Is neoadjuvant immunotherapy recommended for an elderly female patient with a 4 cm stage T3N0 squamous cell carcinoma of the lung and a history of Chronic Obstructive Pulmonary Disease (COPD)?

Neoadjuvant Immunotherapy for 4 cm T3N0 Squamous Cell Lung Cancer in an Elderly Patient with COPD

Neoadjuvant immunotherapy is recommended for this patient, as pembrolizumab combined with platinum-based chemotherapy followed by surgery is FDA-approved for resectable NSCLC ≥4 cm and demonstrates superior pathologic response rates and survival compared to chemotherapy alone, with acceptable toxicity even in elderly patients. 1

Evidence Supporting Neoadjuvant Immunotherapy

FDA-Approved Indication

• Pembrolizumab is FDA-approved for resectable NSCLC (tumors ≥4 cm or node positive) in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by continuation as a single agent as adjuvant treatment after surgery 1
• This patient's 4 cm T3N0 squamous cell carcinoma meets the exact size criterion specified in the FDA label 1

Superior Efficacy Over Chemotherapy Alone

• Neoadjuvant chemoimmunotherapy achieves significantly higher pathologic complete response rates compared to chemotherapy alone (OR 7.63; 95% CI 4.49-12.97; p<0.001) 2
• Progression-free survival is improved with neoadjuvant chemoimmunotherapy versus chemotherapy alone (HR 0.51; 95% CI 0.38-0.67; p<0.001) 2
• Overall survival is superior with neoadjuvant chemoimmunotherapy (HR 0.51; 95% CI 0.36-0.74; p=0.0003) 2

Safety Profile Comparable to Chemotherapy

• Neoadjuvant chemoimmunotherapy yields similar toxicity rates to chemotherapy alone (OR 1.01; 95% CI 0.67-1.52; p=0.97), with an estimated grade ≥3 toxicity rate of 18.0% 2
• The treatment does not cause treatment-related delays in surgery, with a median interval of 36 days between final treatment and surgery 3

Special Considerations for Elderly Patients with COPD

Age Should Not Be a Barrier

• Surgical treatment and systemic therapy should not be denied to elderly patients based on chronological age alone 4, 5
• No overall differences in safety or effectiveness were observed between elderly patients (≥65 years) and younger patients treated with pembrolizumab for NSCLC 1

COPD Management

• Patients with squamous cell lung cancer have a higher incidence of COPD compared to nonsquamous NSCLC 6
• Screen aggressively for immune-mediated pneumonitis during immunotherapy, which requires prompt recognition and high-dose corticosteroid treatment 6
• The risk of high-grade and fatal toxicity is elevated in patients with pre-existing interstitial lung fibrosis, requiring careful evaluation by an expert tumor board 4

Performance Status Requirements

• Patients must have ECOG performance status 0-1 for perioperative immunotherapy eligibility 6
• Treatment decisions should incorporate functional status, comorbidities, and life expectancy rather than chronological age 4, 5

Treatment Protocol

Neoadjuvant Phase

• Administer pembrolizumab in combination with platinum-based chemotherapy (carboplatin plus paclitaxel or paclitaxel protein-bound for squamous histology) 1
• PD-L1 testing is unnecessary for patient selection in neoadjuvant immunotherapy for squamous cell lung cancer 6

Surgical Timing

• Perform surgery 4-6 weeks after the last neoadjuvant dose of nivolumab and chemotherapy 6
• Shorter treatment intervals (≤33 days) are associated with improved disease-free survival without influencing overall survival or pathologic response 7
• Patients should avoid prolonged treatment intervals between neoadjuvant immunochemotherapy and surgery 7

Adjuvant Phase

• Continue pembrolizumab as a single agent following surgery as per FDA-approved protocol 1

Why Not Surgery-First Approach?

Neoadjuvant Advantages Over Adjuvant-Only

• Neoadjuvant immunotherapy facilitates resection of surgically-challenging lung squamous cell carcinoma, achieving an 87% radical resection rate 3
• More than 95% of neoadjuvant patients receive their planned chemotherapy dose compared to only 66% of adjuvant patients 4
• Neoadjuvant treatment achieves downstaging, potentially resulting in less extensive resection 4

Equivalence in Survival

• Comparing outcomes of neoadjuvant versus adjuvant chemotherapy did not reveal a major difference in overall survival 4
• However, the consistent delivery of therapy and potential for downstaging favor the neoadjuvant approach when immunotherapy is added 4

Critical Pitfalls to Avoid

• Do not rely on CT scan-based response assessment: There is very low consistency (weighted kappa=0.122, p=0.315) between CT scan-based and final pathological evaluation after neoadjuvant immunotherapy 3
• Do not extrapolate data from highly selected trial populations to frail elderly patients with multiple comorbidities: The risk-benefit ratio has not been adequately studied in patients over 80 years of age 4, 5
• Do not delay surgery excessively: Treatment intervals >33 days are associated with worse disease-free survival 7
• Do not use this approach if the patient has ECOG PS ≥2: These patients should receive best supportive care 6