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Advances in Clinical Medicine
Vol. 11  No. 09 ( 2021 ), Article ID: 45132 , 10 pages
10.12677/ACM.2021.119578

晚期肺腺癌患者获得性EGFR-TKI耐药后治疗的研究进展

王康，胡雪婷，罗虎，周向东*

陆军军医大学，第一附属医院呼吸与危重症医学科，重庆

收稿日期：2021年8月9日；录用日期：2021年9月1日；发布日期：2021年9月10日

摘要

表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI)的出现给肺腺癌患者带来福音，但EGFR-TKI的耐药问题亟需解决。为了进一步改善患者的生存，本文就晚期肺腺癌患者获得性EGFR-TKI耐药后治疗的研究现状进行综述，探讨EGFR-TKI耐药后治疗策略的临床意义及如何选择个体化治疗方案。

关键词

肺腺癌，表皮生长因子受体，酪氨酸激酶抑制剂，获得性耐药

Research Progress of Acquired EGFR-TKI Resistance in Patients with Advanced Lung Adenocarcinoma

Kang Wang, Xueting Hu, Hu Luo, Xiangdong Zhou*

Institute of Respiratory Diseases, Department of Respiratory, Xinan Hospital, Army Military Medical University, Chongqing

Received: Aug. 9th, 2021; accepted: Sep. 1st, 2021; published: Sep. 10th, 2021

ABSTRACT

The emergence of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) brings good news to patients with lung adenocarcinoma, but the problem of drug resistance of EGFR-TKI needs to be solved urgently. In order to further improve the survival of patients, this paper reviewed the research status of acquired EGFR-TKI post-drug resistance treatment in patients with advanced lung adenocarcinoma, and discussed the clinical significance of EGFR-TKI post-drug resistance treatment strategy and how to select individual treatment plan.

Keywords:Adenocarcinoma of Lung, Epidermal Growth Factor Receptor, Tyrosine Kinase Inhibitors, Acquired Drug-Resistance

Copyright © 2021 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

肺癌在全球的发病率和死亡率居高不下，造成严重的社会和经济负担。虽然从2020新发癌统计来看肺癌发生率已被乳腺癌超过，但肺癌的致死率依然是最高的。肺腺癌是肺癌的主要组织类型，约占40%以上。对于不可切除的晚期肺腺癌来说放化疗曾是经典的治疗策略。表皮生长因子受体酪氨酸激酶抑制剂(epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI)是一种小分子酪氨酸激酶抑制剂，以吉非替尼、厄洛替尼、阿法替尼、达克替尼、奥西替尼等为主的EGFR-TKI已普遍应用于EGFR阳性的肺腺癌患者的治疗。相对于放化疗，EGFR-TKI不仅能使患者有更好的生存获益，而且毒副作用小，大大提高了患者的生存质量。然而尽管EGFR-TKI具有低毒高效的特点，但最终都难免出现耐药的结局。一、二代EGFR-TKI在经过中位8~13个月的疾病控制后，最终会出现耐药。如果三代EGFR-TKI也已经耐药，则无更新的EGFR-TKI可以选用，后续该如何处理？现将晚期肺腺癌患者获得性EGFR-TKI耐药的后续治疗策略作以综述。

2. EGFR-TKI获得性耐药的定义

EGFR-TKI的出现给EGFR突变阳性的这一部分患者带来了福音，但与此同时获得性耐药也成了严峻的挑战。Jackman等 [1] 对EGFR-TKI获得性耐药的定义做了精确描述，即EGFR突变阳性的非小细胞肺癌(Non-Small Cell Lung Cancer, NSCLC)患者在接受EGFR-TKI治疗后，根据实体瘤疗效评价标准(Response Evaluation Criteria In Solid Tumors, RECIST)达到疾病稳定或缓解持续6个月以上，在继续使用EGFR-TKI的时候，出现RECIST评价的疾病进展。

3. EGFR-TKI获得性耐药的临床亚型及一般机制

根据EGFR-TKI获得性耐药后的临床情况的不同，可将其分为三种临床亚型：中枢神经系统(central nervous system, CNS)豁免型、微进展型、全身进展型 [2]。CNS豁免型一般是由于一些TKI对血脑屏障的穿透性很弱，中枢神经系统虽出现病灶，但其他部位对TKI的反应良好 [3]；微进展型一般是指除神经系统以外少于4个局部病灶位点的进展 [4] [5]；全身进展指全身多处多系统的进展；临床上一般根据进展的类型来决定下一步如何对耐药进行处理。

