What is the recommended first‑line therapy for a patient with advanced non‑small cell lung cancer that is epidermal growth factor receptor wild‑type and has programmed death‑ligand 1 expression of approximately 40 %?

First-Line Treatment for EGFR-Negative NSCLC with PD-L1 40%

For a patient with advanced EGFR wild-type non-small cell lung cancer and PD-L1 expression of 40%, pembrolizumab plus platinum-based chemotherapy (pemetrexed plus platinum for non-squamous histology) is the recommended first-line therapy. 1

Why Combination Therapy Over Pembrolizumab Monotherapy

While pembrolizumab monotherapy is reserved for patients with PD-L1 ≥50%, your patient's PD-L1 of 40% falls into the intermediate expression range (1-49%) where combination chemoimmunotherapy demonstrates superior outcomes across all PD-L1 subgroups. 1

The KEYNOTE-189 trial established that pembrolizumab plus pemetrexed and platinum chemotherapy (4 cycles followed by pembrolizumab + pemetrexed maintenance) resulted in superior response rates, progression-free survival, and overall survival compared with chemotherapy alone (median OS not reached versus 11.3 months, HR 0.49). 1

The survival benefit of pembrolizumab-combination therapy is observed across all categories of PD-L1 expression, though it is somewhat diminished among PD-L1-negative patients. 1

Specific Treatment Regimen

For Non-Squamous Histology:

• Pembrolizumab 200 mg IV every 3 weeks
• Plus pemetrexed 500 mg/m² IV
• Plus platinum agent (cisplatin 75 mg/m² or carboplatin AUC 5-6)
• For 4 cycles, followed by maintenance pembrolizumab + pemetrexed until progression 1

For Squamous Histology:

• Pembrolizumab 200 mg IV every 3 weeks
• Plus carboplatin AUC 5-6
• Plus paclitaxel 200 mg/m² or nab-paclitaxel 100 mg/m² (days 1,8,15)
• For 4 cycles, followed by pembrolizumab maintenance 1

Alternative First-Line Options

Atezolizumab-Based Combination (Non-Squamous Only):

Atezolizumab plus bevacizumab plus carboplatin and paclitaxel represents an alternative option for patients with PS 0-1 and non-squamous histology, showing improved PFS and OS (19.2 versus 14.7 months, HR 0.78) irrespective of PD-L1 expression. 1 This regimen is particularly relevant if there are no contraindications to bevacizumab (no hemoptysis, brain metastases requiring anticoagulation, or recent bleeding). 1

Nivolumab Plus Ipilimumab (High TMB):

If tumor mutational burden (TMB) can be accurately evaluated and is ≥10 mutations/megabase, nivolumab plus ipilimumab represents a chemotherapy-free option regardless of PD-L1 expression level. 1 However, this requires validated TMB testing and is associated with higher immune-related toxicity. 1

Critical Eligibility Requirements

Before initiating immunotherapy-based treatment, confirm:

• Performance status 0-1 (PS 2 patients should receive carboplatin-based doublet chemotherapy without immunotherapy) 1
• No contraindications to immunotherapy: active autoimmune disease requiring systemic therapy, conditions requiring immunosuppression, or interstitial lung disease 1, 2
• EGFR and ALK testing completed and negative – genomic results must be obtained before starting immunotherapy to prevent inappropriate therapy selection 1, 3
• Adequate organ function for platinum-based chemotherapy 1

Common Pitfalls to Avoid

Do not use pembrolizumab monotherapy at PD-L1 40%. The single-agent pembrolizumab indication is restricted to PD-L1 ≥50% based on KEYNOTE-024 trial criteria. 1, 4 The KEYNOTE-042 trial confirmed that the OS benefit of pembrolizumab monotherapy is driven by the ≥50% subgroup, not intermediate expressors. 1

Never initiate immunotherapy before confirming EGFR/ALK status. Even with high PD-L1 expression, patients with EGFR mutations show markedly reduced benefit from ICIs and risk increased toxicity with subsequent TKI therapy. 1, 3

Avoid bevacizumab in squamous histology due to increased risk of pulmonary hemorrhage. 1

Treatment Duration and Monitoring

• Continue pembrolizumab for up to 24 months or until disease progression or unacceptable toxicity 2
• First radiologic assessment at 6 weeks, then every 6-9 weeks using RECIST v1.1 or iRECIST criteria to account for pseudoprogression 2
• Monitor for immune-related adverse events: pneumonitis, colitis, hepatitis, endocrinopathies, and dermatologic toxicities occur in approximately 13% of patients 5

Maintenance Strategy

After completing 4 cycles of platinum-based chemotherapy:

• For non-squamous histology: continue pembrolizumab + pemetrexed maintenance until progression 1
• For squamous histology: continue pembrolizumab monotherapy maintenance 1
• Pemetrexed continuation maintenance is supported by Level I, Grade A evidence in non-squamous disease 1