南京大学博士后
美国休斯敦MD Anderson肿瘤中心联合培养博士
华中科技大学同济医学院博士
以第一作者或通讯作者身份发表SCI论文14篇，累计影响因子60.42，其中2020ESI高被引用收录1篇
主持中国博士后科学基金一项，多个SCI期刊审稿人
随着2010年ToGA数据的发布，胃癌的治疗正式进入了靶向时代，曲妥珠单抗与化疗的联合应用显著改善了HER2阳性患者的预后[1]。针对HER2这个靶点，近些年来在胃癌中又进行了诸多尝试，包括KEYNOTE-811中曲妥珠单抗与免疫检查点的联合应用[2]、一线折戟沉沙的帕妥珠单抗[3]、后线表现优秀的抗体偶联药物DS-8201[4]及RC48[5]、以及匠心设计的margetuximab[6]、Zanidatamab[7]、KN026[8]。虽然国外的文献报道HER2阳性的胃癌患者约20%左右[9]，但我国胃癌患者的HER2阳性率仅为10.8%-12.5%[10, 11]，笔者回顾性分析了所在中心近3年的胃癌患者，HER2阳性率为11.4%，故抗HER2治疗覆盖人群有限。随着精准医学的发展，越来越多的靶点被发掘，本文对相关的临床数据进行盘点，期待未来能够有更多的病人在更前线接受到精准的靶向治疗。
1. Claudin 18.2
Claudin家族蛋白是一类存在于上皮和内皮紧密连接中的整合素膜蛋白，由CLDN基因编码，主要功能是通过不同细胞之间的Claudin蛋白多聚体实现紧密连接。Claudin的异常表达可能导致在某些肿瘤中蛋白的定位与功能异常，进而促进肿瘤的侵袭和转移能力[12]。Claudin18在Claudin家族中研究的最为广泛，有两种剪切变体Claudin 18.1及Claudin18.2。Claudin 18.1主要表达于正常及肺癌组织，Claudin 18.2主要表达于正常胃组织及胃癌、胰腺癌、食管癌中[13]。虽然参与了细胞粘附的Claudin 18.2表达下调或缺失后会促进肿瘤的发生和转移，但Claudin 18.2依然可以作为治疗胃癌的靶点，因为在正常胃部组织中Claudin 18.2主要存在于胃粘液细胞紧密连接的超巨分子中，而胃癌组织中Claudin 18.2的表位会暴露出来从而可以与对应抗体结合[12]。日本的一项研究提示Claudin 18.2在胃癌的表达率为51.5%[14]，笔者所在中心的既往研究提示在印戒细胞癌中，Claudin 18.2的表达率为64.8%[15]。
目前在胃癌中针对Claudin 18.2的治疗包括单抗、CAR-T、双抗、抗体偶联药物四大类。表1展示了已有数据发布的相关的临床试验设计及结果。IMAB362/zolbetuximab 是第一个靶向Claudin18.2的单抗。在胃癌后线的临床试验中确立了IMAB362的安全性和抗肿瘤能力（NCT00909025、NCT01197885）。II期临床试验FAST（NCT01630083）纳入了≥40%肿瘤细胞中/高表达Claudin18.2的一线胃癌患者，IMAB362联合EOX相较于EOX展现出了无进展生存期（progression-free survival, PFS）和总生存期（overall survival, OS）的优势，尤其是在≥70%肿瘤细胞中/高表达Claudin18.2的患者中尤为突出，但在40%~69%肿瘤细胞中/高表达Claudin18.2的患者中两组OS无差异。该临床试验主要的不良反应包括恶心、呕吐、中性粒细胞减少、贫血等，多为1-2级[16]。2021ASCO报道了II期临床试验ILUSTRO的队列2的研究结果，纳入了21例≥75%肿瘤细胞中/高表达Claudin18.2的一线胃癌患者，评估mFOLFOX联合IMAB362一线治疗的疗效，其中19例可评估，客观缓解率（objective response rate, ORR）为63.2%[17]。IMAB362一线治疗的III期临床试验SPOTLIGHT及GLOW的数据尚未披露。CT041是全球首个针对Claudin18.2的CAR-T细胞治疗，37例受试者中有36例存在靶病灶，31例患者的靶病灶出现不同程度的缩小，根据RECIST 1.1标准，ORR和疾病控制率（disease control rate, DCR）分别达到48.9%（18/37）和73%（27/37）。在既往接受过≥2线治疗的胃癌患者中，18例患者接受2.5×108 CAR-T细胞治疗，约40%患者既往接受过PD-1单抗治疗，中位随访时间为7.6个月，ORR为61.1%，DCR为83.3%，mPFS为5.6个月，mOS 为9.5个月，100%出现≥G3血液毒性，无免疫相关神经毒性，无≥G3细胞因子风暴[18]。靶向Claudin18.2的双抗及ADC的药物尚无相关临床数据发布。
