What trials have evaluated neoadjuvant immunotherapy in patients with resectable non-small cell lung cancer (NSCLC)?

Key Trials Evaluating Neoadjuvant Immunotherapy in Resectable NSCLC

The landmark CheckMate-816 trial (NCT02998528) is the pivotal phase III study that established neoadjuvant nivolumab plus platinum-doublet chemotherapy as superior to chemotherapy alone, demonstrating improved overall survival (HR 0.72, P=0.048) with 5-year OS of 65.4% versus 55.0%. 1

Major Phase III Trials

CheckMate-816 (NCT02998528)

• Design: Randomized, open-label phase III trial comparing neoadjuvant nivolumab 360 mg plus platinum-doublet chemotherapy versus chemotherapy alone for 3 cycles, followed by surgery 2, 3
• Population: 358 patients with resectable stage IB-IIIA NSCLC without known EGFR/ALK mutations 2
• Primary endpoints: Event-free survival and pathologic complete response (pCR) 4
• Key results:
  • Median EFS: 31.6 months versus 20.8 months (HR 0.63, P=0.005) 4
  • pCR rate: 24.0% versus 2.2% (P<0.001) 2, 4
  • 5-year OS: 65.4% versus 55.0% (HR 0.72, P=0.048) 1
  • Surgery performed in 83.2% versus 75.4% of patients 4
  • Grade 3-4 treatment-related adverse events: 33.5% versus 36.9% 4

CheckMate-77T (NCT04025879)

• Design: Randomized, double-blind trial evaluating neoadjuvant nivolumab plus platinum-doublet chemotherapy followed by surgery and adjuvant nivolumab versus placebo plus chemotherapy 3
• Population: Patients with resectable stage IIA (>4 cm) to IIIB (T3N2 or T4N2) NSCLC 3
• Key safety findings:
  • Serious adverse reactions in 21% during neoadjuvant phase 3
  • 5.3% did not receive surgery due to adverse reactions 3
  • Median duration of exposure: 10.3 months 3

Major Phase II Trials

LCMC3 (NCT02927301)

• Design: Multicenter, single-arm phase II trial evaluating neoadjuvant atezolizumab monotherapy 2
• Key results:
  • MPR rate: 21% overall 2
  • MPR rate in PD-L1 TPS ≥50%: 33% 2

NADIM (NCT03081689)

• Design: Multicenter, single-arm phase II trial of neoadjuvant nivolumab plus paclitaxel/carboplatin for 3 cycles, followed by surgery and adjuvant nivolumab for 1 year 2, 5
• Population: 46 patients with resectable stage IIIA NSCLC 5
• Key results:
  • Median DFS: 21.4 months 2
  • 3-year OS rate: >80% 2
  • 24-month progression-free survival: 77.1% 5
  • Grade 3-4 treatment-related adverse events: 30% 5
  • 93% of patients underwent surgery 5

CheckMate 816 Exploratory Arm (Nivolumab + Ipilimumab)

• Design: Concurrently randomized exploratory arm comparing neoadjuvant nivolumab plus ipilimumab versus chemotherapy 6
• Population: 221 patients (113 nivolumab/ipilimumab, 108 chemotherapy) 6
• Key results:
  • Median EFS: 54.8 months versus 20.9 months (HR 0.77) 6
  • 3-year EFS: 56% versus 44% 6
  • 3-year OS: 73% versus 61% (HR 0.73) 6
  • pCR rate: 20.4% versus 4.6% 6
  • Grade 3-4 treatment-related adverse events: 14% versus 36% 6
  • Surgery performed in 74% versus 76% 6

Chinese Phase I Study (Sintilimab)

• Design: Phase I study evaluating neoadjuvant sintilimab in resectable IA-IIIB NSCLC 2
• Key results:
  • MPR rate: 40.5% 2
  • ORR: 20% 2
  • pCR rate in primary tumors: 16.2% 2

Chinese Subpopulation Analysis of CheckMate-816

• Population: 97 Chinese patients from CheckMate-816 7
• Key results:
  • Median EFS: not reached versus 13.9 months (HR 0.47) 7
  • pCR rate: 25.0% versus 1.9% 7
  • Surgery performed in 82% versus 77% 7
  • Grade 3-4 treatment-related adverse events: 42% in both arms 7

Important Trial Design Considerations

Common eligibility criteria across trials:

• Resectable stage IB (≥4 cm) to IIIA NSCLC 2, 3, 4
• Exclusion of known EGFR/ALK mutations in most trials 2, 3
• ECOG performance status 0-1 3, 5
• No active autoimmune disease or requirement for systemic immunosuppression 3, 5

Standard treatment regimens:

• 2-4 cycles of neoadjuvant therapy 2
• Surgery performed 4-6 weeks after completion of neoadjuvant therapy 2
• Adjuvant immunotherapy for 1 year in responders 2