EGFR-TKI获得性耐药的机制也是多种多样的，根据目前的研究结果来看，耐药的机制大致分为三种情况：EGFR靶基因修饰、其他旁路激活及组织表型转变。EGFR靶基因修饰最常见的就是T790M突变(EGFR 20号外显子第790位点上的苏氨酸被蛋氨酸所取代)，大约占第一、二代EGFR-TKI获得性耐药的50%以上 [6]。C797S突变(EGFR 20号外显子第797位点上的半胱氨酸被丝氨酸所取代)是第三代EGFR-TKI奥西替尼获得性耐药的较常见突变之一 [7]，奥西替尼耐药后的部分患者同时携带T790M突变和C797S突变，当两种突变位于同一条DNA链上时，则称为T790M/C797S顺式突变，当两种突变位于不同DNA链上时，称为T790M/C797S反式突变 [8]。还有部分奥西替尼耐药的患者在发生了C797S突变以后，原有的T790M突变丢失 [9]。另外的EGFR靶基因修饰还有L747S突变、D761Y突变、L792F/H突变、L718Q突变、G796S/R突变等 [10] [11] [12] [13] [14]。其他旁路激活主要有MET扩增、HER2扩增、AXL激活、PIK3CA激活、IGF1R激活、BRAF激活、RAS突变、FGFR扩增、MAPK激活等 [15] - [22]。MET扩增是较常见旁路激活通道，约占EGFR-TKI获得性耐药的5%~10%，可见于吉非替尼、厄洛替尼、阿法替尼、奥西替尼的耐药。扩增的MET基因可以通过ERBB3/PI3K/Akt信号通路来介导EGFR-TKI的耐药 [23]。组织表型转变主要包括肺腺癌转变成小细胞肺癌(Small cell lung cancer, SCLC)或肺鳞癌和上皮间质转化(Epithelial-mesenchymal transition, EMT)。SCLC转化见于大约5%的耐药患者 [24]。Niederst等 [25] 通过研究EGFR-TKI耐药患者的肿瘤和细胞样本发现，所有转换成SCLC的样本都没有RB的表达。RB基因又叫成视网膜细胞瘤基因，它是世界上第一个被克隆和完成全序列测定的抑癌基因。由于原发性SCLC中存在RB基因的缺乏，所以RB的丢失可能是肺腺癌患者在EGFR-TKI获得性耐药后转变为SCLC的原因之一。AXL激酶、TGF-IL6等的激活可能是EMT形成的原因 [18] [26]。

4. 第一、二代EGFR-TKI耐药后的治疗

第一代EGFR-TKI主要包括吉非替尼、厄洛替尼、埃克替尼，第二代EGFR-TKI主要包括阿法替尼、达克替尼。一代EGFR-TKI主要针对19外显子缺失、21外显子L858R点突变等。二代EGFR-TKI对EGFR的G719X、S768I和L861Q等罕见突变位点有较好的效果。在临床上二代TKI并没有明显优于一代TKI且副作用更大，况且一代TKI出现耐药后，二代TKI也不能克服耐药，因此二代TKI临床运用范围比较有限。

4.1. 局部进展

局部进展包括非CNS的微进展和只有CNS进展的豁免进展。CNS豁免进展的目前的主要治疗方案包括：手术切除、手术切除 + 全脑放射治疗(Whole brainradiation therapy, WBRT)、立体放射外科治疗(Stereotactic Radiosurgery, SRS)、WBRT辅助治疗(手术切除或SRS以后)、继续TKI单药治疗、TKI + WBRT、TKI + 鞘内化疗等 [27] [28] [29] [30] [31]。非CNS的微进展一般指原发灶进展或者非CNS有限位点进展。微进展后一般采用局部病灶手术切除、立体定向放疗或者继续使用EGFR-TKI [32] [33]。ASPIRATION研究 [34] 纳入的207例肺腺癌患者中171例出现了无进展生存期(Progression free survival, PFS)终点，其中93例在厄洛替尼进展后继续使用厄洛替尼治疗，这些患者的中位PFS1和PFS2分别为11.0个月(95% CI, 9.2~11.1)和14.1个月(95% CI, 12.2~15.9)；客观缓解率(Overall response rate, ORR)为66.2%；中位总生存期(Overall survival, OS)为31.0个月(95% CI, 27.3-未达到)。对于局部进展后的患者，继续TKI治疗也是可行的策略。有研究表明在使用TKI达到局部进展以后继续TKI联合局部治疗可以使PFS延长6个月以上 [4]。

