KRAS突变晚期非小细胞肺癌生物学特征、临床治疗及预后研究进展

摘 要：KRAS突变是非小细胞肺癌（NSCLC）较为常见的基因突变，中国人群中KRAS G12C突变比例最高，其流行病学特征与西方人群存在差异。由于KRAS蛋白结构特殊、无明显结合位点，一度被冠以“不可成药靶点”。KRAS突变患者相比较于野生型患者生存期更短，预后更差。近年来KRAS G12C小分子抑制剂在临床初步研究中取得了突破性进展，为晚期NSCLC KRAS突变患者带来了生存希望，大量特异性靶点抑制剂、联合治疗等研究也不断深入。全文就晚期NSCLC KRAS突变流行病学特征、生物学特征、临床相关治疗及疗效预测等研究进展作一综述。     

754例Ⅰ期-Ⅲa期可手术切除非小细胞肺癌患者EGFR和KRAS基因突变状态及其临床意义

背景与目的 表皮生长因子受体(epidermal growth factor receptor,EGFR)和KRAS基因是非小细胞肺癌(non-small cell lung cancer,NSCLC)重要的分子靶点,但目前研究主要集中在晚期NSCLC组织和血浆标本的EGFR检测,早期NSCLC组织样本中EGFR和KRAS突变特征尚不清楚.本研究将探讨Ⅰ期-Ⅲa期NSCLC EGFR和KRAS基因突变与相关临床病理特征的关系.方法 采用突变扩增系统(amplification refractory mutation system,ARMS)PCR方法检测北京协和医院病理科提供的754例Ⅰ期-Ⅲa期NSCLC组织样本的EGFR和KRAS基因突变状况,分析基因突变率及其与临床病理特征的关系.结果 EGFR和KRAS基因热点突变的突变率分别为34.5％和13.1％,其中有3例样本具有EGFR和KRAS基因的双突变.EGFR基因在女性中的突变率高于男性(39.5％vs 29.4％,P=0.076),在腺癌中的突变率(38.7％)高于鳞癌、腺鳞癌、大细胞癌(P＜0.01),但仍明显低于其他研究报道的亚裔晚期腺癌突变率(-50％).KRAS基因突变在男性中的突变率高于女性(16.6％vs 9％,P=0.048),且在腺癌中的突变率也高于其他类型,但差异不显著(P=0.268).与KRAS基因突变阳性组相比,EGFR基因突变阳性组在年龄分布上有年轻化的趋势(P=0.031,5),在性别分布上有显著性差异(P＜0.01).结论 Ⅰ期-Ⅲa期NSCLC EGFR基因突变率较晚期患者低,且EGFR和KRAS基因双突变的发生率为0.9％.     

“宣威”多结节非小细胞肺癌驱动基因突变分析

目的：探讨多结节非小细胞肺癌（NSCLC）组织中的驱动基因突变情况与临床病理特征的关系,为多结节NSCLC患者治疗提供分子诊断依据。方法：本研究共纳入2018年1月至2023年10月间云南省肿瘤医院分子诊断中心检测的121例多结节NSCLC患者的253个肺结节肿瘤组织标本,以第二代测序（NGS）技术或扩增阻滞突变系统PCR(ARMS-PCR)技术检测多结节NSCLC组织中驱动基因突变情况,分析其与患者临床病理特征的关系,比较不同结节间肺癌驱动基因的突变异质性。结果：与非“宣威”NSCLC相比,“宣威”多结节NSCLC患者驱动基因突变具有显著的地域特点,表现在“宣威”患者具有较低（20%）的EGFR敏感突变（L858R、19-del）及较高（27.26%）的EGFR少见突变（主要为G719/S768I、G719）;“宣威”多结节NSCLC患者的KRAS突变率（27.27%）亦显著高于非“宣威”患者突变率（12.59%）(P<0.05)。此外,“宣威”多结节NSCLC患者驱动基因突变不一致率高达69.23%,远高于非“宣威”患者驱动基因突变不一致率（55.07%）(P<0.05...     

