Is immunotherapy an option for stage 4a squamous cell carcinoma?

Immunotherapy for Stage 4a Squamous Cell Carcinoma

Yes, immunotherapy is a highly effective treatment option for stage 4a squamous cell carcinoma, with multiple clinical trials demonstrating significant survival benefits compared to chemotherapy alone. 1

Treatment Options Based on PD-L1 Expression

The approach to immunotherapy in stage 4a squamous cell carcinoma depends primarily on PD-L1 expression levels and patient-specific factors:

For Patients with PD-L1 TPS ≥50%:

• First-line options:
  • Pembrolizumab monotherapy
  • Pembrolizumab plus platinum-based chemotherapy
  • Nivolumab plus ipilimumab (dual immunotherapy)
  • Nivolumab plus ipilimumab with limited chemotherapy (CheckMate 9LA protocol)

The 5-year update of the CheckMate 227 trial showed improved overall survival with nivolumab plus ipilimumab compared to chemotherapy alone in squamous histology, with hazard ratio of 0.62 (95% CI, 0.49 to 0.80) 1.

For Patients with PD-L1 TPS 1-49%:

• First-line recommendation: Combination of platinum-based doublet chemotherapy plus immunotherapy
  • Pembrolizumab plus carboplatin and (nab)-paclitaxel (KEYNOTE-407)
  • Cemiplimab plus platinum-doublet chemotherapy (EMPOWER-Lung 3)
  • Nivolumab plus ipilimumab with limited chemotherapy (CheckMate 9LA)

The KEYNOTE-407 trial specifically for squamous cell carcinoma showed 5-year OS rate of 18.4% versus 9.7% favoring pembrolizumab plus chemotherapy (HR, 0.71) 1.

Evidence-Based Selection Criteria

When deciding between immunotherapy options, consider:

1. Disease burden: For symptomatic patients with high disease burden, chemoimmunotherapy is preferable due to higher response rates 1

2. Smoking status: Chemoimmunotherapy may be preferable in never-smokers, as hazard ratios for immunotherapy monotherapy are consistently lower in this population 1

3. Performance status: For patients with good performance status (ECOG 0-1), combination therapy is well-tolerated; for poorer performance status, monotherapy may be preferred

4. Comorbidities: Consider immunotherapy-related adverse events risk based on patient's comorbidities

Specific Regimens with Proven Efficacy

For Squamous Histology:

• CheckMate 9LA protocol: Nivolumab plus ipilimumab with two cycles of chemotherapy showed median OS of 14.5 months versus 9.1 months with chemotherapy alone (HR, 0.62) 1

  • At 4 years, twice as many patients were alive with this regimen compared to chemotherapy alone (20% vs 10%) 1

• KEYNOTE-407 protocol: Pembrolizumab plus carboplatin/(nab)-paclitaxel showed median OS of 17.1 versus 11.6 months (HR, 0.71) 1

• EMPOWER-Lung 3: Cemiplimab plus chemotherapy showed median OS of 21.9 months versus 13.8 months with chemotherapy alone (HR, 0.56) 1

Special Considerations

1. Contraindications to immunotherapy: If immunotherapy is contraindicated, platinum-based chemotherapy remains the standard option 1

2. Head and neck squamous cell carcinoma: For recurrent/metastatic HNSCC, pembrolizumab monotherapy is recommended for PD-L1 positive tumors, while pembrolizumab plus platinum/5-FU is recommended for PD-L1 negative tumors 1

3. Cutaneous squamous cell carcinoma: Both cemiplimab and pembrolizumab have shown efficacy and are FDA-approved for advanced cutaneous SCC 2

Monitoring and Response Assessment

• Assess tumor response every 6-9 weeks initially, then every 9-12 weeks
• Continue treatment until disease progression, unacceptable toxicity, or maximum of 24 months
• Consider treatment beyond progression if clinical benefit is observed and patient is clinically stable

Potential Challenges

• Immune-related adverse events require careful monitoring and prompt management
• Limited biomarkers beyond PD-L1 for patient selection
• Potential for primary or acquired resistance to immunotherapy 3

Immunotherapy has revolutionized the treatment landscape for stage 4a squamous cell carcinoma, offering significant survival benefits compared to traditional chemotherapy approaches. The choice between monotherapy, dual immunotherapy, or chemoimmunotherapy should be guided by PD-L1 expression, disease burden, and patient characteristics.