What is the treatment regimen for achieving a pathological complete response in patients with lung cancer (lung ca) from perioperative systemic treatment?

Pathological Complete Response Rates from Perioperative Systemic Treatment in Lung Cancer

Perioperative immunotherapy combined with platinum-based chemotherapy achieves pathological complete response (pCR) rates of 17-37% in resectable non-small cell lung cancer (NSCLC), representing a dramatic improvement over chemotherapy alone which achieves only 4-8% pCR rates.

Perioperative Immunotherapy Plus Chemotherapy Regimens

Pembrolizumab-Based Perioperative Treatment

• Neoadjuvant pembrolizumab 200 mg every 3 weeks combined with cisplatin-based chemotherapy (either cisplatin 75 mg/m² plus pemetrexed 500 mg/m² or gemcitabine 1000 mg/m²) for 4 cycles, followed by surgery and adjuvant pembrolizumab for 13 cycles, achieved an 18.1% pCR rate in the KEYNOTE-671 trial 1
• This represented a statistically significant improvement compared to 4.0% pCR with chemotherapy plus placebo (p<0.0001) 1
• Major pathological response (≤10% viable tumor) was achieved in 30.2% versus 11.0% with placebo (p<0.0001) 1

Durvalumab-Based Perioperative Treatment

• Neoadjuvant durvalumab plus platinum-based chemotherapy for 4 cycles followed by surgery and adjuvant durvalumab for 12 cycles achieved a 17.2% pCR rate in the AEGEAN trial 2
• This compared to only 4.3% pCR with chemotherapy alone (difference 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001) 2
• The pCR benefit was observed regardless of disease stage (II vs III) or PD-L1 expression level 2

Nivolumab-Based Perioperative Treatment

• Perioperative nivolumab plus platinum-based chemotherapy achieved the highest reported pCR rate of 37% in the NADIM II trial for stage IIIA/IIIB NSCLC 3
• This dramatically exceeded the 7% pCR rate with chemotherapy alone (relative risk 5.34; 95% CI, 1.34 to 21.23; P=0.02) 3
• The regimen consisted of neoadjuvant nivolumab plus chemotherapy followed by surgery and 6 months of adjuvant nivolumab 3

Chemotherapy-Only Perioperative Regimens

Historical Context

• Traditional platinum-doublet neoadjuvant chemotherapy alone achieves pCR rates of only 6-8% 4, 5
• Preoperative platinum-doublet chemotherapy improved survival over surgery alone with a hazard ratio of 0.87, similar to adjuvant chemotherapy (HR 0.89) 4
• Increasing from 2 to 4 preoperative chemotherapy cycles did not significantly increase pathological response rates (8.2% vs 6.1%) 5

Clinical Significance of Pathological Response

Major Pathological Response as Prognostic Marker

• Patients achieving major pathological response (MPR), defined as ≤10% viable tumor, demonstrate significantly improved survival across multiple studies 4
• The College of American Pathologists and Royal College of Pathologists recommend recording the presence of greater than or less than/equal to 10% residual viable tumor 4
• MPR has become a primary endpoint in neoadjuvant lung cancer clinical trials 4

Survival Outcomes with Perioperative Immunotherapy

• The KEYNOTE-671 trial demonstrated that pCR and mPR translated into improved event-free survival (HR 0.58; 95% CI, 0.46 to 0.72; p<0.0001) and overall survival (HR 0.72; 95% CI, 0.56 to 0.93; p=0.0103) 1
• The AEGEAN trial showed event-free survival benefit with durvalumab (HR 0.68; 95% CI, 0.53 to 0.88; P=0.004) 2
• The NADIM II trial reported 24-month progression-free survival of 67.2% with nivolumab versus 40.9% with chemotherapy alone (HR 0.47; 95% CI, 0.25 to 0.88) 3

Treatment Selection Algorithm

Patient Eligibility Criteria

• Resectable stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition 1, 2
• Exclude patients with active autoimmune disease requiring systemic therapy within 2 years, medical conditions requiring immunosuppression, or history of interstitial lung disease/pneumonitis requiring steroids 1, 2
• Treatment benefit occurs regardless of PD-L1 expression level 1, 2

Recommended Perioperative Regimen

• Administer 4 cycles of neoadjuvant immunotherapy (pembrolizumab 200 mg or durvalumab) every 3 weeks combined with cisplatin 75 mg/m² plus either pemetrexed 500 mg/m² (for non-squamous) or gemcitabine 1000 mg/m² (for squamous histology) 1, 2
• Perform surgery within 4-12 weeks following completion of neoadjuvant therapy 1
• Continue adjuvant immunotherapy for 12-13 cycles (pembrolizumab every 3 weeks for 13 cycles or durvalumab every 4 weeks for 12 cycles) 1, 2

Safety Profile

Toxicity Considerations

• Grade 3-4 adverse events occurred in 42.4% with durvalumab plus chemotherapy versus 43.2% with chemotherapy alone, indicating no significant increase in severe toxicity 2
• Grade 3-4 adverse events occurred in 19% with nivolumab plus chemotherapy versus 10% with chemotherapy alone 3
• The safety profile was consistent with the known toxicities of individual agents 2

Critical Pitfalls to Avoid

Imaging Limitations

• CT RECIST response has a 41-45% discordant rate with histopathologic response and cannot reliably predict pCR 4
• Inflammatory, stromal, or fibrotic changes confound radiographic interpretation and may appear similar to viable cancer cells 4
• Do not rely solely on radiographic response to determine treatment efficacy; pathological assessment remains the gold standard 4

Molecular Testing Requirements

• Patients with documented EGFR or ALK alterations should be excluded from perioperative immunotherapy protocols as efficacy data are limited 1
• These patients may benefit more from perioperative targeted therapy approaches 6