鼠类肉瘤病毒癌基因突变型晚期非小细胞肺癌的靶向治疗和免疫治疗进展

非小细胞肺癌（NSCLC）是最常见的肺癌类型,约10%的亚洲NSCLC患者存在鼠类肉瘤病毒癌基因（KRAS）突变。与表皮生长因子受体（EGFR）驱动基因阳性的NSCLC患者不同,KRAS突变型NSCLC的靶向治疗疗效欠佳,且对化疗的反应较差。既往直接针对KRAS突变靶向药物的研发大多失败,这主要与KRAS信号通路特殊的结构相关,目前针对KRAS G12C的特殊位点研发了直接针对KRAS突变的药物,为KRAS突变NSCLC患者的靶向治疗带来了希望。KRAS突变通常与更高的程序性死亡受体配体1(PD-L1)表达相关,意味着免疫治疗可以为这类患者带来更大的应用价值。本文主要以KRAS抑制剂为切入点,介绍靶向治疗和免疫治疗在KRAS突变型NSCLC应用中的研究进展,旨在为患者的个体化治疗提供参考。     

非小细胞肺癌患者RAS基因突变临床特征和预后分析

摘 要：［目的］ 探讨非小细胞肺癌RAS基因突变的临床特征和预后。［方法］ 对475例非小细胞肺癌患者进行RAS基因检测和随访。Kaplan-Meier法计算生存率,Log-rank法进行生存率检验。［结果］ 475例非小细胞肺癌中,KRAS基因突变的突变率为8.00% (38/475),其中吸烟患者的KRAS突变频率远高于非吸烟患者(15.76% vs 4.41%,P<0.01)。 346例非小细胞肺癌中NRAS基因突变的突变率为0.29% (1/346);315例非小细胞肺癌中HRAS基因突变的突变率为0.63% (2/315)。RAS基因复合其他基因突变15例,中位生存时间29.8个月;而单纯RAS突变26例中位生存时间16.3个月(P=0.15)。［结论］ 在NSCLC患者中,吸烟患者的KRAS基因突变频率高于非吸烟患者。RAS基因突变的非小细胞肺癌临床特征上无统计学差异;复合突变比单纯突变临床获益更多。     

江苏地区肺癌和胃癌患者 KRAS 基因突变状态分析*

目的:检测江苏地区肺癌和胃癌患者KRAS基因突变状态及其与临床病理特征的关系,并比较其在两种癌症间的异同。方法:收集肺癌128 例,胃癌115 例。采用直接测序法检测KRAS基因第2 号外显子突变,分析基因突变状态及其与临床病理特征的相关性。结果:KRAS基因突变率在肺癌和胃癌中无显著性差异（6.3% vs. 4.3% ,P > 0.05）。 两种癌症中,KRAS 基因突变都以第12密码子为主。KRAS 突变与年龄,性别无明显相关。肺腺癌患者KRAS基因突变高于非腺癌包括鳞癌等（10.7% vs. 0 ,P < 0.05）。 结论:江苏地区肺癌和胃癌患者中,KRAS第2 外显子突变率均较低,男性和女性的突变率无明显差异。肺腺癌患者KRAS基因突变率相对较高,因此个体化治疗前应同时检测KRAS 基因,以筛选出对靶向治疗耐药的肺癌患者,从而更好地指导患者的个体化分子靶向治疗。      

