The Prognostic Value of Lymph Node Downstaging Following Neoadjuvant Chemoimmunotherapy for Non-Small Cell Lung Cancer

<b>Background</b>: The use of immune checkpoint inhibitors (ICI) and other targeted molecular agents for non-small cell lung cancer (NSCLC) has led to unprecedented rates of major pathologic response and improvements in overall survival. The aim of this study was to evaluate the prognostic significance of lymph node downstaging following neoadjuvant chemoimmunotherapy for resectable NSCLC. <b>Methods</b>: This study used retrospective data from the National Cancer Database (NCDB), which was queried for all patients diagnosed with NSCLC between 2017-2021 who underwent lung cancer surgery after receiving neoadjuvant chemoimmunotherapy. Only those staged as cN1 or cN2 were included. Patients were stratified according to post-therapy pathologic lymph node status, whether positive (ypN+) or negative (ypN-). Five-year overall survival (OS) was examined using Kaplan-Meier analyses with log-rank tests. Univariate and multivariate Cox regression analyses were conducted to identify significant predictors of survival. <b>Results</b>: Of the total 621 patients, 229 (37%) were diagnosed with cN1 disease and 392 (63%) with cN2. With neoadjuvant chemoimmunotherapy, 59% of cN1 and 40% of cN2 patients were down-staged to ypN0. While 5-year OS was not significantly different according to clinical N stage (76% for cN1 vs. 63% for cN2, p=0.08), higher post-therapy nodal staging correlated with poorer long-term survival (5-year OS of 84% for ypN0, 64% for ypN1, and 51% for ypN2, p <0.001). On multivariate analysis, cN1 to ypN+ (HR 2.56, p=0.009) and cN2 to ypN+ (HR 3.09, p=0.001) were predictors of worse OS compared to cN1 to ypN-, while the difference was not statistically significant for cN2 to ypN- (HR 1.01, p=0.051). Among ypN- patients, similar 5-year OS was seen among those who received adjuvant chemoimmunotherapy and those who did not (82.2% vs. 86.2%, p = 0.26). <b>Conclusion</b>: Patients receiving neoadjuvant chemoimmunotherapy for resectable NSCLC experience high rates of nodal down-staging. Achieving ypN0 status post-therapy strongly predicts favorable long-term survival in this population, while pretreatment cN stage becomes less prognostically relevant.