Clinical outcomes of KRAS G12C versus non-G12C mutant NSCLC treated with immunotherapy: a multicentre real-world study

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BACKGROUND: KRAS is the most heterogeneous and frequent oncogenic driver in non-small cell lung cancer (NSCLC). KRAS alleles and co-mutations shape the tumour microenvironment, potentially influencing benefit from immune checkpoint inhibitors (ICI). The aim of our study was to evaluate the patterns of KRAS mutations, their correlation with clinical and pathological features and their association with ICI outcomes. METHODS: We conducted a multicentre retrospective analysis of patients with advanced KRAS-mutant NSCLC treated with ICI. Clinical, pathological and molecular data were collected, including KRAS mutation type (G12C vs non-G12C), key co-mutations and PD-L1 expression. These variables were correlated with clinical outcomes. Survival outcomes were analysed using Kaplan-Meier estimates and multivariate Cox regression models. RESULTS: A total of 198 patients with KRAS mutant NSCLC were evaluated, with 49.5% carrying a G12C mutation. Overall, 81% of patients received first-line ICI, either as monotherapy or combined with chemotherapy. After a median follow-up of 48 months, G12C cases showed significantly longer median overall survival (OS) (15 vs 9 months; HR 0.71; p = 0.031). Multivariate analysis indicated that G12C mutations correlated with improved OS, as well as good performance status and absence of central nervous system (CNS) metastases. CONCLUSIONS: In this retrospective real-world cohort, KRAS mutation subtype was associated with differences in ICI outcomes, particularly OS. These findings should be considered hypothesis-generating and warrant prospective validation in molecularly characterized cohorts.

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