4.2. T790M突变

对于全身性进展的患者，局部治疗难以奏效，此时就需要寻求靶向治疗、免疫治疗或者全身放化疗。研究显示未经治疗的NSCLC患者标本中出现T790M阳性突变的概率大约为3.6%，而经过吉非替尼、厄洛替尼或阿法替尼治疗耐药以后的NSCLC患者，其阳性率达到50%以上。由此可见T790M突变与TKI耐药有很大的相关性 [35] [36]。第三代EGFR-TKI奥西替尼在T790M突变阳性的耐药患者中发挥了显著的效果。AURA2期扩展研究 [37] 纳入201例经一、二代TKI治疗后进展并携带T790M突变的患者，对其中的198例进行了疗效评估，ORR为62% (95% CI, 54%~68%)，疾病控制率 (Disease control rate, DCR)为90% (95% CI, 85~94)，中位PFS为12.3个月(95% CI, 9.5~13.8)，122位患者的中位缓解持续时间(Duration of response, DOR)为15.2个月(95% CI, 11.3-未达到)。

4.3. MET扩增

MET扩增是引起EGFR-TKI获得性耐药比较常见的旁路激活突变，MET的抑制剂主要有卡马替尼(capmatinib, INC280)、卡博替尼(cabozantinib, xl184)等。Wu等 [38] 的一项Ib/II临床研究表明：在TKI耐药以后携带MET扩增的患者后续吉非替尼联合卡马替尼治疗的ORR达27%，在MET基因拷贝数 ≥6的这一批患者中ORR达到47%，中位PFS为5.45个月(95% CI, 3.71~7.10)。另一项关于卡博替尼的临床研究显示EGFR-TKI获得性耐药后TKI联合卡博替尼的中位PFS达到了4.7个月 [39]。因此对于TKI获得性耐药以后携带MET扩增的患者TKI联合MET抑制剂是可行的选择。另外对于同时携带MET扩增和T790突变的患者可以用奥西替尼联合MET抑制剂来治疗。

4.4. HER2扩增

人表皮生长因子受体-2 (Human Epidermal GrowthFactor Receptor 2, HER2)是一种原癌基因。阿法替尼是多靶点蛋白激酶不可逆抑制剂，属于第二代EGFR-TKI，同时它还是HER2的抑制剂之一 [40]。Landi等 [41] 的一项临床研究指出吉非替尼、厄洛替尼治疗进展后出现HER2突变的这部分患者接受阿法替尼治疗的中位PFS为3.9个月。

4.5. PIK3CA激活突变

PIK3CA基因编码的蛋白是PI3Ks的催化亚单位，PI3Ks是一种脂激酶。PIK3CA基因的突变可以导致PI3Ks的催化活性异常增强，促使细胞发生癌变。PIK3CA激活突变主要通过PI3K/PTEN/AKT信号通路来产生TKI的获得性耐药 [42]。Buparlisib (BKM120)是PIK3的抑制剂，有关研究表明在TKI获得性耐药后BKM120联合吉非替尼的PFS为2.8个月，但研究只纳入10例进行研究，因此BKM120的临床价值还有待进一步研究 [43]。

4.6. AXL激活突变

AXL是一种调控多个下游信号通路的受体酪氨酸激酶，它在肿瘤的增殖、入侵、迁移、上皮间质细胞转化(EMT)、肿瘤血管生成以及肿瘤微环境中的免疫调节等过程中发挥重要的作用。有研究表明AXL激酶的激活可以引起TKI获得性耐药 [18]。Bemcentinib (R428, BGB324)是一种AXL抑制剂，关于AXL激活突变所致的TKI耐药的临床研究正在进行中 [44]。

4.7. 无相应靶点

当TKI获得性耐药后检测不到新增靶点时，化疗、抗血管生成治疗、三代TKI、免疫治疗等都是可用的选择。有研究认为TKI耐药后化疗联合TKI不仅不能使患者生存获益，而且还会增加毒副作用 [45]。Johnson等 [46] 认为在不考虑突变靶点的情况下，热休克蛋白90 (HSP90)的抑制剂AUY922联合吉非替尼可以使TKI耐药的患者缓解获益。

