【肿瘤靶向药物基因检测】靶向晚期非小细胞肺癌中的 KRASp.G12C 突变

基因检测费用关键点

深研检测与解码的装备与选择做备注《Curr Treat Options Oncol》在2022 Dec;23(12):1699-1720发表了一篇题目为《靶向晚期非小细胞肺癌中的 KRASp.G12C 突变：一个新时代已经开始》肿瘤靶向药物治疗基因检测临床研究文章。该研究由Maristella Bungaro, Silvia Novello, Francesco Passiglia等完成。促进了肿瘤的正确治疗与个性化用药的发展，进一步强调在临床的基础上开展基因检测应用研究的有效性。

肿瘤基因检测及靶向药物治疗研究关键词：

阿达格拉西布,KRASp.G12C,非小细胞肺癌,抵抗性,索托拉西

肿瘤治疗检测基因临床应用结果

KRASp.G12C 突变发生在 12% 的新诊断晚期 NSCLC 中，最近已成为选择可能对新型 KRASp.G12C 抑制剂有反应的晚期 NSCLC 患者的阳性预测生物标志物。 最近在 KRAS G12C 癌蛋白效应区下发现了一个新的结合口袋，使得对 KRASp.G12 突变的直接药理学抑制成为可能，从而导致了一系列新的直接选择性抑制剂的临床开发，对患者具有潜在的重大影响 '生存和生活质量。 早期 CodeBreak 试验中出现的有希望的疗效和耐受性数据已经支持监管机构批准 sotorasib 作为 KRASp.G12C 阳性 NSCLC 人群二线治疗的首个靶向治疗，继以免疫疗法为基础的一线治疗后， 而随机 III 期 CodeBreak 200 临床研究最近证实，就无进展生存期和生活质量而言，sotorasib 明显优于多西紫杉醇。 然而，KRAS 突变型 NSCLC 是一种高度异质性疾病，其特征是共突变率高，最常见的是 P53、STK11 和 KEAP1 基因，它们显着调节肿瘤微环境的组成，从而影响对免疫治疗和靶向治疗的临床反应 目前临床上可用的抑制剂。 临床前和临床转化系列最近都揭示了在选择性 KRASG12C 抑制剂下发生的广泛耐药机制，包括在靶和脱靶分子改变以及形态转换，在使用时对这些药物的抗肿瘤活性产生负面影响 作为单药治疗。 对这种生物学背景的理解以及临床前数据的出现为研究不同的组合策略提供了强有力的理由，包括抑制 SHP2、SOS1 和 KRAS G12C 下游效应器，以及添加免疫疗法和/或化学疗法 到靶向治疗。 这些试验的初步结果最近表明，SHP2 抑制剂在一线环境中具有良好的活性，而毒性问题限制了免疫检查点抑制剂和 sotorasib 的同时给药。 预测性基因组/免疫生物标志物的鉴定对于了解如何优化测序/组合不同药物并最终在临床研究下个性化治疗策略以明确提高 KRASp.G12C 突变晚期 NSCLC 患者的生存结果至关重要。阿达格拉西布； KRASpG12C； 非小细胞肺癌； 抵抗性; 索托拉西。

肿瘤发生与恶化、耐药的基因检测国际数据

KRASp.G12C mutation occurs in 12% of newly diagnosed advanced NSCLC and has recently emerged as a positive predictive biomarker for the selection of advanced NSCLC patients who may respond to novel KRASp.G12C inhibitors. The recent discovery of a new binding pocket under the effector region of KRAS G12C oncoprotein has made direct pharmacological inhibition of the KRASp.G12 mutation possible, leading to the clinical development of a new series of direct selective inhibitors, with a potential major impact on patients' survival and quality of life. Promising efficacy and tolerability data emerging from the early phase CodeBreak trial have already supported the regulatory approval of sotorasib as first in class targeted treatment for the second-line treatment of KRASp.G12C-positive NSCLC population, following immunotherapy-based first-line therapies, while the randomized phase III CodeBreak 200 clinical study has recently confirmed a significant superiority of sotorasib over docetaxel in terms of progression-free survival and quality of life. However, KRAS mutant NSCLC is a high heterogeneous disease characterized by a high rate of co-mutations, most frequently involving P53, STK11, and KEAP1 genes, which significantly modulate the composition of the tumor microenvironment and consequently affect clinical responses to both immunotherapy and targeted inhibitors now available in clinical practice. Both pre-clinical and clinical translational series have recently revealed a wide spectrum of resistance mechanisms occurring under selective KRASG12C inhibitors, including both on-target and off-target molecular alterations as well as morphological switching, negatively affecting the antitumor activity of these drugs when used as single agent therapies. The understanding of such biological background along with the emergence of pre-clinical data provided a strong rational to investigate different combination strategies, including the inhibition of SHP2, SOS1, and KRAS G12C downstream effectors, as well as the addition of immunotherapy and/or chemotherapy to targeted therapy. The preliminary results of these trials have recently suggested a promising activity of SHP2 inhibitors in the front-line setting, while toxicity issues limited the concurrent administration of immune-checkpoint inhibitors and sotorasib. The identification of predictive genomic/immunological biomarkers will be crucial to understand how to optimally sequencing/combining different drugs and ultimately personalize treatment strategies under clinical investigation, to definitively increase the survival outcomes of KRASp.G12C mutant advanced NSCLC patients.

Keywords: Adagrasib; KRAS G12C; Non-small cell lung cancer; Resistance; Sotorasib.

Curr Treat Options Oncol

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