Jacob J. Adashek , Shumei Kato , Jason K. Sicklick , Scott M. Lippman , Razelle Kurzrock
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Hence, we now have multiple genomic biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted therapies (larotrectinib/entrectinib, for <em>NTRK</em> fusions; selpercatinib, <em>RET</em> fusions; dabrafenib plus trametinib, <em>BRAF<sup>V600E</sup></em> mutations; pembrolizumab/dostarlimab, microsatellite instability; and pembrolizumab for high tumor mutational burden; pemigatinib is also approved for <em>FGFR1</em>-rearranged myeloid/lymphoid neoplasms). There are emerging targets as well, including but not limited to <em>ALK</em>, <em>BRCA</em> and/or homologous repair deficiency, <em>ERBB2 (HER2), IDH1/2, KIT, KRAS<sup>G12C</sup>, NRG1,</em> and <em>VHL.</em> Many tissue-agnostic approvals center on rare/ultra-rare biomarkers (often < 1 % of cancers), necessitating screening hundreds of tumors to find a single one harboring the cognate molecular alteration. 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引用次数: 0
摘要
癌症的诊断和治疗传统上以原发器官为基础(如肺癌或结肠癌)。然而,原发器官诊断并不能揭示潜在的致癌因素。幸运的是,分子诊断技术以惊人的速度发展,人们越来越清楚地认识到癌症是一种基因组疾病。因此,我们现在有多种基于基因组生物标志物、组织诊断的基因和免疫靶向疗法获得了美国食品药品管理局的批准(拉罗替尼/埃克替尼,治疗 NTRK 融合;赛铂替尼,治疗 RET 融合;dabrafenib plus trametinib,治疗 BRAFV600E 突变;pembrolizumab/dostarlimab,治疗微卫星不稳定;pembrolizumab,治疗高肿瘤突变负荷;pemigatinib 也被批准用于治疗 FGFR1 重组的骨髓/淋巴肿瘤)。还有一些新出现的靶点,包括但不限于 ALK、BRCA 和/或同源修复缺陷、ERBB2(HER2)、IDH1/2、KIT、KRASG12C、NRG1 和 VHL。许多组织诊断药物的批准都以罕见/超罕见生物标记物(通常占癌症的 1%)为中心,需要筛查数以百计的肿瘤,才能找到一个携带相应分子改变的肿瘤。批准通常基于小型单臂研究(30-100 例患者),这些研究的反应率较高(30% 到 75%),且具有显著的持久性。由于生物标志物的稀缺性,单基因检测并不实用;必须对数百个基因进行新一代测序,才能及时获得答案。对生物标志物驱动疗法的抗药性通常是由于继发性突变或共同驱动基因缺陷造成的;目前的研究正在解决根据每个肿瘤的复杂分子改变组合定制药物组合的需求。未来的研究应扩大组织诊断疗法的范围,将血液和实体恶性肿瘤都包括在内,并纳入DNA生物标志物以外的生物标志物。
If it’s a target, it’s a pan-cancer target: Tissue is not the issue
Cancer is traditionally diagnosed and treated on the basis of its organ of origin (e.g., lung or colon cancer). However, organ-of-origin diagnostics does not reveal the underlying oncogenic drivers. Fortunately, molecular diagnostics have advanced at a breathtaking pace, and it is increasingly apparent that cancer is a disease of the genome. Hence, we now have multiple genomic biomarker-based, tissue-agnostic Food and Drug Administration approvals for both gene- and immune-targeted therapies (larotrectinib/entrectinib, for NTRK fusions; selpercatinib, RET fusions; dabrafenib plus trametinib, BRAFV600E mutations; pembrolizumab/dostarlimab, microsatellite instability; and pembrolizumab for high tumor mutational burden; pemigatinib is also approved for FGFR1-rearranged myeloid/lymphoid neoplasms). There are emerging targets as well, including but not limited to ALK, BRCA and/or homologous repair deficiency, ERBB2 (HER2), IDH1/2, KIT, KRASG12C, NRG1, and VHL. Many tissue-agnostic approvals center on rare/ultra-rare biomarkers (often < 1 % of cancers), necessitating screening hundreds of tumors to find a single one harboring the cognate molecular alteration. Approval has generally been based on small single-arm studies (<30–100 patients) with high response rates (>30 % to > 75 %) of remarkable durability. Because of biomarker rarity, single-gene testing is not practical; next generation sequencing of hundreds of genes must be performed to obtain timely answers. Resistance to biomarker-driven therapeutics is often due to secondary mutations or co-driver gene defects; studies are now addressing the need for customized drug combinations matched to the complex molecular alteration portfolio in each tumor. Future investigation should expand tissue-agnostic therapeutics to encompass both hematologic and solid malignancies and include biomarkers beyond those that are DNA-based.
期刊介绍:
Cancer Treatment Reviews
Journal Overview:
International journal focused on developments in cancer treatment research
Publishes state-of-the-art, authoritative reviews to keep clinicians and researchers informed
Regular Sections in Each Issue:
Comments on Controversy
Tumor Reviews
Anti-tumor Treatments
New Drugs
Complications of Treatment
General and Supportive Care
Laboratory/Clinic Interface
Submission and Editorial System:
Online submission and editorial system for Cancer Treatment Reviews