What are the recommended neoadjuvant chemo-immunotherapy (chemotherapy and immunotherapy) regimens for a patient with clinical stage T2N1 (cT2N1) lung adenocarcinoma?

Neoadjuvant Chemo-Immunotherapy for cT2N1 Lung Adenocarcinoma

For resectable cT2N1 lung adenocarcinoma, the recommended neoadjuvant regimen is pembrolizumab 200 mg every 3 weeks combined with cisplatin 75 mg/m² and pemetrexed 500 mg/m² for up to 4 cycles, followed by surgery and adjuvant pembrolizumab for up to 13 cycles. 1

Primary Treatment Recommendation

The FDA-approved regimen based on KEYNOTE-671 demonstrates superior outcomes with neoadjuvant pembrolizumab plus platinum-pemetrexed chemotherapy followed by surgery and adjuvant pembrolizumab, showing statistically significant improvements in both overall survival (HR 0.72,95% CI 0.56-0.93) and event-free survival (HR 0.58,95% CI 0.46-0.72) compared to chemotherapy alone. 1

Specific Dosing Protocol

• Neoadjuvant phase: Pembrolizumab 200 mg IV on Day 1 combined with cisplatin 75 mg/m² and pemetrexed 500 mg/m² on Day 1 of each 21-day cycle for up to 4 cycles 1
• Surgery: Performed within 4-12 weeks following completion of neoadjuvant therapy 1
• Adjuvant phase: Pembrolizumab 200 mg IV every 3 weeks for up to 13 cycles 1

Required Supportive Medications

• Vitamin B12: 1000 μg intramuscularly starting at least 1 week before first pemetrexed dose, continued every 9 weeks throughout treatment 2
• Folic acid: 0.4-1.0 mg orally daily starting at least 1 week before first dose, continued throughout entire treatment course 2

Alternative Neoadjuvant Regimens

Nivolumab-Based Options

• Nivolumab monotherapy: 3 mg/kg IV every 2 weeks for 2-3 cycles achieved major pathologic response (MPR) rates of 17-45% and pathologic complete response (pCR) rates of 5-15% in early trials 3
• Nivolumab plus ipilimumab: Demonstrated higher MPR (33%) and pCR (29%) rates compared to nivolumab monotherapy in the NEOSTAR trial 3

Real-World Chemo-Immunotherapy Data

Real-world evidence from 76 patients with resectable NSCLC (92% stage III) receiving neoadjuvant pembrolizumab or nivolumab combined with chemotherapy demonstrated an MPR rate of 64%, pCR rate of 37%, and 1-year progression-free survival of 91% for stage III patients. 4 This study showed that 69% of patients with clinical N2 disease were downstaged to pathological N0 or N1 4.

Pathologic Response as Surrogate Endpoint

Major pathologic response (≤10% residual viable tumor) serves as a key efficacy endpoint for neoadjuvant immunotherapy, though its value as a surrogate marker remains under investigation. 3 The KEYNOTE-671 trial demonstrated pCR and mPR rates that correlated with improved survival outcomes 1.

Immune Microenvironment Changes

Tumors achieving MPR after neoadjuvant chemo-immunotherapy show increased infiltration of CD8+ T cells, GZMB+ CD8+ T cells, PD-1+ CD8+ T cells, macrophages, and M1 macrophages, with higher CD8+ T/Treg ratios. 5 Patients with higher densities of macrophages in the tumor microenvironment had significantly longer progression-free survival 5.

Surgical Considerations

Timing and Feasibility

• Surgery should be performed 4-12 weeks after completing neoadjuvant therapy 1
• Approximately 81% of patients receiving neoadjuvant pembrolizumab plus chemotherapy underwent definitive surgery in KEYNOTE-671, compared to 76% in the chemotherapy-alone arm 1
• The risk of disease progression preventing curative resection is less than 10% with neoadjuvant immunotherapy 3

Surgical Outcomes

Preoperative and intraoperative unresectability rates after neoadjuvant immune checkpoint inhibitors appear comparable to those observed with neoadjuvant chemotherapy alone. 6 R0 resection remains achievable in the majority of patients, with thoracoscopic minimally invasive surgery being the predominant approach 5.

Monitoring Requirements

During Neoadjuvant Treatment

• Complete blood counts on days 8 and 15 of each cycle to assess blood cell nadirs 2
• Tumor assessment at baseline, Week 7, and Week 13 during neoadjuvant phase 1
• Assessment within 4 weeks prior to surgery 1

Post-Surgery Surveillance

• Tumor assessment every 16 weeks through Year 3, then every 6 months thereafter 1
• Clinical and laboratory evaluation every 3 months during first year, then every 6 months 2

Critical Safety Considerations

Immune-Related Adverse Events

Immune-related adverse events can develop at any time during or even months after treatment completion, requiring ongoing vigilance. 2 Key warning signs include:

• Pneumonitis: New or worsening shortness of breath, cough, or chest pain requiring immediate medical attention 2
• Colitis: Diarrhea, abdominal pain, or blood in stool prompting urgent evaluation 2
• Cardiovascular toxicity: Any new cardiovascular symptoms warrant immediate evaluation 2

Chemotherapy Toxicity

Overall, 62% of patients receiving pemetrexed plus carboplatin experience grade 3-4 adverse events, with blood count nadirs typically occurring on days 8 and 15 of each cycle. 2 Adequate hydration is essential, particularly on treatment days 2.

Biomarker Considerations

PD-L1 expression and tumor mutational burden (TMB) as predictive biomarkers remain controversial in the neoadjuvant setting. 3 In KEYNOTE-671, patients were enrolled regardless of PD-L1 expression, and the trial demonstrated benefit across all PD-L1 subgroups 1. Some studies showed MPR occurred irrespective of PD-L1 expression and TMB 3, while others suggested correlation 3.

Common Pitfalls to Avoid

• Do not delay surgery beyond 12 weeks after completing neoadjuvant therapy 1
• Do not omit vitamin B12 and folic acid supplementation, as this significantly increases pemetrexed toxicity 2
• Do not assume radiologic response captures immunotherapy effect—objective response rates by RECIST occur in only 7-22% of cases despite higher pathologic response rates 3
• Be aware of nodal immune flares (occurring in approximately 22% of patients), which may mimic progression and require pathologic evaluation before excluding potentially curative surgery 3