Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and adagrasib) have now overcome this therapeutic hurdle. We discuss the evidence for these medications, their pitfalls and adverse effects, as well as future directions in this space. Though these medications demonstrate substantial response rates in a heavily pre-treated advanced NSCLC cohort, as phase-3 evidence does not yet demonstrate an overall survival benefit versus standard-of-care chemotherapy, docetaxel. Additionally, these medications appear to have a negative interaction in combination with immunotherapies, with substantially greater hepatotoxicity rates observed. Despite this, it is undeniable that these medications represent an important advancement in targeted and personalised oncological treatment. Current and future trials assessing these medications in combination and through sequencing strategies will likely yield further clinically meaningful outcomes to guide treatment in this patient cohort.
非小细胞肺癌（NSCLC）是一种常见且高致死率的恶性肿瘤。过去十年间，靶向治疗的发展显著改善了NSCLC患者的临床结局。克尔斯滕大鼠肉瘤病毒癌基因（KRAS）是NSCLC中常见的突变致癌基因，在肿瘤发生与增殖过程中起关键作用。尽管长期以来KRAS被视为难以靶向治疗的靶点，但近期研发的KRAS G12C抑制剂（sotorasib与adagrasib）已突破这一治疗瓶颈。本文系统探讨了这些药物的临床证据、局限性及不良反应，并展望该领域未来发展方向。虽然这些药物在经多线治疗的晚期NSCLC患者群体中显示出显著应答率，但现有三期临床试验证据尚未证实其相较于标准治疗药物多西他赛能带来总生存获益。此外，这些药物与免疫疗法联用时存在负面相互作用，观察到显著升高的肝毒性发生率。尽管如此，不可否认这些药物代表了靶向与个体化肿瘤治疗领域的重要进展。当前及未来通过联合用药与序贯策略评估这些药物的临床试验，有望为这一患者群体提供更具临床指导意义的治疗依据。
Targeted Therapies for Kirsten Rat Sarcoma (KRAS) G12C Mutant Metastatic Non-Small-Cell Lung Cancers
肿瘤(癌症)患者之家