Research Progress on Brain Metastases to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in EGFR-mutated Non-small Cell Lung Cancer Patients
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摘要:
非小细胞肺癌患者中约30%~50%有脑转移(brain metastases,BM),严重影响生活质量和总生存期。系统性的治疗仍然是转移性疾病的标准策略。到目前为止,化疗与全脑放疗(whole brain radiation therapy,WBRT)的结合,手术或立体定向放射外科(stereotactic radiosurgery,SRS)是脑转移患者常用的治疗手段。针对表皮生长因子受体(epidermal growth factor receptor,EGFR)的靶向治疗,如吉非替尼、厄洛替尼和埃克替尼,对EGFR基因突变阳性的患者取得了显著的疗效,埃克替尼不良反应方面优势明显,临床使用安全性更好,在加量治疗时优势更加突出。报道的客观缓解率和良好的安全性、耐受性使表皮生长因子-酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitors,EGFR-TKIs)广泛用于非小细胞肺癌脑转移患者,特别是那些EGFR基因突变阳性的患者。此外,新一代TKIs,比如AZD9291和AZD3759,效果显著,一些试验正在如火如荼的进行。本文对EGFR-TKIs治疗敏感突变肺癌脑转移的研究进展进行综述。
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关键词:
- 脑转移 /
- 表皮生长因子-酪氨酸激酶抑制剂 /
- 非小细胞肺癌
Abstract:Brain metastases(BM) complicate clinical evolution of non-small cell lung cancer (NSCLC) in approximately 30%-50% of cases, adversely influencing quality of life(QOL) and overall survival (OS). Systemic therapy remains the standard strategy for metastatic disease. To date, the combination of chemotherapy with whole brain radiation therapy(WBRT), surgery or stereotactic radiosurgery(SRS) represent the most common treatments for BM patients. Therapies targeting epidermal growth factor receptor(EGFR), such as gefitinib, erlotinib and icotinib, achieve important improvements in EGFR-mutated NSCLC with favorable toxicity profile. The incidence of adverse reactions in icotinib is lower, the clinical use is safer, and the advantage is more pronounced when increasing the dose. The reported objective response rate (ORR), well safety and tolerance make EGFR-tyrosine kinase inhibitors(TKIs) an interesting valid alternative for NSCLC patients with BM, especially for those harboring EGFR mutations. Furthermore, new-generation TKIs, such as AZD9291 and AZD3759, have already shown important activity on intracranial disease and several trials are still ongoing to evaluate their efficacy. In this review, we want to highlight literature data about the use and the effectiveness of EGFR-TKIs on patients with BM from EGFR-mutated NSCLC.
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Key words:
- Brain metastases /
- EGFR-TKIs /
- Non-small cell lung cancer
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0 引言
脑是晚期非小细胞肺癌(non-amall cell lung cancer, NSCLC)较常见的转移部位,初诊晚期肺癌患者中10%左右发生脑转移,所有NSCLC患者中约30%~50%有脑转移[1],尤其在腺癌患者中,严重影响患者的生活质量,预后非常差,缺乏非常有效的治疗方法,脑转移也被认为是影响肺癌患者总生存的不良预后因素,因为发生脑转移的患者,在不治疗的情况下中位生存期仅为4~7周[2]。
1 非小细胞肺癌脑转移治疗现状
化疗在肺癌脑转移的治疗效果有限,首诊出现无症状脑转移的NSCLC,含铂化疗方案中位生存期为3~6月,颅内客观缓解率(objective response rate, ORR)为23%~50%,化疗药物颅内外ORR相似,提示与药物本身活性有关,而与血脑屏障通过率无关[3]。
肺癌脑转移的放射治疗仍不理想,全脑放疗(whole brain radiotiontherapy, WBRT)中位生存期为3~6月,WBRT+化疗的中位生存期为7.6~8月,WBRT曾是肺癌脑转移的标准治疗方案,ORR为50%~70%,1年生存率为10%~15%,不良反应为损伤大脑功能,发生率为25%,并可导致严重脱发[4]。立体定向放射外科(stereotactic radiosurgery, SRS)微创,对认知功能影响较小,但SRS治疗对潜在病灶无效,较WBRT,颅内转移率高[5]。
