ROS1融合基因在非小细胞肺癌（NSCLC）中属于可有效治疗的异常。除了耐靶向治疗的溶剂前突变（SFM）外，小规模ROS1突变很大程度上尚未被了解。我们对NSCLC患者中不具有ROS1融合基因或SFM的小规模ROS1突变的临床和分子特征进行了探索性分析。我们在网络基因组医学中的NSCLC患者组织样本上进行了下一代测序。我们排除了具有ROS1融合基因和SFM的患者。我们分析了携带小规模ROS1突变、ROS1突变以及共同突变的患者的临床特征以及对全身治疗的反应。在经过分析的10,396名患者中，有101名（1.0%）患者携带有小规模ROS1突变。大多数患者为男性（73.3%）和吸烟者（96.6%）。近一半的患者呈现鳞状细胞癌（SqCC，40.4%）。大多数突变为转换突变（50.5%），并且66%的突变位于激酶结构域。除了TP53突变（65.3%），还伴随发生KRAS（22.8%）、EGFR（5.9%）、PIK3CA（9.9%）和FGFR1-4（8.9%）突变。在10名（9.9%）患者中，ROS1突变是唯一检测到的异常。在具有或不具有KRAS共同突变的患者中，中位总生存期（mOS）显著不同（9.7 vs 21.5个月，p = 0.02），在治疗过程中使用或不使用免疫检查点阻断（ICB）的患者中，mOS也存在显著差异（21.5 vs 4.4个月，p = 0.003）。该队列的临床特征与ROS1融合基因队列不同。KRAS突变的共同发生导致了缩短的生存期，并且患者从ICB中受益。我们的数据不支持ROS1小规模突变作为NSCLC中强的致癌驱动因子的观点，而是将其视为影响治疗策略效果的相关旁观者。版权所有© 2023作者。由Elsevier B.V.出版。保留所有权利。

ROS1 fusions are well treatable aberrations in NSCLC. Besides solvent-front mutations (SFM) in resistance to targeted therapy, small-scale ROS1 mutations are largely unknown. We exploratively analyzed the clinical and molecular characteristics of small-scale ROS1 mutations in NSCLC patients without activating ROS1 fusions or SFMs.Next-generation sequencing was performed on tissue samples from NSCLC patients within the Network Genomic Medicine. Patients with ROS1 fusions and SFMs were excluded. We analyzed clinical characteristics of patients harboring small-scale ROS1-mutations, ROS1- and co-occurring mutations, and their response to systemic therapy.Of 10,396 patients analyzed, 101 (1.0%) patients harbored small-scale ROS1 mutations. Most patients were male (73.3%) and smokers (96.6%). Nearly half of the patients presented with squamous-cell carcinoma (SqCC, 40.4%). Most mutations were transversions (50.5%), and 66% were in the kinase domain. Besides TP53 mutations (65.3%), KRAS (22.8%), EGFR (5.9%), PIK3CA (9.9%) and FGFR1-4 mutations (8.9%) co-occurred. In 10 (9.9%) patients, ROS1 mutation was the only aberration detected. Median overall survival (mOS) differed significantly in patients with or without KRAS co-mutations (9.7 vs 21.5 months, p = 0.02) and in patients treated with or without immune-checkpoint blockade (ICB) during treatment (21.5 vs 4.4 months, p = 0.003).The cohort's clinical characteristics contrasted ROS1-fused cohorts. Co-occurrence of KRAS mutations led to shortened survival and patients benefited from ICB. Our data does not support the idea of ROS1 small-scale mutations as strong oncogenic drivers in NSCLC, but rather as relevant bystanders altering the efficacy of treatment approaches.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.