CI 0.65-0.92) but did not improve PFS (HR 1.04), making it less suitable when disease control is a priority. 4

Lung Squamous Cell Carcinoma

For metastatic squamous cell lung cancer, pembrolizumab plus carboplatin and paclitaxel (or nab-paclitaxel) is the standard first-line treatment regardless of PD-L1 expression. 5

• This regimen demonstrated superior overall survival (15.9 vs 11.3 months, HR 0.64) in the KEYNOTE-407 trial. 5
• Pembrolizumab monotherapy is only appropriate for lung cancer patients with PD-L1 TPS ≥50%, not CPS 5. 1, 5

Critical Clinical Considerations

When to Choose Combination Therapy Over Monotherapy

Combination pembrolizumab plus chemotherapy should be prioritized over monotherapy when:

• Rapid tumor shrinkage is clinically necessary (symptomatic disease, impending organ compromise). 1
• The patient has good performance status (PS 0-1) and can tolerate chemotherapy. 1
• CPS is between 1-19, where the survival benefit of monotherapy versus combination therapy remains unclear. 1

Contraindications to Immunotherapy

EXTREME regimen (platinum/5-FU/cetuximab) remains standard of care for patients with:

• Contraindications to anti-PD-1 inhibitors. 1
• Tumors not expressing PD-L1 (CPS <1), though this does not apply to your patient. 1

Common Pitfalls to Avoid

• Do not use pembrolizumab monotherapy as first-line treatment for CPS 5 if the patient is symptomatic or requires rapid disease control, as response rates and PFS are significantly inferior to combination therapy. 1
• Do not assume CPS and TPS are interchangeable—pembrolizumab dosing for HNSCC and esophageal cancer uses CPS, while lung cancer monotherapy requires TPS ≥50%. 1, 2
• Ensure adequate performance status assessment—all immunotherapy regimens require PS 0-2, with combination chemotherapy typically limited to PS 0-1. 1, 5