Kirsten大鼠肉瘤病毒基因同源物突变非小细胞肺癌内科治疗现状与展望

近年来, 靶向药物治疗和免疫检查点抑制剂的临床应用极大地改变了晚期非小细胞肺癌(NSCLC)的治疗格局。表皮生长因子受体和间变性淋巴瘤受体酪氨酸激酶等驱动基因改变NSCLC的TKI靶向治疗均已取得了良好临床疗效, 而Kirsten大鼠肉瘤病毒基因同源物(KRAS)作为较早发现和突变频率较高的癌基因之一, 其靶向药物治疗研究进展缓慢, 法尼基转移酶抑制剂、KRAS信号通路下游蛋白抑制剂等靶向治疗研究均未取得预期结果, 使得KRAS长期以来被定义为"不可成药的靶点"。KRAS蛋白作为分子开关, 通过与三磷酸鸟苷结合而被激活, 引发系列级联反应, 在细胞增殖和有丝分裂中发挥作用。KRAS突变的NSCLC患者对内科系统性治疗反应性差, 预后不佳。随着对KRAS晶体结构认识的不断深入, 研究者发现了KRAS潜在的治疗位点, 进而开发出了多个直接针对KRAS的靶向药物, 尤其是KRAS G12C抑制剂, 如AMG510(sotorasib)和MRTX849(adagrasib), 其临床试验获得了令人鼓舞的结果。文章在系统介绍KRAS突变NSCLC患者临床特征及内科治疗方法的基础上, 重点就KRA...     

107例KRAS突变阳性非小细胞肺癌患者临床分析

背景与目的鼠类肉瘤病毒癌基因（Kirsten rat sarcoma viral oncogene,KRAS）是非小细胞肺癌（non-small cell lung cancer, NSCLC）的重要驱动基因之一,研究显示KARS是表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitors, EGFR-TKIs）药物的耐药标志,但其对于化疗敏感性及预后方面的意义存在争议。本研究旨在积累KRAS突变阳性的NSCLC患者治疗经验。方法我们回顾性分析了107例KRAS突变阳性的NSCLC患者的临床资料,分析KRAS突变阳性的NSCLC患者一线化疗疗效以及靶向治疗疗效。结果52例接受一线化疗的晚期KARS突变阳性NSCLC患者客观缓解率（objective response rate, ORR）为9.6%,疾病控制率（disease control rate, DCR）为53.8%,中位疾病无进展生存期（progression-free survival, PFS）为3个月;21例接受EGFR-TKIs药物治疗的KRAS突变阳性NSCLC患者ORR为9.5%,DCR为23.8%,PFS为1个月,其中EGFR/KRAS共突变患者接受EGFR-TKIs治疗的ORR及DCR均要显著高于单纯KRAS突变人群（50%vs 0,P=0.029;75%vs11.8%, P=0.043）,EGFR/KARS共突变患者接受EGFR-TKIs治疗的PFS较单纯KARS突变患者延长,可见统计学差异（3个月vs 1个月,P=0.004）。结论KRAS突变阳性NSCLC患者化疗有效率低,缓解时间短,EGFR-TKIs治疗效果差,亟需研发新的药物;EGFR/KARS共突变现象客观存在,EGFR-TKIs药物可作为这类患者有效的治疗选择之一。     

KRAS突变晚期非小细胞肺癌分子分型、治疗及预后分析

目的:分析晚期Kirsten鼠类肉瘤(Kirsten rat sarcoma,KRAS)突变非小细胞肺癌(non-small cell lung cancer,NSCLC)的临床病理特征、分子分型、治疗及预后。方法:回顾性分析2019年01-2022年01我院33例晚期KRAS+NSCLC患者的临床病理资料。分析KRAS亚型、TP53共突变及不同治疗方案和生存预后的相关性。结果:33例晚期KRAS+NSCLC患者,男性大约占90.9%（30/33);KRAS p.G12C突变为最常见分子分型,约42.4%（14/33）;另外,KRAS p.G12C突变人群对比其他KRAS突变患者,无进展生存期（progression-free survival,PFS)(6.5个月 vs 7.0个月;P=0.799)和总生存(overall survival,OS)(18.0个月 vs 24.0个月;P=0.266)均未见显著差异。亚组分析中,免疫联合化疗对比化疗+抗血管和单一化疗,可延长PFS(13.5个月 vs 7.5个月 vs 5.5个月;P=0.033),但OS却未见差异(25.0个月 vs 18.0个月 vs 25.0个月;P=0.854)。KRAS+/TP53+ NSCLC对比KRAS+/TP53-NSCLC,显著缩短PFS(5.5个月 vs 7.5个月;P=0.019)和OS(18.0个月vs 28.0个月;P=0.004)。多因素分析发现TP53共突变（HR=3.394;P=0.005）、治疗方案（HR=0.473;P=0.003）为PFS的预后因素;TP53共突变（HR=8.235;P=0.004）为OS的独立预后因素。结论:中国人群中,晚期KRAS+NSCLC患者男性较为多见,p.G12C为最常见分子分型。免疫治疗联合化疗可能延长晚期KRAS+NSCLC的PFS,但仍需进一步探索;TP53共突变可能为晚期KRAS+NSCLC不良预后因素。晚期NSCLC中KRAS和TP53共突变患者的治疗及预后需要进一步探索。     

