What is the role of perioperative immunotherapy in a patient with resectable non-small cell lung cancer (NSCLC) undergoing surgery?

Perioperative Immunotherapy in Resectable Non-Small Cell Lung Cancer

For patients with resectable NSCLC (stage IB ≥4 cm or node-positive disease through stage IIIA), neoadjuvant chemo-immunotherapy followed by surgery and adjuvant immunotherapy is now the standard of care, demonstrating superior pathologic response rates and survival compared to chemotherapy alone. 1

Patient Selection Criteria

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

• Stage IB (tumors ≥4 cm) through IIIA resectable NSCLC 1
• No known EGFR mutations or ALK rearrangements 1, 2
• Performance status 0-1 1
• No active autoimmune disease requiring immunosuppression 2

PD-L1 testing is NOT required for treatment selection in the neoadjuvant setting - benefit is demonstrated across all PD-L1 expression levels. 1 This differs fundamentally from metastatic disease, where PD-L1 ≥50% is required for single-agent pembrolizumab. 3

Treatment Algorithm

Neoadjuvant Phase (Pre-Surgery)

Administer 2-4 cycles of platinum-doublet chemotherapy plus PD-1/PD-L1 inhibitor: 1

• Standard regimen for adenocarcinoma: carboplatin/pemetrexed plus pembrolizumab 1
• FDA-approved regimen: nivolumab plus platinum-doublet chemotherapy 2
• Duration: 3 cycles is most commonly used 1

Response assessment before surgery: 1

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

Critical pitfall: Immune-related nodal flares occur in approximately 22% of patients and may mimic progression - these require pathologic evaluation before excluding potentially curative surgery. 1 Do not abandon surgery based on imaging alone if nodal enlargement occurs.

Surgical Phase

Timing: Perform surgery 4-6 weeks after last neoadjuvant treatment dose. 1

Safety data from CheckMate-77T: 2

• 5.3% of nivolumab-treated patients did not receive surgery due to adverse reactions (vs 3.5% placebo)
• 4.5% experienced surgical delay >6 weeks due to adverse reactions (vs 3.9% placebo)
• Fatal adverse reactions occurred in 2.2% during neoadjuvant phase

Adjuvant Phase (Post-Surgery)

For patients achieving major pathologic response (≤10% viable tumor) or pathologic complete response: 1

• Continue single-agent immunotherapy for 1 year 1, 2
• FDA-approved: nivolumab monotherapy after neoadjuvant nivolumab plus chemotherapy 2

For stage II-IIIA disease with complete resection (R0) and incidental N2 disease found at surgery: 4

• Platinum-based adjuvant chemotherapy is recommended (Grade 1A) 4
• Typically 3-4 cycles of doublet regimen initiated within 12 weeks 4
• Adjuvant atezolizumab improves disease-free survival regardless of PD-L1 status for tumors with PD-L1 ≥1% 1

Efficacy Data

Neoadjuvant chemo-immunotherapy demonstrates superior outcomes: 1

• Major pathologic response: 41.9% vs 15% for chemotherapy alone
• Pathologic complete response: significantly higher than chemotherapy alone
• 5-year survival benefit: 6-14% absolute improvement across stage IIIA patients 4

Compliance advantage: >90% of patients complete neoadjuvant therapy vs only 45-60% completing full adjuvant chemotherapy. 4

Safety Monitoring and Management

Common adverse reactions (>20%) during neoadjuvant phase: 2

• Nausea (38%)
• Constipation (34%)
• Fatigue (26%)
• Decreased appetite (20%)
• Rash (20%)

Serious immune-related adverse events requiring immediate evaluation: 2

• Pneumonitis (most critical in lung cancer patients): cough, shortness of breath, chest pain
• Colitis: diarrhea, abdominal pain, blood/mucus in stool
• Hepatitis: elevated transaminases, jaundice, right upper quadrant pain
• Endocrinopathies: thyroid dysfunction, adrenal insufficiency, hypophysitis
• Nephritis: decreased urine output, elevated creatinine

Management approach: 2

• Corticosteroids for grade ≥2 immune-related adverse events
• Permanent discontinuation may be required for grade 3-4 events
• 13% of patients permanently discontinued neoadjuvant therapy due to adverse reactions 2

Stage-Specific Considerations

Stage IA disease: Adjuvant chemotherapy is NOT recommended - potential harm demonstrated. 4

Stage IB disease: 4

• Efficacy remains controversial
• Consider only for tumors >4 cm based on CALGB 9633 subgroup analysis
• Not routinely recommended

Stage II-IIIA disease: 4

• Clear benefit for adjuvant platinum-based chemotherapy (Grade 1A)
• Neoadjuvant chemo-immunotherapy now preferred approach for resectable disease 1

Stage IIIA-N2 (bulky/multistation): 4

• Concurrent chemoradiotherapy may be superior to surgery for unresectable N2 disease
• Trimodality treatment (induction chemoradiotherapy + surgery) shows improved progression-free survival but not overall survival in some trials

Adjuvant Radiation Therapy

Postoperative radiation therapy (PORT) is generally NOT recommended: 4

• Appears detrimental to survival in stage IB and II 4
• May confer modest benefit only in stage IIIA with high local recurrence risk 4
• Reduces local recurrence but unclear survival benefit 4
• If used, give sequentially after adjuvant chemotherapy, not concurrently 4

Key Clinical Pitfalls to Avoid

1. Do not wait for PD-L1 results before initiating neoadjuvant chemo-immunotherapy - benefit is PD-L1-independent in this setting. 1

2. Do not abandon surgery for immune-related nodal enlargement without pathologic confirmation - 22% experience benign inflammatory flares. 1

3. Do not use adjuvant immunotherapy in stage IA disease - no benefit and potential harm. 4

4. Do not give concurrent chemoradiotherapy postoperatively - increased toxicity without proven benefit. 4

5. Screen for contraindications: Active autoimmune disease and conditions requiring immunosuppression are absolute contraindications. 2