What is the role of neoadjuvant immunotherapy, including checkpoint inhibitors such as pembrolizumab (pembrolizumab) or nivolumab (nivolumab), in the treatment of resectable non-small cell lung cancer (NSCLC)?

Neoadjuvant Immunotherapy in Resectable Non-Small Cell Lung Cancer

Neoadjuvant chemo-immunotherapy is now the standard of care for patients with resectable stage IB (≥4 cm) to IIIA NSCLC without EGFR mutations or ALK rearrangements, based on FDA approval and major society recommendations. 1, 2, 3

Patient Selection Criteria

Offer neoadjuvant chemo-immunotherapy to patients meeting ALL of the following:

• Resectable NSCLC with tumors ≥4 cm OR node-positive disease (stage IB-IIIA) 1, 2, 3
• No known EGFR mutations or ALK rearrangements 2, 3
• Performance status 0-1 2
• PD-L1 testing is NOT required for patient selection - benefit is seen across all PD-L1 expression levels 2

Treatment Regimen

Standard approach consists of:

• 2-4 cycles of platinum-doublet chemotherapy plus PD-1/PD-L1 inhibitor (nivolumab, pembrolizumab, or atezolizumab) 1, 2
• For adenocarcinoma: carboplatin/pemetrexed plus pembrolizumab is a standard regimen 2
• Surgery performed 4-6 weeks after completing neoadjuvant therapy 1, 2
• Single-agent immunotherapy for 1 year as adjuvant treatment after surgery 2, 3

Efficacy Data Supporting This Approach

Neoadjuvant chemo-immunotherapy dramatically outperforms chemotherapy alone:

• Pathologic complete response (pCR) rates: 28.1% with chemo-immunotherapy versus 6-8% with chemotherapy alone 4, 5
• Major pathologic response (MPR) rates range from 27-86% depending on regimen, with combination therapy achieving 41.9% versus 15% for chemotherapy alone 6, 7
• 7.6-fold higher odds of achieving pCR compared to chemotherapy alone (OR 7.63,95% CI 4.49-12.97) 5
• 49% reduction in disease progression (HR 0.51,95% CI 0.38-0.67) 5
• 49% reduction in mortality (HR 0.51,95% CI 0.36-0.74) 5

The CheckMate-816 trial specifically demonstrated that neoadjuvant nivolumab plus platinum-doublet chemotherapy achieved significantly higher pCR, MPR, and objective response rates compared to chemotherapy alone, leading to FDA approval 2, 3.

Response Assessment

Evaluate treatment response using:

• PET-CT plus serum tumor markers and/or ctDNA load 2
• Critical caveat: CT RECIST response has a 41-45% discordant rate with histopathologic response and cannot reliably predict pCR 4
• Pathologic assessment at surgery using standardized criteria: MPR defined as ≤10% viable tumor 6, 4

Adjuvant Management Strategy

Post-surgical treatment depends on pathologic response:

• For patients achieving MPR or pCR: 1-year maintenance immunotherapy is recommended 2
• For stage II-IIIA disease: adjuvant atezolizumab improves disease-free survival regardless of initial PD-L1 status 2
• The NADIM trial demonstrated that neoadjuvant nivolumab plus chemotherapy combined with adjuvant nivolumab achieved median DFS of 21.4 months and 3-year OS rate over 80% 1, 2

Safety Profile

Neoadjuvant chemo-immunotherapy is well-tolerated:

• Grade ≥3 toxicity rate: 18.0% 5
• No increase in toxicity compared to chemotherapy alone (OR 1.01,95% CI 0.67-1.52) 5
• Failure to undergo resection: 0-46% depending on regimen, with most modern protocols showing rates <20% 8
• No major delays in surgery with standard 2-4 cycle regimens 6

Important Clinical Caveats

Watch for these potential pitfalls:

• Immune-related nodal flares occur in approximately 22% of patients and may mimic progression - require pathologic evaluation before excluding potentially curative surgery 6
• Patients achieving pathologic response have dramatically improved survival: 75% reduction in progression risk (HR 0.25) and 74% reduction in mortality (HR 0.26) 5
• PD-L1 expressors (≥1%) are more likely to achieve pCR (OR 2.93), but benefit is seen across all PD-L1 levels, so testing should not delay treatment 2, 5

Monotherapy Immunotherapy: Not Recommended

While neoadjuvant immunotherapy monotherapy has been studied, it achieves substantially lower response rates:

• Nivolumab monotherapy: 17-45% MPR rate, 7-16% pCR rate 6, 8
• Atezolizumab monotherapy: 19-21% MPR rate overall (33% in PD-L1 ≥50%) 6, 1

The combination of immunotherapy plus chemotherapy is superior and should be the standard approach given the 7.6-fold improvement in pCR rates and survival benefits demonstrated in randomized trials 5.