基于cSMART技术检测ctDNA驱动基因突变指导非小细胞肺癌精准治疗的疗效研究

目的  探讨非小细胞肺癌（non-small cell lung cancer，NSCLC）基于环化单分子扩增和重测序技术（cSMART）检测循环肿瘤DNA（ctDNA）驱动基因突变，并指导其治疗的疗效。方法 选取2016年7月至2018年12月于辽宁省肿瘤医院治疗的NSCLC患者107例，采用cSMART技术检测患者血清中EGFR，ALK，KRAS，BRAF，PIK3CA，ERBB2，ROS1，RET和MET  共9种ctDNA驱动基因的突变情况。每2~4个治疗疗程后评估9种ctDNA驱动基因突变分布，并基于NCCN指南和9种基因检测结果指导患者用药。将生存信息完整且完成后续治疗的57例NSCLC患者，按照是否遵循指导方案治疗，分为规范治疗组（n=39）和非规范治疗组（n=18），比较其疗效。 结果 基于cSMART技术检测ctDNA 9种驱动基因突变78例，无突变28例。驱动基因突变的78例患者中，单基因突变27例，双基因突变24例，3基因突变11例，4基因突变5例，5基因突变5例。106例NSCLC患者无突变26人次，累计突变160人次，其中EGFR突变61人次，ALK突变11人次（包括ALK融合和点突变），TP53和KRAS突变分别为54人次和26人次，罕见突变PIK3CA发生基因突变5人次， BRAF、MET和ERBB2发生基因突变各1人次。规范治疗组患者的中位无进展生存期较非规范治疗组患者长（10.0个月vs 5.5个月，χ2=6.420，P=0.011）。结论 基于cSMART技术测定ctDNA识别NSCLC驱动基因突变简便、无创，其中EGFR及ALK为NSCLC常见驱动突变，针对其进行靶向治疗疗效较好。     

KRAS Mutations in Lung Cancer

Epidermal growth factor receptor (EGFR) gene mutations and increased EGFR copy numbers have been associated with a favorable response to EGFR tyrosine kinase inhibitors (TKI) in patients with non–small-cell lung cancer (NSCLC), and several markers have been identified that predict response to treatment. Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and mutations in EGFR and KRAS appear to be mutually exclusive. Even though KRAS mutations were identified in NSCLC tumors more than 20 years ago, we have only just begun to appreciate the clinical value of determining KRAS tumor status. Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy and do not respond to EGFR inhibitors. There is a clear need for therapies specifically developed for patients with KRAS-mutant NSCLC. In this review, we summarize the clinical and pathologic characteristics of patients with NSCLC and with KRAS mutations, describe work that explores the predictive and prognostic influence of KRAS mutations, and provide an overview of the “synthetic lethal” interactions and current approaches to targeting KRAS-mutant NSCLC.     