4.8. 转变为小细胞肺癌或肺鳞癌

TKI获得性耐药部分肺腺癌的患者转变为SCLC或肺鳞癌，后续的治疗一般为化疗或者放疗。SCLC一般采用EP方案(依托泊苷 + 顺铂)，肺鳞癌为GP方案(吉西他滨 + 顺铂)。另外抗血管生成治疗、免疫治疗或与化疗联合治疗都是可选方案。

5. 第三代EGFR-TKI耐药后的治疗

第三代EGFR-TKI是不可逆的酪氨酸激酶抑制剂，主要代表是奥西替尼(osimertinib)，又称泰瑞沙或AZD9291。AURA的一系列临床研究已经证明了奥西替尼的卓越效果，FLAURA研究 [47] 也证实了奥西替尼作为一线治疗的优势。第三代EGFR-TKI局部进展后的治疗方案与第一、二代相似，在此不再赘述。

5.1. C797S突变

C797S突变是奥西替尼耐药后较常见的突变，有T790M/C797S顺式突变及反式突变之分，有些患者在耐药后出现T790M丢失的情况。Wang等 [48] 的研究指出布加替尼联合西妥昔单抗可以使奥西替尼耐药后出现T790M/C797S顺式突变这一部分患者获益。西妥昔单抗(Cetuximab)属于嵌合型IgG1单克隆抗体，分子靶点为EGFR，布加替尼(Brigatinib)是间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)的抑制剂。二者联合治疗后的ORR为60%，中位PFS为14个月。本研究虽然病例数较少，但也给T790M/C797S顺式突变的这部分患者带来希望。部分个案研究表明对于T790M/C797S反式突变，联合一代EGFR-TKI和三代EGFR-TKI有不错的效果 [49] [50]。对于奥西替尼耐药后出现T790M丢失的这部分患者也有使用一代EGFR-TKI进行治疗的案例，大型的临床研究也处于入组阶段。

5.2. MET扩增

MET介导的TKI突变大多是由于扩增引起的，三代TKI耐药发生后也可以发生MET扩增。沃利替尼(Savolitinib)是MET的抑制剂之一，Sequist等 [51] 的一项多中心临床研究中携带MET突变的69例奥西替尼耐药患者经Savolitinib联合奥西替尼治疗后的ORR为30%，中位PFS为5.4个月。Amivantamab (JNJ-372)是EGFR-MET双抗，在一项临床研究中Amivantamab联合三代TKI效果显著，58例EGFR三代药耐药患者总有效率为28%，27例EGFR 20外显子插入突变患者的总有效率为30% [52]。

5.3. HER2扩增或突变

HER2是奥西替尼耐药后出现的突变之一，其中大部分为HER2扩增，目前有几项关于克服TKI耐药后HER2突变的临床研究正在进行中。恩美曲妥珠单抗(T-DM1)是HER2的靶向药，Peters等 [53] 的一项研究中，部分患者为TKI耐药并HER2过表达的患者，T-DM1能够使这部分患者获益。HER2的16外显子跳跃突变是新发现的奥西替尼耐药的机制之一，阿法替尼在显示对这类患者有效 [54]。

5.4. Kras突变

Kras是一种鼠类肉瘤病毒癌基因，正常的Kras基因可抑制肿瘤细胞生长和发展。一旦发生突变，就会持续刺激细胞生长从而导致肿瘤的发生。奥西替尼耐药的部分患者也检测到了Kras突变，它主要通过RAS-MAPK通路来促进耐药。这个突变尚无明显有效靶向药物，不过丝裂原活化蛋白激酶激酶(MEK)抑制剂可以抑制这个通路 [55]。TATTON研究中，司美替尼(Selumetinib)联合奥西替尼对于TKI耐药的患者有效，Selumetinib是MEK抑制剂，纳入的36例患者的ORR为42% [56]。

5.5. BRAF突变

BRAF基因是一种原癌基因，编码RAF家族丝氨酸/苏氨酸蛋白激酶，该蛋白在调节MAPK/ERK信号通路中起作用，参与细胞分裂，分化等，一旦发生了突变，身体就易于患癌。V600E是BRAF基因最容易癌变的一个位点。Ho等 [15] 指出BRAF V600E是奥西替尼获得性耐药的机制之一，从他们的一项体外细胞试验来看BRAF V600E的抑制剂康奈非尼(Encorafenib)联合奥西替尼能够很好地抑制奥西替尼耐药后体外肿瘤组织细胞的生长，为临床研究奠定细胞学基础。

