What are the current guidelines for first‑line therapy of an adult with advanced/metastatic squamous non‑small cell lung cancer lacking targetable EGFR, ALK, or ROS1 alterations?

First-Line Treatment for Advanced Squamous Cell Lung Cancer

For patients with advanced/metastatic squamous NSCLC without targetable mutations and PD-L1 ≥50%, pembrolizumab monotherapy is the preferred first-line treatment; for those with PD-L1 <50% or unknown status, platinum-based chemotherapy combined with a PD-1/PD-L1 inhibitor is the standard of care. 1

Treatment Algorithm Based on PD-L1 Expression

High PD-L1 Expression (≥50%)

• Pembrolizumab monotherapy is the category 1 preferred option for patients with PD-L1 tumor proportion score ≥50% 1
• This approach demonstrated superior outcomes in the squamous subgroup with a hazard ratio of 0.35 (95% CI: 0.17–0.71) for progression-free survival compared to chemotherapy 1
• Pembrolizumab monotherapy offers improved response rates (44.8% vs 27.8%) and 12-month overall survival (70.3% vs 54.8%) with fewer treatment-related adverse events than chemotherapy 1

Low or Unknown PD-L1 Expression (<50%)

For performance status 0-1 patients:

• Platinum-based doublet chemotherapy combined with immunotherapy is the standard approach 1, 2
• Preferred chemotherapy backbones include:
  • Carboplatin plus paclitaxel (most commonly used, 37.6% of real-world practice) 3
  • Carboplatin plus nab-paclitaxel (21.1% utilization) 3
  • Cisplatin plus gemcitabine (can be combined with necitumumab for additional benefit) 1, 4

For performance status 2 patients:

• Carboplatin-based doublet chemotherapy or single-agent chemotherapy in select cases 1
• Options include gemcitabine, vinorelbine, or docetaxel as monotherapy 1

Special Consideration: Necitumumab

• Necitumumab plus cisplatin-gemcitabine is an option for patients with EGFR expression by immunohistochemistry 1
• The SQUIRE trial demonstrated improved overall survival and disease control with manageable toxicity when necitumumab was added to cisplatin-gemcitabine 4
• However, patient selection remains challenging due to lack of robust predictive biomarkers 4

Performance Status Considerations

PS 0-1: Full platinum-based doublet chemotherapy with immunotherapy is appropriate 1

PS 2: Consider carboplatin-based regimens or single-agent therapy in carefully selected patients 1

PS 3-4: Best supportive care is recommended 1

Critical Pitfalls to Avoid

• Do not use immunotherapy monotherapy in patients with PD-L1 <50% – nivolumab monotherapy failed to show benefit in the CheckMate 026 trial for this population 1
• Do not use targeted therapies as first-line treatment – unlike nonsquamous NSCLC, squamous histology rarely harbors EGFR, ALK, or ROS1 alterations that would benefit from targeted agents 1, 2
• Avoid pemetrexed-based regimens – these are contraindicated in squamous histology due to lack of efficacy and are reserved for nonsquamous NSCLC 3

Maintenance Therapy

• Continuation maintenance with gemcitabine (if used in induction) is a category 2B option 1
• Switch maintenance with docetaxel is also category 2B 1
• Close observation is an acceptable alternative, as maintenance therapy is not universally recommended for squamous histology 1

Expected Outcomes

Real-world data from the pre-immunotherapy era showed median overall survival of 8.5 months for squamous NSCLC with platinum-based chemotherapy alone 3. Current immunotherapy-containing regimens have substantially improved these outcomes, with approximately 50% of appropriately selected patients achieving meaningful survival benefits 2.