Abstract
BACKGROUND: Neoadjuvant chemoimmunotherapy demonstrates favorable survival outcomes and high pathological complete response (pCR) rates, but its efficacy in resectable N1/N2 nonsmall cell lung cancer (NSCLC) remains unproven. Additionally, predictive biomarkers for treatment efficacy and the relationship between lymph node status postneoadjuvant therapy and survival are unclear. This prospective study evaluates the efficacy and safety of combining penpulimab with chemotherapy for resectable N1/N2 NSCLC. MATERIALS AND METHODS: This prospective cohort study enrolled patients aged ≥18 years with resectable N1/N2 NSCLC. Patients received penpulimab, carboplatin, and paclitaxel (for squamous cell carcinoma) or pemetrexed (for adenocarcinoma) every 21 days for three cycles, followed by surgery within 6 weeks. Primary endpoint: major pathological response (MPR). Secondary endpoints: pCR, objective response rate (ORR), R0 resection rate, disease-free survival (DFS), overall survival (OS), and treatment- and surgery-related adverse events. The study was Ethics Committee-approved. RESULTS: From August 2022 to August 2023, 32 patients were enrolled. The preoperative ORR was 75.0%. R0 resection was achieved in 96.9%. MPR and pCR were achieved in 51.6% and 22.6% of patients, respectively. Significant associations between pCR and Response Evaluation Criteria in Solid Tumors response categories ( P < 0.001), downstaging of nodal status ( P = 0.007), and tumor mutational burden (TMB) ( P = 0.037) were observed in our analysis. Multivariate regression analysis showed that no clinical factor other than TMB was predictive of the pCR. One-year DFS was 84.4%, and OS was 96.9%, with a median follow-up of 18 months. DFS was 100% in the MPR group versus 66.7% in the non-MPR group ( P < 0.001) and higher in the pCR group ( P = 0.0074). Nodal downstaging was observed in 50.0%, with superior survival in this group. Adverse events occurred in 93.8%, primarily fatigue, nausea, vomiting, and rashes. CONCLUSION: This is the first report of neoadjuvant penpulimab in N1/N2 NSCLC, demonstrating efficacy, feasibility, and survival benefits, especially in patients with high tumor mutational burden.