What is the recommended first-line treatment for a patient with advanced non-small cell lung cancer (NSCLC), considering therapies such as pembrolizumab?

First-Line Treatment for Advanced Non-Small Cell Lung Cancer (NSCLC)

For patients with advanced NSCLC without actionable mutations (EGFR/ALK negative), pembrolizumab combined with platinum-based chemotherapy and pemetrexed (for non-squamous) or taxanes (for squamous) is the preferred first-line treatment, regardless of PD-L1 status, with pembrolizumab monotherapy reserved only for those with PD-L1 ≥50%. 1

Treatment Algorithm Based on PD-L1 Expression and Histology

For PD-L1 ≥50% (High Expression)

• Pembrolizumab monotherapy (200 mg IV every 3 weeks) is a standard first-line option for patients with PD-L1 tumor proportion score (TPS) ≥50%, achieving median overall survival of 30 months versus 14 months with chemotherapy alone (HR 0.69) 1, 2

• However, combination chemo-immunotherapy may be preferred over monotherapy for patients requiring rapid tumor burden reduction or those with high disease burden 1

• Pembrolizumab monotherapy demonstrates an ESMO-MCBS score of 5, indicating substantial clinical benefit 1

For PD-L1 <50% or Any PD-L1 Level (Preferred Approach)

Non-Squamous Histology:

• Pembrolizumab + pemetrexed + platinum (cisplatin or carboplatin) for 4 cycles, followed by pembrolizumab + pemetrexed maintenance is the standard regimen 1, 2

• This combination achieved median OS of 22.0 months versus 10.6 months with chemotherapy alone (HR 0.56,95% CI 0.46-0.69, P<0.001) in the KEYNOTE-189 trial 1, 3

• The OS benefit was observed across all PD-L1 subgroups, including those with PD-L1 <1% 1, 3

• Alternative regimens include atezolizumab + bevacizumab + carboplatin + paclitaxel (ESMO-MCBS score: 3) or nivolumab + ipilimumab plus 2 cycles of chemotherapy (ESMO-MCBS score: 4) 1

Squamous Histology:

• Pembrolizumab + carboplatin + (nab-)paclitaxel for 4 cycles, followed by pembrolizumab maintenance is the standard regimen (ESMO-MCBS score: 4) 1, 2

• Alternative: nivolumab + ipilimumab plus 2 cycles of chemotherapy (ESMO-MCBS score: 4) 1

Critical Pre-Treatment Requirements

• Molecular testing is mandatory before initiating any systemic therapy to exclude EGFR mutations and ALK rearrangements, as these patients should receive targeted therapy instead 1, 2

• PD-L1 testing using an FDA-approved assay is required to guide treatment selection 1, 2

• Performance status assessment: Systemic therapy should be offered to all stage IV patients with PS 0-2 1

Treatment Duration and Monitoring

• Pembrolizumab is administered at 200 mg IV every 3 weeks for up to 35 cycles (approximately 2 years) 1, 2, 3

• Response evaluation should occur after 2-3 cycles using the same radiographic modality that demonstrated baseline disease 1

• Immunotherapy can be discontinued after 2 years of treatment based on registration trial protocols 1

Common Pitfalls to Avoid

Do not use pembrolizumab monotherapy in patients with PD-L1 <50% unless there are contraindications to chemotherapy, as the benefit is primarily driven by the high PD-L1 expression group 1

Do not use pembrolizumab monotherapy in never-smokers regardless of PD-L1 status, as this population shows minimal benefit (HR 0.57,95% CI 0.18-1.80, P=0.34) 4

Exercise caution in patients ≥75 years, as the benefit of chemo-immunotherapy is unclear in this age group, though pembrolizumab monotherapy remains an option for those with PD-L1 ≥50% 1, 4

Do not skip molecular testing even in patients with high PD-L1 expression, as actionable mutations require targeted therapy first-line 1, 2

Pemetrexed use is restricted to non-squamous histology only in any line of treatment 1

Special Populations

Performance Status 2:

• Platinum-based doublets (preferably carboplatin) should be considered in eligible patients with PS 2 1
• Monotherapy immunotherapy can be considered but data are limited 1

Performance Status 3-4:

• Best supportive care is recommended 1

Elderly Patients (≥75 years):

• Treatment recommendations are similar to the general population for those with good PS and adequate organ function 1
• The toxicity of platinum doublets should be carefully evaluated, with carboplatin preferred when tolerable 1

Contraindications to Immunotherapy

Pembrolizumab should not be used in patients with severe autoimmune disease or solid organ transplantation 1