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齐长松：2019年胃肠道间质瘤治疗进展盘点

2020-01-05 齐长松 肿瘤综合治疗电子杂志

齐长松胃肠道间质瘤
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齐长松，刘丹，李健，沈琳 （北京大学肿瘤医院暨北京市肿瘤防治研究所　消化肿瘤内科　恶性肿瘤发病机制及转化研究教育部重点实验室，北京　100142） 胃肠道间质瘤（gastrointestinal stromal tumors，GIST）是胃肠道最常见的间叶源性肿瘤，而伊马替尼在GIST领域的辉煌成就标志着实体瘤靶向治疗时代的来临。但从舒尼替尼、瑞戈非尼相继上市至今近10年的时间内，GI

齐长松，刘丹，李健，沈琳

（北京大学肿瘤医院暨北京市肿瘤防治研究所　消化肿瘤内科　恶性肿瘤发病机制及转化研究教育部重点实验室，北京　100142）

胃肠道间质瘤（gastrointestinal stromal tumors，GIST）是胃肠道最常见的间叶源性肿瘤，而伊马替尼在GIST领域的辉煌成就标志着实体瘤靶向治疗时代的来临。但从舒尼替尼、瑞戈非尼相继上市至今近10年的时间内，GIST领域再也没有新药上市，甚至在其它领域如火如荼的免疫治疗也在GIST领域遭遇了滑铁卢。还好，在即将过去的2019年，不管是基础研究还是药物治疗，GIST领域均迸发出希望的火花，其中备受瞩目的依然是BLU-285和DCC2618两个明星药物。

Avapritinib（BLU-285）最新的治疗数据发表在ASCO年会上，在121例既往治疗≥4线的转移性胃肠道间质瘤患者中，22%患者获得部分缓解，约60%患者肿瘤出现不同程度的退缩，中位肿瘤控制时间达到10.2个月；在43例PDGFRA 18号外显子突变患者中，除2例患者出现肿瘤增大之外，其余全部患者均出现肿瘤退缩，86%患者获得肿瘤缓解，其中有6例患者达到完全缓解。中位随访10.9个月时，仍有78%患者在持续治疗有效过程中；

Ripretinib（DCC-2618）治疗转移性胃肠道间质瘤的III期研究（INVICTUS）数据发表在ESMO年会上，在随机双盲的Ripretinib对比安慰剂四线及四线以上治疗转移性GIST的研究中，主要研究终点PFS为6.3个月∶1.0个月（P<0.0001），与安慰剂组相比，接受Ripretinib治疗患者肿瘤进展或死亡风险降低了85%，独立影像评估RR＝9.4%，中位OS为15.1个月（安慰剂组为6.6个月），主要3~4度不良反应为贫血（9%）、腹痛（7%）、高血压（7%）。

这两个明星药物可以说吊足了国人的胃口，好在国内多家中心相继参加了BLU-285的国际III期临床研究，中国I/II期研究也在有条不紊的进行当中，该药所带来的治疗效果也确实没有让williamhill asia 失望。

相信在不久的将来，GIST靶向治疗大家庭将迎来这两位重量级成员，而相比于BLU-285的专一（PDGFRA D842V），DCC2618被认为是对几乎全部Kit/PDGFRA基因都有显著抑制作用的药物。非常期待能有更多不同基因分型亚组患者的临床数据，来帮助医生筛选最获益的人群；此外，两种药物在GIST后线治疗中的布局也非常值得期待，是按照传统药物从四线开始一步一步向二线甚至一线前进，还是能够根据自身优势基因分型打破传统线数的束缚？期待相关研究的早日开展。

此外，MEK抑制剂Binimetinib联合CSF1R、KIT和FLT3抑制剂Pexidatinib，CDK4抑制剂Palbociclib，VEGFR2、EGFR和RET抑制剂Vandetanib等新药也公布了其在GIST领域早期临床研究的结果，无一例外，这些新药均未显示出令人满意的效果。

