Eklund Ella A, Sayin Sama I, Jonsson Jonas Smith, van Renswoude Hannes, Nyman Jan, Hallqvist Andreas, Wiel Clotilde, Sayin Volkan I
Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden.
JTO Clin Res Rep. 2025 Jul 17;6(10):100880. doi: 10.1016/j.jtocrr.2025.100880. eCollection 2025 Oct.
Immune checkpoint blockade (ICB) is a standard first-line treatment for stage IV NSCLC without actionable oncogenic alterations. mutations, prevalent in 30% to 40% lung adenocarcinomas (LUAD) in Western populations, currently lack targeted first-line therapies. This study aimed to assess the predictive value of mutations for clinical outcomes after distinct ICB regimens, validating our previous findings in a larger cohort with extended follow-up.
We conducted a retrospective multicenter study including consecutive stage IV LUAD patients (n = 424) treated with either ICB or platinum-doublet chemotherapy between 2016 and 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. mutational status was assessed by next-generation sequencing. Primary end points included overall survival (OS) and progression-free survival (PFS), analyzed using Kaplan-Meier curves and multivariate Cox regression.
Among 424 patients diagnosed with metastatic LUAD, 40% harbored mutations ( ). patients exhibited significant improvement in OS (16 versus 8 mo, < 0.001) and PFS (8 mo versus 5 mo, < 0.001) with ICB monotherapy. In contrast, wild-type ( ) patients derived no survival advantage from ICB monotherapy (OS, 8 mo versus 8 mo, = 0.648; PFS 4 mo versus 5 mo, = 0.871) although they did so with chemoimmunotherapy (OS, 15 mo versus 8 mo, = 0.032; PFS, 6 mo vs 5 mo, = 0.033). On multivariate analysis, monotherapy was confirmed as an independent factor improving outcomes in KRAS-mutated patients (hazard ratio [HR] 0.533, 95% confidence interval 0.311-0.912, = 0.018). Finally, we identified (OS: 13.7 mo versus 10.5 mo, = 0.0046, PFS: 7.7 mo versus 6.2 mo, = 0.002) and (OS: 24.2 mo versus 7.2 mo, = 0.0204; PFS: 13.7 mo versus 4.5 mo, = 0.063) but not (OS, 5.8 mo versus 6.2 mo, = 0.777; PFS, 4.6 mo versus 3.2 mo, = 0.694) as distinctly and independently predictive of improved survival after receiving ICB-containing treatment.
mutations predict substantial and sustained clinical benefit from first-line ICB monotherapy in metastatic LUAD, whereas wild-type patients do not. and mutations confer improved survival, whereas does not. Integrating mutation status into clinical practice could guide personalized treatment strategies, optimizing immunotherapy outcomes in stage IV LUAD.
免疫检查点阻断（ICB）是无可操作致癌改变的IV期非小细胞肺癌（NSCLC）的标准一线治疗方法。在西方人群中，30%至40%的肺腺癌（LUAD）中普遍存在的[特定基因突变名称]突变，目前缺乏靶向一线治疗方法。本研究旨在评估[特定基因突变名称]突变对不同ICB方案后临床结局的预测价值，在更大队列并延长随访时间的情况下验证我们之前的发现。
我们进行了一项回顾性多中心研究，纳入了2016年至2021年期间在瑞典西部接受ICB或铂类双联化疗的连续IV期LUAD患者（n = 424）。从患者病历和瑞典国家肺癌登记处回顾性收集患者人口统计学资料、肿瘤特征、治疗细节和生存结局。通过下一代测序评估[特定基因突变名称]突变状态。主要终点包括总生存期（OS）和无进展生存期（PFS），使用Kaplan-Meier曲线和多变量Cox回归进行分析。
在424例诊断为转移性LUAD的患者中，40%携带[特定基因突变名称]突变（[具体情况]）。[特定基因突变名称]突变患者接受ICB单药治疗时，OS（16个月对8个月，P < 0.001）和PFS（8个月对5个月，P < 0.001）有显著改善。相比之下，[特定基因突变名称]野生型（[具体情况]）患者接受ICB单药治疗未获得生存优势（OS，8个月对8个月，P = 0.648；PFS 4个月对5个月，P = 0.871），尽管他们接受化疗免疫治疗时有生存优势（OS，15个月对8个月，P = 0.032；PFS，6个月对5个月，P = 0.033）。多变量分析中，单药治疗被确认为KRAS突变患者改善结局的独立因素（风险比[HR] 0.533，95%置信区间0.311 - 0.912，P = 0.018）。最后，我们确定[特定基因突变名称]（OS：13.7个月对10.5个月，P = 0.0046，PFS：7.7个月对6.2个月，P = 0.002）和[特定基因突变名称]（OS：24.2个月对7.2个月，P = 0.0204；PFS：13.7个月对4.5个月，P = 0.063）而非[特定基因突变名称]（OS，5.8个月对6.2个月，P = 0.777；PFS，4.6个月对3.2个月，P = 0.694）可显著且独立预测接受含ICB治疗后生存期改善。
[特定基因突变名称]突变预示转移性LUAD患者一线ICB单药治疗可获得显著且持续的临床获益，而[特定基因突变名称]野生型患者则不然。[特定基因突变名称]和[特定基因突变名称]突变可改善生存期，而[特定基因突变名称]则不能。将[特定基因突变名称]突变状态纳入临床实践可指导个性化治疗策略，优化IV期LUAD的免疫治疗结局。
