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靶向药物联合治疗在一些高度侵袭性脑肿瘤中显示出前所未有的活性 精选

已有 5269 次阅读 2021-11-27 10:33 |个人分类:新观察|系统分类:海外观察

靶向药物联合治疗在一些高度侵袭性脑肿瘤中显示出前所未有的活性

诸平

据美国丹娜-法伯癌症研究所(Dana-Farber Cancer Institute20211125日提供的消息,靶向药物联合治疗在一些高度侵袭性脑肿瘤中显示出前所未有的活性(Targeted drug combination shows unprecedented activity in some highly aggressive brain tumors)。丹娜-法伯癌症研究所研究人员的一份临床试验报告显示,两种靶向癌症药物的联合治疗,在携带罕见基因突变的恶性脑肿瘤患者身上显示出前所未有的“有临床意义(clinically meaningful)”的活性。相关研究结果于20211124日已经在《柳叶刀肿瘤学》(The Lancet Oncology)杂志网站发表——Patrick Y Wen, Alexander Stein, Martin van den Bent, Jacques De Greve. Antje Wick, Filip Y F L de Vos, Nikolasvon Bubnoff, Myra Evan Linde, Albert Lai, Gerald W Prager, Mario Campone, Angelica Fasolo, Jose A Lopez-Martin, Tae Min Kim, Warren P Mason, Ralf-Dieter Hofheinz, Jean-Yves Blay, Daniel C ChoAnas Gazzah, Damien Pouessel, Jeffrey Yachnin, Aislyn Boran, Paul Burgess, Palanichamy Ilankumaran, Eduard Gasal, Vivek Subbiah. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. The Lancet Oncology (2021). DOI: 10.1016/S1470-2045(21)00578-7. Available online 24 November 2021. https://doi.org/10.1016/S1470-2045(21)00578-7.

参与此项研究的除了来自丹娜-法伯癌症研究所的研究人员之外,还有来自德国汉堡-埃本多夫大学医学中心 (University Medical Center Hamburg-Eppendorf)、德国海德堡大学,德国国家肿瘤疾病中心(University of Heidelberg, National Center for Tumor Diseases)、德国弗莱堡大学医学中心(University Medical Center Freiburg)、德国石勒苏益格-荷尔斯泰因大学医学中心(Medical Center, University of Schleswig-Holstein)、德国曼海姆大学医院(University Hospital of Mannheim);荷兰鹿特丹大学医学中心(University Medical Center Rotterdam)、荷兰乌德勒支大学医学中心(University Medical Center Utrecht)、荷兰阿姆斯特丹自由大学(Vrije Universiteit Amsterdam);美国 加州大学洛杉矶分校(University of California at Los Angeles)、美国纽约医学院(New York Medical College)、美国东汉诺威的诺华制药公司(Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA)、美国德克萨斯大学安德森癌症中心(The University of Texas MD Anderson Cancer Center);法国圣赫布雷恩西部学院(Institut de Cancérologie de l'Ouest, Saint-Herblain, France)、法国古斯塔夫·鲁西癌症研究所(Gustave Roussy Cancer Institute)、法国图卢兹的癌症治疗中心(Institut Universitaire du Cancer de Toulouse-Oncopole)、法国莱昂·贝拉德中心及克劳德·伯纳德里昂一世大学(Center Leon Berard & University Claude Bernard Lyon I);奥地利维也纳医科大学(Medical University of Vienna)、比利时布鲁塞尔自由大学医院(University Hospital Vrije Universiteit Brussel)、意大利米兰圣拉斐尔医院(Ospedale San Raffaele IRCCS, Milan, Italy)、西班牙马德里国庆日大学医院及研究所(12 de Octubre University Hospital & Research Institute, Madrid, Spain)、韩国首尔国立大学医院(Seoul National University Hospital)、加拿大多伦多大学(University of Toronto)、瑞典卡罗林斯卡大学医院(Karolinska University Hospital)以及瑞士巴塞尔的诺华制药公司(Novartis Pharma AG, Basel, Switzerland)的研究人员。

这种药物组合阻断了过度活跃的细胞生长信号通路,在45名难以治疗的高级别胶质瘤( high-grade gliomas)患者(patients)中,三分之一的患者的肿瘤缩小了50%或更多,其中包括最具侵袭性的脑肿瘤——胶质母细胞瘤。之所以选择这些患者进行试验,是因为他们的肿瘤在BRAF基因中携带了一种名为v600E的基因突变。这种突变只在2%- 3%的高级别胶质瘤患者中发现,但在60%的低级别胶质瘤患者中发现。该研究包括13例低级别胶质瘤患者。在这些患者中,9名患者对联合用药的治疗有客观反应,有效率为69%

达纳-法伯神经肿瘤学中心(Center for Neuro-Oncology at Dana-Farber)的主任、也是上述论文的第一作者Patrick Wen医学博士说:“这是第一次有靶向药物在临床试验中被证明对胶质母细胞瘤有效。”他说,目前所有针对胶质母细胞瘤的化疗的有效率都不超过5%,而联合化疗的有效率只有33%。但40岁以下患者的应答率甚至更高,约40%