表1靶向Claudin18.2相关临床试验
2. DKK1
DKK1为一种含有266个氨基酸的分泌型蛋白，是一种Wnt信号通路的天然拮抗物，在组织或者血清中均可检测。生理情况下，DKK1在骨、胎盘、前列腺、脾脏、结肠中均有表达[21]。病理情况下，实验室数据分析显示DKK1能够提高肿瘤细胞的增殖与侵袭能力[22]；临床数据分析显示DKK1在多种肿瘤比如乳腺癌、食管癌、结肠癌、胃癌、子宫内膜癌中高表达[21]，且在头颈鳞癌、肝癌、直肠癌、肺癌、胰腺癌中与不良生物学行为或不佳预后相关[22, 23]。上述实验室及临床研究结果为DKK1成为肿瘤的诊断、预后判断及治疗的新型靶点提供了依据。
DKN-01是一种人源化的IgG4抗体，可与DKK1结合并阻断其活性，目前已有多项相关临床试验（表2）。DKN-01最开始在非小细胞肺癌及妇科肿瘤的后线治疗中崭露头角（NCT01457417[24]、NCT03395080[25]）。在胃/胃食管交界癌的后线治疗中，既往未接受过PD-1/PD-L1抗体治疗且DKK1高表达的患者接受DKN-01+帕博利珠单抗治疗，客观缓解率（objective response rate, ORR）为50%（NCT02013154）[26]。2021年ESMO及2022年的ASCO GI相继报道了DKN-01+替雷利珠+化疗在胃食管腺癌一线治疗中的数据，对于DKK1高表达的患者，在疗效可评估的患者中，ORR高达100%（NCT03395080，DisTinGuish）[27, 28]。
表2 DKK1靶向药物DKN-01相关临床试验
3. FGFR2b
FGFR2b在多种肿瘤中过表达且与不良预后相关，常存在于肠型的胃癌患者，且与HER2过表达互斥[30]，FGFR2b过表达的弥漫型胃癌患者预后极差[31]。Bemarituzumab是靶向FGFR2b的IgG1抗体，在后线FGFR2b阳性的胃癌患者中ORR为18%[32]。2021ASCO报道了Bemarituzumab一线治疗晚期胃癌的II期临床试验（NCT03694522）的相关数据。该项目纳入了FGFR2b过表达（IHC 2+/3+）或FGFR2b扩增晚期胃癌患者，1:1将患者随机分至Bemarituzumab联合mFOLFOX6组与mFOLFOX6组。30%的预筛患者符合FGFR2b表达要求，大部分患者FGFR2b过表达但无FGFR2b扩增。在肿瘤组织≥10% FGFR2b IHC 2+/3+的患者中mPFS长达14.1个月，ORR为54.5%，而mOS尚未达到[33]。
4. MET
促癌基因MET编码酪氨酸激酶受体c-MET，c-MET与其配体肝细胞生长因子HGF形成二聚体激活下游ERK/MAPK、PI3K-AKT通路。MET在胃肠肿瘤中扩增率为8%，且与较差预后相关[34]，我中心检测的胃癌MET扩增率为4.1%[35]。MET抑制剂的应用是基于MET的扩增或突变，而非过表达。一项开放标签、多中心的Ia/Ib期临床试验评价赛沃替尼后线治疗晚期胃癌，结果提示只有MET扩增的患者疾病能得到缓解，ORR为35.7%，主要的不良反应包括恶心、呕吐及外周水肿[36]。针对MET基因扩增的后线胃癌患者，II期临床研究正在进行中。
结语
胃癌无论是发病率还是死亡率，在我国均位于前三位，大部分患者在发病时已难以接受根治手术，病情进展快，预后差。随着基因检测技术的不断发展，分子生物标志物指导下的胃癌的精准治疗逐渐得以实现，HER2靶向药物的成功改善了部分患者的预后，越来越多的分子靶点被研究与挖掘，目前这些靶点的研究数据多为II期临床试验的结果，经历了从后线到前线的推进，相关III期临床试验正在设计或进行中。在这个逐渐完备与成熟的过程中，科学家与临床医师将紧密合作，发掘更多的新型靶点、确定统一的靶点检测手段与判读标准、推广多靶点检测的可及性、多种治疗模式联合应用提高疗效。最后，让我们一起期待下一个站在光里的英雄！
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