What is the recommended first‑line treatment for a stage IV non‑small‑cell lung cancer patient who is EGFR‑negative and has a PD‑L1 tumor proportion score of about 40%?

First-Line Treatment for Stage IV NSCLC with PD-L1 TPS 40% and EGFR-Negative

For this patient with stage IV non-small-cell lung cancer, EGFR-negative status, and PD-L1 tumor proportion score of 40%, you should offer pembrolizumab combined with platinum-based chemotherapy (carboplatin plus pemetrexed for non-squamous, or carboplatin plus paclitaxel/nab-paclitaxel for squamous histology) as the first-line treatment. 1

Rationale for Combination Therapy Over Monotherapy

While pembrolizumab monotherapy is FDA-approved for PD-L1 TPS ≥1% 2, and guidelines support single-agent pembrolizumab for PD-L1 ≥50% 1, your patient's PD-L1 of 40% falls into the intermediate range (1-49%) where combination immunotherapy plus chemotherapy demonstrates superior outcomes compared to either modality alone. 1

• The KEYNOTE-189 trial showed that pembrolizumab plus chemotherapy in patients with PD-L1 1-49% achieved a median overall survival of 21.8 months versus 17.2 months with chemotherapy alone (HR 0.65,95% CI 0.46-0.90), with 5-year follow-up demonstrating durable benefit. 1

• The survival benefit for pembrolizumab-combination therapy is observed across all PD-L1 expression categories, though it remains unclear whether chemotherapy adds benefit specifically in patients with PD-L1 ≥50%. 1

Specific Regimen Selection by Histology

For Non-Squamous NSCLC:

• Pembrolizumab 200 mg IV every 3 weeks + carboplatin AUC 5 + pemetrexed 500 mg/m² for 4 cycles, followed by pembrolizumab plus pemetrexed maintenance until disease progression or unacceptable toxicity. 1, 2

For Squamous NSCLC:

• Pembrolizumab 200 mg IV every 3 weeks + carboplatin AUC 6 + paclitaxel 200 mg/m² (or nab-paclitaxel 100 mg/m² on days 1,8,15) for 4 cycles, followed by pembrolizumab maintenance until disease progression or unacceptable toxicity. 1

Alternative First-Line Options

If pembrolizumab plus chemotherapy is unavailable or contraindicated, consider these alternatives in descending order of preference:

• Cemiplimab plus carboplatin plus paclitaxel (similar efficacy profile to pembrolizumab combinations). 1

• Nivolumab plus ipilimumab with 2 cycles of platinum-based chemotherapy (CheckMate 9LA regimen showed HR 0.61 for OS in PD-L1 1-49% subgroup, though with higher immune-related toxicity). 1

• Durvalumab plus tremelimumab plus platinum-based chemotherapy (emerging option with demonstrated OS benefit). 1

• Atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (for non-squamous only, if no contraindications to bevacizumab). 1

Critical Pre-Treatment Requirements

Before initiating therapy, confirm the following:

• Performance status must be ECOG 0-1 for combination immunotherapy-chemotherapy regimens. 1

• Complete molecular testing must document EGFR-negative and ALK-negative status (already confirmed in this case). 1, 2

• Screen for contraindications to immune checkpoint inhibitors, including active autoimmune disease requiring systemic immunosuppression, organ transplantation, or conditions requiring >10 mg daily prednisone equivalent. 1

• Assess for bevacizumab contraindications if considering atezolizumab-bevacizumab regimens: clinically significant hemoptysis, inadequate organ function, ECOG PS >1, uncontrolled hypertension, or recent cardiovascular events. 1

Treatment Duration and Monitoring

• Continue pembrolizumab for up to 24 months (35 cycles) or until disease progression or unacceptable toxicity, whichever occurs first. 3, 2

• Perform first radiographic assessment at 6 weeks, then every 6-9 weeks using RECIST v1.1 criteria; consider iRECIST or imRECIST to account for pseudoprogression with immunotherapy. 3

• Monitor for immune-related adverse events including pneumonitis, colitis, hepatitis, endocrinopathies, and dermatologic toxicities throughout treatment and for months after discontinuation. 2

Common Pitfalls to Avoid

• Do not use pembrolizumab monotherapy for PD-L1 1-49% despite FDA approval for PD-L1 ≥1%; combination therapy provides superior outcomes in this intermediate expression range. 1

• Do not delay treatment to pursue single-agent immunotherapy in patients with PD-L1 <50%, as combination therapy is the evidence-based standard. 1

• Do not withhold immunotherapy in patients with controlled brain metastases or autoimmune disease on minimal immunosuppression; these patients can often safely receive checkpoint inhibitors with appropriate monitoring. 3

• Ensure smoking cessation counseling, as continued smoking may reduce bioavailability of subsequent therapies and worsen performance status. 1