Santarpia Mariacarmela, Ciappina Giuliana, Spagnolo Calogera Claudia, Squeri Andrea, Passalacqua Maria Ilenia, Aguilar Andrés, Gonzalez-Cao Maria, Giovannetti Elisa, Silvestris Nicola, Rosell Rafael
Department of Human Pathology "G. Barresi", Medical Oncology Unit, University of Messina, Messina, Italy.
Oncology Institute Dr. Rosell, IOR, Dexeus University Hospital, Barcelona, Spain.
Transl Lung Cancer Res. 2023 Feb 28;12(2):346-368. doi: 10.21037/tlcr-22-639. Epub 2023 Feb 20.
Non-small cell lung cancer (NSCLC) with Kirsten rat sarcoma viral oncogene homolog () driver alterations harbors a poor prognosis with standard therapies, including chemotherapy and/or immunotherapy with anti-programmed cell death protein 1 (anti-PD-1) or anti-programmed death ligand-1 (anti-PD-L1) antibodies. Selective KRAS G12C inhibitors have been shown to provide significant clinical benefit in pretreated NSCLC patients with G12C mutation.
In this review, we describe KRAS and the biology of -mutant tumors and review data from preclinical studies and clinical trials on KRAS-targeted therapies in NSCLC patients with KRAS G12C mutation.
is the most frequently mutated oncogene in human cancer. The G12C is the most common mutation found in NSCLC. Sotorasib is the first, selective KRAS G12C inhibitor to receive approval based on demonstration of significant clinical benefit and tolerable safety profile in previously treated, G12C-mutated NSCLC. Adagrasib, a highly selective covalent inhibitor of KRAS G12C, has also shown efficacy in pretreated patients and other novel KRAS inhibitors are being under evaluation in early-phase studies. Similarly to other oncogene-directed therapies, mechanisms of intrinsic and acquired resistance limiting the activity of these agents have been described.
The discovery of selective KRAS G12C inhibitors has changed the therapeutic scenario of G12C-mutant NSCLC. Various studies testing KRAS inhibitors in different settings of disease, as single-agent or in combination with targeted agents for synthetic lethality and immunotherapy, are currently ongoing in this molecularly-defined subgroup of patients to further improve clinical outcomes.
具有 Kirsten 大鼠肉瘤病毒癌基因同源物（KRAS）驱动改变的非小细胞肺癌（NSCLC），采用包括化疗和/或使用抗程序性细胞死亡蛋白 1（抗 PD-1）或抗程序性死亡配体 1（抗 PD-L1）抗体的免疫疗法在内的标准疗法，预后较差。选择性 KRAS G12C 抑制剂已显示在先前接受过治疗的具有 KRAS G12C 突变的 NSCLC 患者中可提供显著的临床益处。
在本综述中，我们描述了 KRAS 及其突变型肿瘤的生物学特性，并回顾了针对具有 KRAS G12C 突变的 NSCLC 患者进行 KRAS 靶向治疗的临床前研究和临床试验数据。
KRAS 是人类癌症中最常发生突变的癌基因。G12C 是 NSCLC 中最常见的 KRAS 突变。索托拉西布是首个基于在先前接受过治疗的 KRAS G12C 突变型 NSCLC 中显示出显著临床益处和可耐受的安全性而获批的选择性 KRAS G12C 抑制剂。阿达格拉西布是一种高度选择性的 KRAS G12C 共价抑制剂，在先前接受过治疗的患者中也显示出疗效，其他新型 KRAS 抑制剂正在进行早期研究评估。与其他癌基因导向疗法类似，已经描述了限制这些药物活性的内在和获得性耐药机制。
选择性 KRAS G12C 抑制剂的发现改变了 KRAS G12C 突变型 NSCLC 的治疗格局。目前正在这个分子定义的患者亚组中进行各种研究，测试 KRAS 抑制剂在不同疾病背景下作为单药或与靶向药物联合用于合成致死和免疫治疗，以进一步改善临床结局。
