Differential Benefit of Immune Checkpoint Blockade by KRAS Mutation Status in Metastatic Lung Adenocarcinoma: Validation from an Extended Swedish Cohort

IntroductionImmune checkpoint blockade (ICB) is a standard first-line treatment for advanced-stage non-small cell lung cancer (NSCLC) without actionable oncogenic alterations. KRAS mutations, prevalent in 30-40% of Western lung adenocarcinomas, currently lack targeted first-line therapies. This study aimed to assess the predictive value of KRAS mutations for clinical outcomes following ICB, validating previous findings in a larger cohort with extended follow-up. MethodsWe conducted a retrospective multicenter study including consecutive stage IV NSCLC adenocarcinoma patients (n = 424) treated with either ICB or platinum-doublet chemotherapy between 2016-2021 in western Sweden. Patient demographics, tumor characteristics, treatment details, and survival outcomes were retrospectively collected from patient charts and the Swedish National Lung Cancer Registry. KRAS mutational status was assessed by next-generation sequencing. Primary endpoints included overall survival (OS) and progression-free survival (PFS), analyzed using Kaplan-Meier curves and multivariate Cox regression. ResultsAmong 424 patients, 40% harbored KRAS mutations (KRASMUT). KRASMUT patients showed significant improvement in OS (16 vs. 8 months, p < 0.001) and PFS (8 vs. 5 months, p < 0.001) with ICB monotherapy compared to chemotherapy. Multivariate analyses confirmed KRAS mutation as an independent predictor for better OS (HR 0.533, p = 0.018) and PFS (HR 0.523, p = 0.018). In contrast, KRAS wild-type (KRASWT) patients derived no survival advantage from ICB monotherapy. Both KRASWT with KRASMUT populations benefited from chemoimmunotherapy. ConclusionsKRAS mutations predict substantial and sustained clinical benefit from first-line ICB monotherapy in advanced NSCLC, whereas KRAS wild-type patients do not. Integrating KRAS mutation status into clinical practice could guide personalized treatment strategies, optimizing immunotherapy outcomes in advanced-stage lung adenocarcinoma.