What is the role of nivolumab (Opdivo) as perioperative immunotherapy in a patient with squamous lung cancer, particularly those with comorbid conditions such as chronic obstructive pulmonary disease (COPD) or asthma?

Nivolumab Perioperative Immunotherapy in Squamous Lung Cancer

Direct Recommendation

For resectable stage IIIA squamous cell lung cancer, perioperative nivolumab combined with platinum-based chemotherapy (3 cycles neoadjuvant followed by 1 year adjuvant nivolumab) achieves exceptional 5-year overall survival of 69.3% and should be strongly considered, with surgical outcomes comparable to chemotherapy or upfront resection. 1, 2

Neoadjuvant Setting for Resectable Disease

Treatment Protocol

• Administer 3 cycles of neoadjuvant chemotherapy (paclitaxel 200 mg/m² + carboplatin AUC 6) combined with nivolumab 360 mg intravenously 1
• Perform surgery 4-6 weeks after the last neoadjuvant dose 3, 1
• Follow with 1 year of adjuvant nivolumab monotherapy (240 mg every 2 weeks for 4 months, then 480 mg every 4 weeks for 8 months) 1

Efficacy Data

• 5-year progression-free survival reaches 65.0% and overall survival 69.3% in stage IIIA disease 1
• Major pathologic response and pathologic complete response serve as primary outcome indicators for neoadjuvant immunotherapy 3
• Only 24% of patients experienced disease progression at 5 years 1

Surgical Safety Considerations

• Perioperative nivolumab does not increase surgical complications compared to chemotherapy or upfront resection 2
• R0 resection achieved in 100% of patients who underwent surgery in the NEOSTAR trial 2
• 30-day mortality is 0% and 90-day mortality 2.7% 2
• Median time to operation is 31 days after last neoadjuvant dose 2
• Conversion rate from minimally invasive to open approach is 17%, comparable to standard practice 2

Management in Patients with COPD or Asthma

Critical Safety Monitoring

• Screen aggressively for immune-mediated pneumonitis, which requires prompt recognition and high-dose corticosteroid treatment 4
• Grade 3 or worse treatment-related adverse events occur in 30% during neoadjuvant treatment and 19% during adjuvant treatment 1
• No treatment-related surgery delays or unexpected long-term toxicities have been reported 1

Comorbidity Considerations

• Squamous cell lung cancer patients have higher incidence of COPD and heart disease compared to nonsquamous NSCLC 3
• All patients must have ECOG performance status 0-1 for perioperative immunotherapy eligibility 1
• Patients with PS 2 were excluded from immunotherapy trials and should receive best supportive care if PS 3-4 4

Biomarker Testing Considerations

PD-L1 Testing

• PD-L1 testing is unnecessary for patient selection in neoadjuvant immunotherapy for squamous cell lung cancer 3
• In the second-line metastatic setting, nivolumab is approved without requiring PD-L1 testing, as PD-L1 expression was not associated with response in squamous histology 4, 5
• For first-line metastatic disease with PD-L1 ≥50%, pembrolizumab monotherapy is an alternative option 5

EGFR/ALK Testing

• For EGFR/ALK-positive patients, neoadjuvant immune checkpoint inhibitor monotherapy should be used judiciously 3
• Mutations/alterations for which targeted treatments are approved are rare in squamous cell lung cancer 3

Metastatic/Advanced Disease Setting

Second-Line Treatment

• Nivolumab 3 mg/kg every 2 weeks is the category 1 (highest level) recommendation for second-line treatment after platinum-based chemotherapy failure 4
• Nivolumab demonstrates superior overall survival (9.2 vs 6.0 months) and improved response rates (20% vs 9%) compared to docetaxel 4, 6
• Grade 3-4 adverse events are significantly lower with nivolumab (7%) compared to docetaxel (55%) 4

First-Line Metastatic Disease

• For PD-L1 1%-49%, pembrolizumab plus platinum-based chemotherapy achieves 5-year OS rate of 18.4% versus 9.7% with chemotherapy alone 3
• Nivolumab plus ipilimumab with 2 cycles of chemotherapy shows 4-year survival of 20% versus 10% with chemotherapy alone in squamous histology 3
• For patients declining chemotherapy with PD-L1 1%-49%, pembrolizumab monotherapy may be given, though OS benefit is not statistically significant (HR 0.88) 3

Common Pitfalls to Avoid

• Do not prematurely discontinue immunotherapy based on traditional RECIST criteria—use immune-related response criteria (irRC) as immunotherapy has delayed response kinetics and pseudoprogression may occur 4, 7
• Do not delay surgery beyond 4-6 weeks after last neoadjuvant dose 3
• Do not use neoadjuvant immunotherapy efficacy assessment based solely on radiographic criteria—incorporate PET-CT, serum tumor markers, and/or ctDNA load 3
• Do not assume histology will remain a distinguishing factor for nivolumab use—evidence shows similar survival benefit in nonsquamous disease 7