靶向高通量测序在非小细胞肺癌中的临床应用

  目的  对8种与非小细胞肺癌（non-small cell lung cancer,NSCLC）个性化治疗高度相关的驱动基因进行检测,分析基因变异与临床病理特征的关系。  方法  收集天津医科大学肿瘤医院2016年6月至2017年8月212例NSCLC患者样本,对EGFR、KRAS、BRAF、ALK、MET、ERBB2、ROS1、RET 8种基因进行高通量测序。  结果  8种基因中EGFR基因变异率高达52.8%,其次为KRAS（8.5%）、ALK（8.0%）、ERBB2（6.1%）、MET（3.8%）、BRAF（1.4%）、RET（0.9%）、ROS1（0.9%）,75%样本检出至少1个驱动基因变异,驱动基因变异间呈现强烈互斥。最常见的EGFR突变为19外显子缺失和L858R突变,EGFR T790M突变与前面两个突变位点伴随出现。19外显子缺失患者携带非EGFR T790M突变比例低于L858R突变患者携带非EGFR T790M突变比例（P=0.04）。15.2%EGFR突变伴EGFR扩增,携带EGFR扩增且EGFR突变率 > 40%患者比例高于无EGFR扩增且EGFR突变率 > 40%患者（P < 0.01）。女性、不吸烟、腺癌患者易发生EGFR特别是EGFR敏感突变（P < 0.01）。肺腺癌（P=0.013）、临床分期晚（P=0.048）、淋巴结转移（P=0.027）患者携带EGFR扩增比例高。男性（P=0.009）、左侧肺癌（P=0.048）,吸烟患者（P=0.037）KRAS突变发生率较高。携带非KRAS突变、ALK融合的患者更年轻（P=0.005,P=0.031）,而携带KRAS突变患者年龄较高（P=0.055）。  结论  高通量测序可同时高效检测NSCLC患者中8种与靶向治疗相关驱动基因的变异谱,为临床医生的个体化诊疗提供参考,以多基因为基础的高通量测序为NSCLC诊疗提供更多的可能性。      

KRAS as a druggable target in NSCLC: Rising like a phoenix after decades of development failures

Cancers of nearly all lineages harbor alterations that deregulate mitogen-activated protein kinase signaling, a crucial signaling pathway for tumor formation and maintenance. Of these, KRAS mutations are the most frequent gain-of-function alterations found in patients with cancer. In particular they represents the most common molecular alteration detected in non-small cell lung cancer (NSCLC) accounting for up to 25% of all oncogenic mutations. They were identified decades ago and prior efforts to target these proteins have been unsuccessful. KRAS mutation profiles (i.e. frequency of specific codon substitutions) in smokers and never-smokers are distinct and not all KRAS alterations are driver mutations. KRAS has evolved from a mutation with possible predictive value to a therapeutic target with great promise. Here, we will discuss the biology of KRAS in lung cancer and its clinical implications in oncology today and in the foreseeable future.     

ADx-ARMS方法检测晚期非小细胞肺癌患者胸水标本癌细胞基因突变的临床意义

目的:探讨应用ADx-ARMS方法检测非小细胞肺癌患者胸水标本癌细胞基因突变应用于指导小分子EGFR酪氨酸激酶抑制剂（EGFR-TKIs）治疗的可行性与临床意义。方法:ADx-ARMS检测24例非小细胞肺癌患者胸水标本EGFR基因第19、20和21外显子突变与KRAS基因第2外显子突变。统计分析胸水标本与前期检测过的非小细胞肺癌组织中的EGFR、KRAS突变率差异。结果:24例胸水标本中,EGFR突变与KRAS突变分别为14例（58.3%）和1例（4.2%）。前期检测过的非小细胞肺癌组织EGFR和KRAS突变率分别为47.6%和4.5%。EGFR和KRAS突变率在胸水标本与前期肺癌组织中差异无统计学意义（P>0.05）。结论:对失去手术机会而难以获得组织标本的晚期非小细胞肺癌患者,可应用ADx-ARMS方法选择胸水标本筛查EGFR、KRAS基因突变,从而指导EGFR-TKIs的临床应用。     

Identification of subsets of actionable genetic alterations in KRAS-mutant lung cancers using association rule mining

Background

Lung cancer is the leading cause of cancer-related death in both men and women. KRAS mutations occur in ~ 25% of patients with lung cancer, and the presence of these mutations is associated with a poor prognosis. Unfortunately, efforts to directly target KRAS or its associated downstream MAPK or PI3K/AKT/mTOR pathways have seen little or no benefits. Here, I hypothesize that KRAS-mutant tumors do not respond to KRAS pathway therapies due to the co-occurrence of other activated cell survival pathways and/or mechanisms.

