What are the treatment options for squamous cell (SqCC) adenocarcinoma of the lung?

Treatment Options for Squamous Cell Carcinoma of the Lung

For patients with advanced squamous cell carcinoma (SqCC) of the lung, first-line treatment should include platinum-based chemotherapy combinations, with cisplatin plus gemcitabine or paclitaxel as the preferred regimens, while immunotherapy options are recommended based on PD-L1 expression status. 1, 2

First-Line Treatment Options

Performance Status 0-1 Patients

Chemotherapy Options:

• Platinum doublet therapy is the cornerstone of treatment:
  • Cisplatin or carboplatin plus gemcitabine
  • Cisplatin or carboplatin plus paclitaxel/nab-paclitaxel
  • Necitumumab plus gemcitabine-cisplatin

Important: Pemetrexed-based combinations are contraindicated in SqCC due to inferior outcomes compared to other agents 1, 2

Immunotherapy Options:

• PD-L1 ≥50%: Single-agent pembrolizumab is recommended as first-line therapy 2, 3
• Any PD-L1 expression: Pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel 3

Performance Status 2 Patients

• Single-agent chemotherapy (gemcitabine, docetaxel, or vinorelbine)
• Non-platinum doublet therapy may be considered for select patients 1, 2

Performance Status 3-4 Patients

• Best supportive care is recommended 2

Molecular Testing Considerations

Although molecular alterations are less common in SqCC compared to adenocarcinoma, targeted testing should be considered:

• EGFR mutation testing: Recommended for select patients (never/light smokers) 1
• PD-L1 expression testing: Essential for determining immunotherapy eligibility 2
• Emerging targets: FGFR1 amplification, PI3K pathway alterations, and DDR2 mutations are emerging as potential therapeutic targets 4, 5, 6

Clinical Pearl: If EGFR mutations are detected, EGFR TKIs should be prioritized over chemotherapy or immunotherapy 1

Second-Line Treatment Options

After progression on first-line therapy, options include:

• After chemotherapy:

  • Immunotherapy: Nivolumab, pembrolizumab, or atezolizumab 1, 2
  • Docetaxel (75 mg/m² IV every 3 weeks) 7
  • Ramucirumab plus docetaxel 1, 4
  • Afatinib for patients progressing after platinum-based chemotherapy 4

• After immunotherapy:

  • Docetaxel-based regimens 4
  • Platinum-based chemotherapy if not used in first line 1

Warning: Higher doses of docetaxel (100 mg/m²) are associated with unacceptable toxicity and mortality 2, 7

Treatment Algorithm for Advanced SqCC

1. Assess patient performance status and PD-L1 expression
2. PS 0-1:
   • PD-L1 ≥50%: Pembrolizumab monotherapy
   • PD-L1 <50%: Platinum doublet (cisplatin/gemcitabine or cisplatin/paclitaxel) or pembrolizumab combination therapy
3. PS 2:
   • Single-agent chemotherapy (gemcitabine, docetaxel)
   • Consider attenuated platinum doublet in select patients
4. PS 3-4:
   • Best supportive care

Maintenance Therapy

For patients with stable disease or response after 4-6 cycles of first-line chemotherapy:

• Continuation maintenance with necitumumab (if used in initial regimen)
• Continuation maintenance with gemcitabine (if used in initial regimen)
• Observation 1

Special Considerations

• Adenosquamous carcinoma: This subtype has worse prognosis than pure SqCC or adenocarcinoma, with median survival rates significantly lower than either histology alone 8
• Elderly patients: Single-agent chemotherapy is generally preferred, though fit elderly patients (PS 0-1) may tolerate platinum-based combinations 2
• Comorbidities: Treatment choice should account for comorbidities, with dose adjustments as needed 1

Emerging Therapies

Recent research has identified several promising therapeutic targets in SqCC:

• SOX2 amplification
• NFE2L2 and KEAP1 mutations
• PI3K pathway alterations
• FGFR1 amplification
• DDR2 mutations 5, 6, 9

Clinical trials targeting these molecular alterations should be considered for eligible patients, especially in the second-line setting and beyond 4, 9.