Improvement of survival outcomes in patients with advanced-stage non-small-cell lung cancer treated with chemotherapy: a retrospective cohort study evaluating the role of immune checkpoint inhibitors.

Background: Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape of advanced non-small-cell lung cancer (NSCLC). However, there is limited real-world evidence on their impact in patients with driver mutation-negative or unknown mutation status. This subgroup remains underrepresented in the literature despite having fewer treatment options and a historically poor prognosis. This study aimed to evaluate the long-term impact of ICIs on survival outcomes in this patient population. Methods: We retrospectively reviewed patients with stage IV NSCLC who were treated at our institution between 2007 and 2024. Patients with driver mutation-negative or unknown mutation status who did not receive molecular-targeted therapies were included. We divided the study cohort into three periods based on the timing of chemotherapy initiation: period 1 [2007-2015], period 2 [2016-2018], and period 3 [2019-2024]. Overall survival (OS) was calculated from the start of chemotherapy to the date of death or last follow-up. Kaplan-Meier curves and Cox regression analysis were used to evaluate survival, with propensity score matching (PSM) conducted for sensitivity analysis. Results: A total of 762 patients met the inclusion criteria. Patient demographics changed over time, with an increasing median age and a higher proportion of elderly patients (≥75 years) in later periods. The use of ICIs increased significantly over the three periods, from 0% in period 1 to 79.4% in period 3. Median OS (mOS) improved from 11.5 to 20.7 months and then to 19.1 months (P<0.001). In the multivariate Cox regression analysis, ICI use was significantly associated with improved OS [hazard ratio (HR) =0.52; 95% confidence interval (CI): 0.43-0.64; P<0.001], whereas treatment period itself was not an independent prognostic factor. The matched cohort analysis confirmed significant survival gains in periods 2 and 3 compared to period 1. Conclusions: The widespread adoption of ICIs has significantly improved survival in patients with driver mutation-negative or unknown mutation status in a real-world setting. These findings support the integration of ICI-based regimens into routine clinical practice and underscore the need for ongoing efforts to optimize treatment strategies for patients without actionable mutations.