Methods and results

To identify other potentially activated cell survival pathways in KRAS-mutant tumors, I performed association rule mining on somatic mutations in 725 metastatic lung cancer patient samples. I identified 67 additional genes that were mutated in at least 10% of the samples with KRAS mutations. This gene list was enriched with genes involved in the MAPK, AKT and STAT3 pathways, as well as in cell-cell adhesion, DNA repair, chromatin remodeling and the Wnt/β-catenin pathway. I also identified 160 overlapping subsets of three or more genes that code for oncogenic or tumor suppressive proteins that were mutated in at least 10% of the KRAS-mutant tumors.

Conclusions

I identified several genes that are co-mutated in primary KRAS-mutant lung cancer samples. I also identified subpopulations of KRAS-mutant lung cancers based on sets of genes that were co-mutated. Pre-clinical models that capture these subsets of KRAS-mutant tumors may enhance our understanding of lung cancer development and, in addition, facilitate the design of personalized treatment strategies for lung cancer patients carrying KRAS mutations.

     

Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.

PURPOSE: Epidermal growth factor receptor (EGFR) mutations have been associated with tumor response to treatment with single-agent EGFR inhibitors in patients with relapsed non-small-cell lung cancer (NSCLC). The implications of EGFR mutations in patients treated with EGFR inhibitors plus first-line chemotherapy are unknown. KRAS is frequently activated in NSCLC. The relationship of KRAS mutations to outcome after EGFR inhibitor treatment has not been described. PATIENTS AND METHODS: Previously untreated patients with advanced NSCLC in the phase III TRIBUTE study who were randomly assigned to carboplatin and paclitaxel with erlotinib or placebo were assessed for survival, response, and time to progression (TTP). EGFR exons 18 through 21 and KRAS exon 2 were sequenced in tumors from 274 patients. Outcomes were correlated with EGFR and KRAS mutations in retrospective subset analyses. RESULTS: EGFR mutations were detected in 13% of tumors and were associated with longer survival, irrespective of treatment (P < .001). Among erlotinib-treated patients, EGFR mutations were associated with improved response rate (P < .05) and there was a trend toward an erlotinib benefit on TTP (P = .092), but not improved survival (P = .96). KRAS mutations (21% of tumors) were associated with significantly decreased TTP and survival in erlotinib plus chemotherapy-treated patients. CONCLUSION: EGFR mutations may be a positive prognostic factor for survival in advanced NSCLC patients treated with chemotherapy with or without erlotinib, and may predict greater likelihood of response. Patients with KRAS-mutant NSCLC showed poorer clinical outcomes when treated with erlotinib and chemotherapy. Further studies are needed to confirm the findings of this retrospective subset analysis.     

驱动基因突变非小细胞肺癌免疫治疗的研究进展

随着肺癌靶点的发现和药物研发,靶向治疗改善了驱动基因突变非小细胞肺癌(NSCLC)的临床预后。同时,免疫检查点抑制剂在驱动基因阴性NSCLC中也取得了良好的疗效。虽然部分驱动基因突变患者从对应靶向治疗中明显获益,但对免疫治疗反应欠佳。在大部分免疫治疗临床研究和日常实践中,EGFR/ALK等驱动基因突变阳性的NSCLC患者也被排除在外,或者仅占少数。免疫治疗如何应用于驱动基因突变患者,以及如何在靶向治疗、化疗及免疫治疗中选择最佳治疗方案,制定最优治疗策略,对改善晚期驱动基因突变NSCLC患者预后至关重要。本文对不同基因突变肿瘤免疫微环境的特点及免疫治疗在不同基因突变的NSCLC患者中的应用进行简要综述。     

