Does the decision to use neoadjuvant chemo-immunotherapy in a patient with clinical stage T2N1 lung adenocarcinoma depend on Programmed Death-Ligand 1 (PD-L1) status?

Neoadjuvant Chemo-Immunotherapy for Stage T2N1 Lung Adenocarcinoma: PD-L1 Status Is NOT Required

For patients with resectable stage T2N1 lung adenocarcinoma, neoadjuvant chemo-immunotherapy should be offered regardless of PD-L1 status, as current expert consensus and clinical trial data demonstrate significant benefit across all PD-L1 expression levels. 1

Guideline-Based Recommendation

The Chinese expert consensus on neoadjuvant immunotherapy explicitly states that "considering the limited predictive performance of biomarkers in neoadjuvant immunotherapy, it is unnecessary to apply biomarker detection for patient selection in clinic." 1 This represents the most direct guideline addressing your specific question about neoadjuvant therapy in resectable NSCLC.

Key Consensus Points:

• Neoadjuvant ICI plus chemotherapy is a promising regimen for patients with resectable stage IB-IIIA NSCLC 1
• Biomarker testing (including PD-L1) is not necessary for patient selection in the neoadjuvant setting 1
• The only exception is EGFR/ALK-positive patients, where neoadjuvant ICI monotherapy should be used judiciously 1

Evidence Supporting PD-L1-Independent Benefit

Meta-Analysis Data Shows Benefit Across All PD-L1 Levels

The most comprehensive 2024 meta-analysis of randomized controlled trials specifically addressed this question and found: 2

For PD-L1 <1% (negative) patients:

• pCR rate: 18.3% with nCIT vs 3.0% with chemotherapy alone (OR 5.64, p<0.001) 2
• MPR rate: 38.9% with nCIT vs 15.5% with chemotherapy alone (OR 3.57, p<0.001) 2
• Event-free survival significantly improved (HR 0.75, p=0.002) 2

For PD-L1 ≥1% (positive) patients:

• Higher response rates than PD-L1 negative (pCR 32.8% vs 18.3%, OR 2.28) 2
• Better EFS (HR 0.44 vs 0.75) 2
• However, both groups benefit significantly from adding immunotherapy 2

Supporting Meta-Analysis Findings

A 2023 systematic review of 66 studies demonstrated: 3

• Overall pooled pCR rate of 28.1% with neoadjuvant immunotherapy 3
• PD-L1 expressors (≥1%) were more likely to achieve pCR (OR 2.93), but PD-L1-negative patients still achieved substantial benefit 3
• Grade ≥3 toxicity rate was only 18.0%, indicating acceptable safety across all PD-L1 levels 3

Clinical Algorithm for Your T2N1 Patient

Step 1: Confirm Eligibility

• Resectable stage T2N1 lung adenocarcinoma (stage IIB-IIIA) 1
• Performance status 0-1 1
• No EGFR or ALK mutations 1

Step 2: Offer Neoadjuvant Chemo-Immunotherapy

• Do NOT wait for PD-L1 testing results 1
• Recommend 2-4 cycles of platinum-based chemotherapy plus PD-1/PD-L1 inhibitor 1
• Standard regimen: carboplatin/pemetrexed plus pembrolizumab for adenocarcinoma 1, 2

Step 3: Timing

• Perform surgery 4-6 weeks after completing neoadjuvant therapy 1
• Assess response with PET-CT plus serum tumor markers and/or ctDNA 1

Step 4: Adjuvant Therapy

• For patients achieving MPR/pCR: consider 1-year maintenance immunotherapy 1
• For stage II-IIIA disease: adjuvant atezolizumab improves disease-free survival regardless of initial PD-L1 status 1

Important Caveats

When PD-L1 Testing Matters (Metastatic Disease Context)

The guidelines emphasizing PD-L1 testing apply to metastatic stage IV disease, not resectable disease: 1

• Single-agent pembrolizumab requires PD-L1 ≥50% in metastatic setting 1
• Combination chemo-immunotherapy shows benefit across all PD-L1 levels in metastatic disease 1
• Your T2N1 patient has resectable disease, where different principles apply 1

PD-L1 as an Imperfect Biomarker

Multiple guidelines acknowledge PD-L1 limitations: 1

• Some patients with low PD-L1 respond to immunotherapy while others with high levels do not 1
• PD-L1 expression is more useful for deciding between single-agent vs combination therapy in metastatic disease, not for excluding patients from neoadjuvant therapy 1
• Technical variability exists across different PD-L1 testing platforms 4

Survival Benefit Regardless of PD-L1

The 2024 meta-analysis found that neoadjuvant chemo-immunotherapy improved event-free survival in PD-L1-negative patients (HR 0.75) 2, though the magnitude was greater in PD-L1-positive patients (HR 0.44) 2. Importantly, both groups crossed the threshold for clinically meaningful benefit, and the study authors concluded that nCIT should be recommended for resectable NSCLC patients with negative PD-L1 expression 2.

The NADIM trial demonstrated 3-year overall survival >80% with neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab, establishing proof of concept for this approach 1.