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

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. 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. 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. 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.