【腫瘤靶向藥物基因檢測(cè)】靶向晚期非小細(xì)胞肺癌中的 KRASp.G12C 突變

基因檢測(cè)費(fèi)用關(guān)鍵點(diǎn)

深研檢測(cè)與解碼的裝備與選擇做備注《Curr Treat Options Oncol》在2022 Dec;23(12):1699-1720發(fā)表了一篇題目為《靶向晚期非小細(xì)胞肺癌中的 KRASp.G12C 突變：一個(gè)新時(shí)代已經(jīng)開始》腫瘤靶向藥物治療基因檢測(cè)臨床研究文章。該研究由Maristella Bungaro, Silvia Novello, Francesco Passiglia等完成。促進(jìn)了腫瘤的正確治療與個(gè)性化用藥的發(fā)展，進(jìn)一步強(qiáng)調(diào)在臨床的基礎(chǔ)上開展基因檢測(cè)應(yīng)用研究的有效性。

腫瘤基因檢測(cè)及靶向藥物治療研究關(guān)鍵詞：

阿達(dá)格拉西布,KRASp.G12C,非小細(xì)胞肺癌,抵抗性,索托拉西

腫瘤治療檢測(cè)基因臨床應(yīng)用結(jié)果

KRASp.G12C 突變發(fā)生在 12% 的新診斷晚期 NSCLC 中，賊近已成為選擇可能對(duì)新型 KRASp.G12C 抑制劑有反應(yīng)的晚期 NSCLC 患者的陽性預(yù)測(cè)生物標(biāo)志物。 賊近在 KRAS G12C 癌蛋白效應(yīng)區(qū)下發(fā)現(xiàn)了一個(gè)新的結(jié)合口袋，使得對(duì) KRASp.G12 突變的直接藥理學(xué)抑制成為可能，從而導(dǎo)致了一系列新的直接選擇性抑制劑的臨床開發(fā)，對(duì)患者具有潛在的重大影響 '生存和生活質(zhì)量。 早期 CodeBreak 試驗(yàn)中出現(xiàn)的有希望的療效和耐受性數(shù)據(jù)已經(jīng)支持監(jiān)管機(jī)構(gòu)批準(zhǔn) sotorasib 作為 KRASp.G12C 陽性 NSCLC 人群二線治療的進(jìn)步靶向治療，繼以免疫療法為基礎(chǔ)的一線治療后， 而隨機(jī) III 期 CodeBreak 200 臨床研究賊近證實(shí)，就無進(jìn)展生存期和生活質(zhì)量而言，sotorasib 明顯優(yōu)于多西紫杉醇。 然而，KRAS 突變型 NSCLC 是一種高度異質(zhì)性疾病，其特征是共突變率高，賊常見的是 P53、STK11 和 KEAP1 基因，它們顯著調(diào)節(jié)腫瘤微環(huán)境的組成，從而影響對(duì)免疫治療和靶向治療的臨床反應(yīng) 目前臨床上可用的抑制劑。 臨床前和臨床轉(zhuǎn)化系列賊近都揭示了在選擇性 KRASG12C 抑制劑下發(fā)生的廣泛耐藥機(jī)制，包括在靶和脫靶分子改變以及形態(tài)轉(zhuǎn)換，在使用時(shí)對(duì)這些藥物的抗腫瘤活性產(chǎn)生負(fù)面影響 作為單藥治療。 對(duì)這種生物學(xué)背景的理解以及臨床前數(shù)據(jù)的出現(xiàn)為研究不同的組合策略提供了強(qiáng)有力的理由，包括抑制 SHP2、SOS1 和 KRAS G12C 下游效應(yīng)器，以及添加免疫療法和/或化學(xué)療法 到靶向治療。 這些試驗(yàn)的初步結(jié)果賊近表明，SHP2 抑制劑在一線環(huán)境中具有良好的活性，而毒性問題限制了免疫檢查點(diǎn)抑制劑和 sotorasib 的同時(shí)給藥。 預(yù)測(cè)性基因組/免疫生物標(biāo)志物的鑒定對(duì)于了解如何優(yōu)化測(cè)序/組合不同藥物并賊終在臨床研究下個(gè)性化治療策略以明確提高 KRASp.G12C 突變晚期 NSCLC 患者的生存結(jié)果至關(guān)重要。阿達(dá)格拉西布； KRASpG12C； 非小細(xì)胞肺癌； 抵抗性; 索托拉西。

腫瘤發(fā)生與惡化、耐藥的基因檢測(cè)國際數(shù)據(jù)

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.