Why is the dose of nivolumab (Opdivo) potentially higher in neoadjuvant immunotherapy for an elderly female patient with stage T3N0 squamous cell carcinoma of the lung and a history of chronic obstructive pulmonary disease (COPD)?

Why Nivolumab Dose is Higher in Neoadjuvant Immunotherapy for Lung Cancer

The dose of nivolumab is NOT actually higher in neoadjuvant immunotherapy—it remains 360 mg every 3 weeks (or 480 mg every 4 weeks) regardless of treatment setting, as nivolumab demonstrates a flat exposure-response relationship with a wide therapeutic margin across doses of 1-10 mg/kg every 2 weeks. 1

Understanding Nivolumab Dosing Principles

The perception of "higher" dosing in neoadjuvant settings is a misconception. The key pharmacologic principle is that nivolumab exhibits no significant exposure-response relationship for either efficacy or safety across a broad dose range:

• Nivolumab exposure (Cavg1) was not associated with overall survival in squamous NSCLC (HR 0.802,95% CI 0.555-1.16) or nonsquamous NSCLC (HR 0.94,95% CI 0.683-1.29), demonstrating a flat efficacy curve 1
• Similarly, nivolumab exposure showed no association with adverse events leading to discontinuation or death (HR 0.917,95% CI 0.644-1.31) 1
• This wide therapeutic margin supports consistent dosing across all treatment settings—whether neoadjuvant, adjuvant, or metastatic disease 1

Standard Dosing Across Treatment Settings

The FDA-approved dosing for nivolumab in combination with chemotherapy is uniform:

• Nivolumab 360 mg every 3 weeks in combination with platinum-doublet chemotherapy for up to 4 cycles, followed by nivolumab 480 mg every 4 weeks as monotherapy 2
• No overall differences in safety or effectiveness were observed between elderly patients (≥65 years) and younger patients receiving this regimen 2
• The original weight-based dosing of 3 mg/kg every 2 weeks produces equivalent exposures to the flat-dose regimens now commonly used 1

Why Neoadjuvant Immunotherapy May Appear More Intensive

The neoadjuvant approach achieves superior treatment delivery compared to adjuvant therapy, which may create the impression of higher dosing:

• More than 95% of neoadjuvant patients receive their planned chemotherapy dose compared to only 66% of adjuvant patients, due to better tolerance before surgery 3
• Neoadjuvant immunotherapy achieves tumor downstaging, potentially allowing less extensive resection 3
• The consistent delivery of therapy favors the neoadjuvant approach when immunotherapy is added to chemotherapy 3

Critical Considerations for Your Elderly Patient with COPD

For an elderly female with stage T3N0 squamous cell carcinoma and COPD, neoadjuvant immunotherapy should NOT be used—proceed directly to surgical resection if pulmonary function is adequate (VO2 max ≥15 ml/kg/min AND FEV1 >35% predicted), with consideration of adjuvant therapy postoperatively based on pathologic findings. 4

Why Surgery-First is Superior in This Case:

• Elderly patients (≥75 years) receiving neoadjuvant chemotherapy experience significantly higher incidence and severity of postoperative complications compared to younger patients, with no demonstrated mortality benefit 5, 4
• The risk-benefit ratio for neoadjuvant therapy has not been adequately studied in patients over 80 years, and extrapolation from highly selected trial populations to real-world elderly patients with comorbidities is inappropriate 4
• Surgery-first allows pathologic staging to guide treatment intensity rather than relying on potentially inaccurate clinical staging 4
• This approach permits assessment of surgical recovery and functional status before initiating systemic therapy, avoiding compounding surgical complications with chemotherapy-related toxicity 4

Postoperative Management Algorithm:

• Perform lobectomy (not pneumonectomy) using video-assisted thoracoscopic surgery (VATS) when available to minimize postoperative morbidity 4
• Adjuvant chemotherapy should be considered based on final pathologic staging and demonstrates survival benefit in elderly patients with tolerability similar to younger patients (<70 years) 4
• Postoperative radiotherapy is NOT indicated for pathologically confirmed N0 tumors with complete resection 4

Important Caveats

• Treatment decisions must be based on functional status, comorbidities, and life expectancy—not chronological age alone, as performance status 0-1 elderly patients should receive the same aggressive curative approach as younger patients 4, 3
• The presence of COPD necessitates careful pulmonary function testing but does not automatically preclude surgery; conservative resection (lobectomy rather than pneumonectomy) is particularly important in patients with baseline lung disease 4
• Patients with squamous cell lung cancer have higher incidence of COPD and should be screened aggressively for immune-mediated pneumonitis during immunotherapy, which requires prompt recognition and high-dose corticosteroid treatment 3
• No overall difference in safety was reported between elderly patients and younger patients treated with pembrolizumab for NSCLC, though discontinuation rates were higher in patients aged 75 years or older (38% vs 23% overall) 2