Genomic Landscape of Non-Small Cell Lung Cancer (NSCLC) in East Asia Using Circulating Tumor DNA (ctDNA) in Clinical Practice

Plasma-based next-generation sequencing (NGS) has demonstrated the potential to guide the personalized treatment of non-small cell lung cancer (NSCLC). Inherent differences in mutational genomic profiles of NSCLC exist between Asian and Western populations. However, the published mutational genomic data of NSCLC has largely focused on Western populations. We retrospectively analyzed results from comprehensive NGS of plasma (Guardant360^®) from patients with advanced non-squamous NSCLC, as seen in clinical practice. Tests were ordered between January 2016 and December 2020 in Hong Kong, Korea, Taiwan, Japan and Southeast Asia. The assay identified single-nucleotide variants (SNV), insertions and deletions, and fusions and amplifications in 74 genes. In total, 1608 plasma samples from patients with advanced non-squamous NSCLC were tested. The median turnaround time for test results was 7 days. Of the samples with detectable ctDNA (85.6%), 68.3% had alterations in at least one NCCN-recommended NSCLC biomarker. EGFR driver mutations were most frequent (48.6%), followed by alterations of KRAS (7.9%), ERBB2 (4.1%) and ALK (2.5%). Co-mutations of EGFR and KRAS occurred in 4.7% of samples. KRAS G12C was identified in 18.6% of all samples with KRAS mutations. Common mutations, such as exon 19 deletions and L858R, accounted for 88.4% of EGFR driver mutations. Among the samples with any EGFR driver mutation, T790M was present in 36.9%, including 7.7% with additional alterations associated with osimertinib resistance (MET amplification, C797X). Comprehensive plasma-based NGS provided the timely and clinically informative mutational genomic profiling of advanced non-squamous NSCLC in East Asian patients.     

Clinical outcomes to pemetrexed-based versus non-pemetrexed-based platinum doublets in patients with KRAS-mutant advanced non-squamous non-small cell lung cancer

KRAS mutation has been associated with enhanced dependency on the folate metabolism in preclinical studies. However, whether KRAS mutation correlates to increased sensitivity to pemetrexed in patients with advanced NSCLC is unknown. Patients with advanced non-squamous NSCLC who had a documented EGFR and ALK WT genotype with simultaneous KRAS mutation assessment were evaluated for clinical outcome to pemetrexed- and non-pemetrexed-based first-line platinum doublet according to KRAS mutation status. Of 356 patients identified, 138 harbored a KRAS mutation. Among KRAS-mutant NSCLCs, those treated with platinum/pemetrexed (81/138) had significantly lower ORR (30.9% versus 47.4%, P = 0.05), DCR (51.8% versus 71.9%, P = 0.02) and shorter median progression-free survival [mPFS 4.1 versus 7.1 months, HR 1.48 (95% CI 1.03–2.12), P = 0.03] and median overall survival [mOS 9.7 versus 26.9 months, HR 1.93 (95% CI 1.27–2.94), P = 0.002] compared to those who received a non-pemetrexed-based platinum doublet (57/138). No difference in ORR, DCR, mPFS and mOS was observed between KRAS WT patients who received a pemetrexed-based (124/218) versus non-pemetrexed base platinum doublets (94/218). After adjusting for performance status, age and the presence of brain metastasis at baseline, treatment with pemetrexed-based platinum doublet was associated with an increased risk of death [HR 2.27 (95% CI 1.12–4.63), P = 0.02] among KRAS-mutant patients in multivariate analysis. Patients with KRAS-mutant lung adenocarcinoma have a poorer outcome on pemetrexed-based first-line chemotherapy. Whether KRAS-mutant NSCLCs should be excluded from pemetrexed-containing regimens should be assessed prospectively.