BACKGROUND: KRAS (Kirsten rat sarcoma viral oncogene homolog) gene mutation is one of the common driver gene mutations in non-small cell lung cancer (NSCLC) with poor prognosis. There are limited effective treatments for advanced NSCLC patients with KRAS mutation. This study aimed to evaluate the effectiveness of PD-1/L1 immune checkpoint inhibitors (ICIs) as a first-line immunotherapy for advanced NSCLC patients harboring KRAS oncogene mutation. METHODS: This multicenter retrospective real-world study was conducted from 2019 to 2024 at Shanghai Changzheng Hospital and Shanghai Municipal Hospital of Traditional Chinese Medicine, including 78 patients who received immunotherapy using PD-1/L1 ICIs, and 29 patients who received traditional platinum-doublet chemotherapy. The primary endpoints were progression-free survival (PFS) and overall survival (OS). The secondary endpoints included the objective response rate (ORR), disease control rate (DCR), and correlation of prognostic biomarkers with survival outcomes. RESULTS: No significant difference in ORR and DCR was observed between the two groups. The median PFS in immunotherapy group was longer than that in chemotherapy group [7.9 months (95% CI: 5.3-10.5) vs. 6.0 months (95% CI: 3.8-8.2), P = 0.030], and there was no significant difference in OS between the two groups (16.2 vs. 19.2 months, P >
0.05). Multivariate analysis identified PD-L1 expression as an independent protective factor for PFS (HR = 0.397, 95% CI: 0.178-0.887, P = 0.024), and elevated CRP (HR = 1.005, 95% CI: 1.001-1.010, P = 0.022), CEA (HR = 1.008, 95% CI: 1.001-1.014, P = 0.030) and neutrophil-to-lymphocyte ratio (NLR) (HR = 1.105, 95% CI: 1.024-1.193, P = 0.010) were independent risk factors for progression. CONCLUSION: The first-line treatment with PD-1/PD-L1 ICIs showed numerically better clinical efficacy than the traditional double-agent chemotherapy in patients with KRAS-mutated NSCLC, especially in PFS. Additionally, PD-L1 expression, C reactive protein, CEA, and NLR could serve as markers for predicting the efficacy of immunotherapy in patients with KRAS-mutated NSCLC.