5.6. RET融合

RET是一种原癌基因，它可以编码一种称为RET的跨膜蛋白，该蛋白属于一种受体酪氨酸激酶。RET蛋白发挥生物学作用的信号通路包括PI3K-AKT-mTOR途径以及RAS-RAF-MEK-ERK途径。RET基因发生突变可造成细胞过度增殖，进而导致肿瘤的发生发展。Xu等 [57] 的一项研究回顾性分析了3873例EGFR突变的肺癌患者的基因检测资料，发现6例患者出现RET融合，而这六例患者都是使用奥西替尼耐药以后出现的RET融合。卡博替尼(Cabozantinib)是VEGFR2、MET、RET的强效抑制剂，一项二期临床研究 [58] 纳入26例RET重排(其中16例RET融合)的肺腺癌患者，使用Cabozantinib后25例产生反应，ORR为28%。因此对于奥西替尼耐药后出现RET融合的患者Cabozantinib有一定的应用前景。普雷西替尼(Pralsetinib, BLU-667)也是对RET融合有靶向作用的新药，Piotrowska等 [59] 分析了41例奥西替尼耐药患者标本，其中包括2例RET融合。在体外用BLU-667处理以后细胞以后，携带RET融合的细胞再次对奥西替尼产生反应。后续又用BLU-667联合奥西替尼治疗这两例患者，最终都产生了影像学反应且不良反应可耐受。

5.7. 无相应靶点

奥西替尼治疗后无明确靶点或者出现无特定抑制剂的罕见靶点时，可以选择化疗、抗血管生成(单药或者联合化疗)、免疫单药或者免疫联合化疗与抗血管生成等。雷莫芦单抗(Ramucirumab)是抗血管生成药物，它是血管内皮细胞生长因子受体2 (Vascular Endothelial Growth Factor Receptor 2, VEGFR2)的拮抗剂，它联合奥西替尼的一项I期临床研究结果显示二者联合有广阔应用前景 [60]。Patritumab Deruxtecan (U3-1402)是HER3的抗体药物偶联物(antibody-drug conjugate, ADC)，一项体外研究表明U3-1402能够明显抑制奥西替尼耐药细胞系 [61]。2019年世界肺癌大会上的一项研究数据显示，I期临床的30名EGFR突变的晚期NSCLC患者中既有第一、二代治疗后耐药的，也有第三代耐药的，而且部分患者耐药后无相应的靶点。U3-1402对TKI耐药患者的疾病控制率达95.7% (23例可评估的患者中22例患者的病灶缩小)。目前一项评估U3-1402与奥希替尼联合治疗EGFR突变的晚期或转移性NSCLC患者的临床试验已经展开。

5.8. 转变为小细胞肺癌或肺鳞癌

第三代TKI奥西替尼耐药后也会转变为小细胞肺癌或肺鳞癌，只是几率比第一、二代要低 [62] [63]。奥西替尼耐药转变为SCLC或鳞癌的患者在选择标准放化疗的同时还可以行组织表本的基因检测，如果患者依然保留EGFR突变，尤其是有脑转移的患者，化疗联合奥西替尼可能会使这部分患者获益。

6. 小结与展望

EGFR-TKI是目前携带EGFR突变的晚期肺腺癌患者的一线治疗方法，一线治疗耐药后对其耐药原因进行研究有重要意义。肺腺癌患者的驱动基因突变率比较高，靶向治疗不仅延长了肺腺癌患者的生命，而且也大大提高了他们的生活质量。用于克服奥西替尼耐药的第四代EGFR-TKI也已处于临床试验阶段，随着对驱动基因及其耐药机制的不断研究以及各大临床实验的不断推广，针对晚期肺腺癌治疗的策略也会越来越多。将肺癌患者个体化治疗与综合治疗相结合，相信在不久的将来，肺癌一定能成为像高血压、糖尿病一样的慢性病。

基金项目

重庆市项目[卫计委适宜技术推广项目] (2020jstg016)。

文章引用

王 康,胡雪婷,罗 虎,周向东. 晚期肺腺癌患者获得性EGFR-TKI耐药后治疗的研究进展
Research Progress of Acquired EGFR-TKI Resistance in Patients with Advanced Lung Adenocarcinoma[J]. 临床医学进展, 2021, 11(09): 3949-3958. https://doi.org/10.12677/ACM.2021.119578

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    64. NOTES

    *通讯作者。

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