脑毛细血管内皮细胞无窗孔、内皮细胞间紧密连接,从而限制了许多药物进入神经组织,通常能溶于脂类、在正常pH值时不解离、分子量小的药物易通过血脑屏障,小分子TKIs脂溶性好,能一定比例透过血脑屏障[6],对于NSCLC脑转移灶有治疗作用,因此,目前临床研究的热点集中于EGFR-TKIs在非小细胞肺癌脑转移中的价值。
2 TKIs单药
多数研究入组的患者为EGFR基因突变率较高的人群,如:东亚、女性、非吸烟、腺癌等,中位无进展生存时间(progress free survival, PFS)为6.6~23.2月,中位总生存期(overall survival, OS)在12.9~21.9月[7-10]。对于优势人群或EGFR基因突变阳性的NSCLC脑转移患者,近年来,TKIs单药治疗的地位在逐步确立[11]。
Zhao等[12]报道了一项回顾性对照临床研究,该研究入组396例晚期肺腺癌患者,埃克替尼组131例、标准含铂两药方案化疗组265例,埃克替尼组的大脑累积转移率低于化疗组,然而,两组OS并无显著差异,表明埃克替尼在EGFR基因突变的晚期肺腺癌患者的初始治疗中对脑转移有预防作用,可以有效地降低脑转移的发生率,因此改善预后。
Welsh等[13]入组40例非小细胞肺癌脑转移患者,其中基因状态明确17例,EGFR突变9例,EGFR阴性8例,进行EGFR-TKIs联合全脑放疗,EGFR突变阳性患者OS为19.1月,明显长于EGFR突变阴性患者的9.3月,这说明对于EGFR突变阳性患者,TKI联合全脑放疗,可延长脑转移患者OS。
基于以上循证医学证据,目前NCCN指南建议所有晚期腺癌患者均进行EGFR基因检测,所有有EGFR基因突变患者可EGFR-TKIs作为一线药物[14]。对于野生型患者,没有数据建议一线使用EGFR-TKIs。
3 伴脑转移NSCLC经EGFR-TKIs治疗进展的处理
EGFR-TKIs治疗后颅内进展的耐药机制不明,进展后T790M突变的比例低于颅外病灶,可能与TKI药物CNS低浓度有关[15],也可能与颅内的“pharmacokinetic failure”现象有关[16]。
3.1 联合/换为放疗
Wu等[17]团队的一项随机、开放、平行对照、多中心评价埃克替尼与全脑放疗治疗EGFR突变的晚期NSCLC脑转移患者的Ⅲ期临床试验(BRAIN研究)显示:中位颅内PFS分别为10.0月和4.8月(HR=0.56, P=0.014),6月颅内PFS率分别是72.0%和48.0%(P < 0.001),颅内ORR分别为67.1%和40.9%,总体ORR分别为66.07%和13.33%,疗效初步表明EGFR-TKIs可延缓放疗并提高疗效。
3.2 EGFR-TKIs药物剂量增加
Jackman等[18]发现吉非替尼可加量用于肺癌脑膜转移的晚期患者,吉非替尼剂量由500 mg/d增至1 000 mg/d,吉非替尼脑脊液浓度增加,由18 nmol/L增至42 nmol/L,肝转氨酶ALT/AST由19/15 mg/dL上升至122/47 mg/dL,减量后转氨酶下降,患者临床症状改善,注意力和记忆力提高。
Grommes等[19]报道了Erlotinib“Pulse”给药模式,9例接受单药Erlotinib脉冲给药,平均剂量1500 mg/w(900~1500 mg),中枢神经系统进展的平均时间为2.7月(0.8~14.5月),中位总生存期为12.0月(2.9~25.4月)。
ICOME研究结果显示:WBRT联合埃克替尼(125~375 mg)治疗EGFR敏感突变阳性NSCLC患者耐受性良好,患者认知功能在治疗前后及随访过程中无明显降低,375~500 mg剂量组单药即对颅内有效,且起效时间短(7日内),375 mg可达到最佳的脑脊液药物浓度及脑脊液药物浓度/血药浓度,埃克替尼脑脊液平均渗透率为4.04%(1.23%~9.71%),WBRT未明显增加脑脊液药物浓度/血药浓度,此种治疗模式,颅外进展为7/9(肺内病灶),在加用局部治疗(联合埃克替尼)后患者继续获益,颅内外ORR均为73.3%,总体ORR为80%,疾病控制率(disease control rate, DCR)为100%[20]。
3.3 换用新一代EGFR-TKI
AZD9291是第三代EGFR-TKIs,为不可逆EGFR基因敏感突变和T790M突变阳性抑制剂,AZD9291对野生型细胞株EGFR磷酸化的抑制作用较轻,而第一代和第二代EGFR-TKIs则对于野生型和突变型均有抑制作用,这可能是第三代药物可以在临床有效浓度下抑制T790M突变的原因所在[21]。Ballard等[22]在2015年世界肺癌大会(WCLC)上报道了一项动物实验显示:AZD9291在小鼠脑组织中浓度远远大于吉非替尼、CO-1686和阿法替尼,药峰浓度(maximum concentration, Cmax)脑内/血浆比率(brain/plasma Cmax rate)在AZD9291、吉非替尼、CO-1686和阿法替尼分别是3.4、0.21、 < 0.36和 < 0.36,EGFR突变脑转移小鼠移植瘤模型使用AZD9291较使用CO-1686可导致肿瘤明显退化。Goss等[23]在2016年WCLC上汇集来自两个Ⅱ期临床试验的数据,汇报了T790M突变阳性的晚期NSCLC脑转移患者服用AZD9291,中枢神经系统在6周内ORR可达54%、DCR为92%。近年多报道AZD9291有较好的安全性和耐受性,对颅内病灶有良好的控制,除了克服T790M突变耐药,其一线治疗ECFR突变阳性的晚期肺癌患者的前景广阔[24]。
AZD3759是针对L858R突变和19del作用的EGFR-TKIs,专门设计用于穿透血脑屏障而达到治疗NSCLC脑转移的目的。Chen等[25]在2015年WCLC上汇报AZD3759治疗脑转移Ⅰ期临床试验,结果表明AZD3759具有非常高的血脑屏障被动渗透率(29.5×10-6 cm/s),在EGFR阳性的脑转移动物模型中,AZD3759可明显使肿瘤减小。Ahn等[26]报道的Ⅰ期临床试验,入组了至少经过一代EGFR-TKIs或一线化疗的NSCLC脑转移患者,取得足够的脑脊液浓度,在剂量升级阶段有较好的抗癌活性,在颅内肿瘤可测量的20例患者中,8例患者肿瘤缩小,6例部分缓解,最常见的不良事件是皮疹和腹泻。
4 结语
综上所述,非小细胞脑转移发生率高,预后差,传统疗法效果不理想;第一代EGFR-TKIs可以延缓脑转移发生,对于脑转移患者可以提高疗效,可以联合放疗或者替代早期放疗;治疗失败后增加剂量仍有可能使脑转移获得缓解;新一代EGFR-TKIs很好地解决了脑转移的治疗难题。
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