最后，表观遗传学、免疫分型等基础研究以及以影像组学为代表的多组学技术在GIST领域的应用也取得了一定程度的进展，期待这些结果能够早日应用于临床，为GIST患者带来直接获益。

参考文献

1.Chen T, Liu S, Li Y, Feng X, Xiong W, Zhao X, et al. Developed and validated a prognostic nomogram for recurrence-free survival after complete surgical resection of local primary gastrointestinal stromal tumors based on deep learning. EBioMedicine 2019;39:272-9 doi 10.1016/j.ebiom.2018.12.028.

2.Flavahan WA, Drier Y, Johnstone SE, Hemming ML, Tarjan DR, Hegazi E, et al. Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs. Nature 2019;575(7781):229-33 doi 10.1038/s41586-019-1668-3.

3.Glod J, Arnaldez FI, Wiener L, Spencer M, Killian JK, Meltzer P, et al. A Phase II Trial of Vandetanib in Children and Adults with Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor. Clin Cancer Res 2019;25(21):6302-8 doi 10.1158/1078-0432.CCR-19-0986.

4.Jin C, Huang Y, Nasim M, Yang Y, Lee L. Gastrointestinal Stromal Tumors Risk Stratification Utilizing Phospho-Histone H3 Evaluated by Manual Counting and Computer-Assisted Image Analysis. Int J Surg Pathol 2019;27(7):706-12 doi 10.1177/1066896919851866.

5.Rosenbaum E, Kelly C, D'Angelo SP, Dickson MA, Gounder M, Keohan ML, et al. A Phase I Study of Binimetinib (MEK162) Combined with Pexidartinib (PLX3397) in Patients with Advanced Gastrointestinal Stromal Tumor. Oncologist 2019;24(10):1309-e983 doi 10.1634/theoncologist.2019-0418.

6.Rowe SP, Fishman EK. Cinematic Rendering of Neurofibromatosis Type I Gastrointestinal Stromal Tumors. Radiology 2019;291(2):298 doi 10.1148/radiol.2019190104.

7.Toulmonde M, Blay JY, Bouche O, Mir O, Penel N, Isambert N, et al. Activity and Safety of Palbociclib in Patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib: A Biomarker-driven Phase II Study. Clin Cancer Res 2019;25(15):4611-5 doi 10.1158/1078-0432.CCR-18-3127.

8.Vitiello GA, Bowler TG, Liu M, Medina BD, Zhang JQ, Param NJ, et al. Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor. J Clin Invest 2019;129(5):1863-77 doi 10.1172/JCI124108.

9.Wang C, Li H, Jiaerken Y, Huang P, Sun L, Dong F, et al. Building CT Radiomics-Based Models for Preoperatively Predicting Malignant Potential and Mitotic Count of Gastrointestinal Stromal Tumors. Transl Oncol 2019;12(9):1229-36 doi 10.1016/j.tranon.2019.06.005.

10.Clinical Activity of Avapritinib in ≥4th Line (4L+) and PDGFRA Exon 18 Gastrointestinal Stromal Tumors (GIST). Michael Heinrich,  Robin L. Jones,  Margaret von Mehren, et al. 2019 ASCO.


齐长松

北京大学肿瘤医院消化内科主治医师，医学博士。

主要从事胃肠肿瘤的综合诊疗、腹膜转移癌的转化治疗、GIST的个体化治疗及NGS指导下消化系统肿瘤的精准治疗。目前任中国临床肿瘤学会（CSCO）胃肠间质瘤专业委员会委员、中国抗癌协会肿瘤营养与支持治疗专业委员会癌性肠梗阻学组委员、中国临床肿瘤学会（CSCO）青年委员会统计小组成员、《肿瘤综合治疗电子杂志》编委等。

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    2020-10-27 zhlpower

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    2020-01-07 liao1619

    #胃肠道#

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    2020-01-07 zhty5338

    #间质瘤#

    0