在这项研究中,两种药物是达拉法尼(dabrafenib)和曲美替尼(trametinib)。这两种药物都以MAPK通路(MAPK pathway)中的蛋白质为靶点,MAPK通路是一种蛋白信号链,充当细胞生长的开关,可能会卡在“开”的位置,导致不受控制的生长,导致肿瘤。

3名患者有完全的反应,他们的肿瘤在影像学扫描上看不到,12名患者的肿瘤有部分缩小。虽然患者未被治愈,但那些对药物有反应的人在一项评估中经历了显著的持久获益,中位反应持续时间为13.6个月,另一项评估中为36.9个月。

这些发现来自一项名为罕见肿瘤学不可知论研究(Rare Oncology Agnostic Research简称ROAR)的二期研究,该研究从2014年开始在13个国家的27个社区和学术癌症中心招募患者。这项研究是一项所谓的“篮子”试验("basket" trial),旨在招募具有共同肿瘤特征(在本例中为BRAF v600E突变)的患者,尽管他们可能患有一系列不同的癌症。ROAR研究包括甲状腺癌(thyroid cancer)和胆道癌(biliary tract cancer)、胃肠道间质瘤(gastrointestinal stromal tumors)、毛细胞白血病(hairy cell leukemia)、多发性骨髓瘤(multiple myeloma)、低级别和高级别胶质瘤脑瘤(low- and high-grade glioma brain tumors)等患者。该研究旨在确定达拉法尼联合曲美替尼在BRAF v600e突变癌症患者中的总有效率。BRAF蛋白是一种生长信号蛋白激酶,在调节MAPK信号通路中发挥作用。BRAF v600E突变通过激活MAPK通路(由许多蛋白质组成)驱动癌症,导致细胞生长(cell growth)失控和肿瘤(tumor)的发展。

在这项研究中使用的药物,达拉法尼和曲美替尼,是阻断部分过度活跃的MAPK信号通路的口服药物。达拉法尼抑制一种酶,B-Raf,而曲美替尼抑制分子MEK1MEK2,它们是MAPK途径的一部分。它们已被用于联合治疗黑色素瘤、非小细胞肺癌和甲状腺癌。

神经胶质瘤是起源于神经胶质的癌症,是大脑的支持细胞,而不是大脑神经元本身。神经胶质瘤占所有恶性脑肿瘤(malignant brain tumors)的80%。一些是生长缓慢的低级别胶质瘤,而另一些是侵袭性的高级别胶质瘤,包括难以移除且几乎总是复发的胶质母细胞瘤。该报告的作者说,近年来在治疗胶质瘤方面没有重大进展,但有个别报告显示,达拉法尼和曲美替尼联合治疗胶质瘤表现出活性。他们在ROAR研究中的报告“是BRAF抑制剂(dabrafenib)MEK抑制剂(trametinib)的组合首次在这些难以治疗的胶质瘤中显示出显著的活性,包括历史上显示了治疗耐药性的恶性胶质瘤(glioblastomas)。”

虽然这些药物只帮助了携带罕见V600E突变的肿瘤患者,但温说,结果令人鼓舞,“因为人们开始认为,永远不会有任何针对胶质母细胞瘤的靶向治疗。”他补充说,有新的证据表明,在神经胶质瘤中可能有其他的靶点可以被设计药物阻断。

上述介绍,仅供参考。欲了解更多信息,敬请注意浏览原文或者相关报道

Practice-changing trial results for advanced melanoma skin cancer

Summary

Background

Effective treatments are needed to improve outcomes for high-grade glioma and low-grade glioma. The activity and safety of dabrafenib plus trametinib were evaluated in adult patients with recurrent or progressive BRAFV600E mutation-positive high-grade glioma and low-grade glioma.

Methods

This study is part of an ongoing open-label, single-arm, phase 2 Rare Oncology Agnostic Research (ROAR) basket trial at 27 community and academic cancer centres in 13 countries (Austria, Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, South Korea, Spain, Sweden, and the USA). The study enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Patients with BRAFV600E mutation-positive high-grade glioma and low-grade glioma received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until unacceptable toxicity,disease progression, or death. In the high-grade glioma cohort, patients were required to have measurable disease at baseline using the Response Assessment in Neuro-Oncology high-grade glioma response criteria and have been treated previously with radiotherapy and first-line chemotherapy or concurrentchemoradiotherapy. Patients with low-grade glioma were required to have measurable non-enhancing disease (except pilocytic astrocytoma) at baseline using the Response Assessment in Neuro-Oncology low-grade glioma criteria. The primary endpoint, in the evaluable intention-to-treat population, was investigator-assessed objective response rate (complete response plus partial response for high-grade glioma and complete response plus partial response plus minor response for low-grade glioma). This trial is ongoing, but is closed for enrolment, NCT02034110.

Findings

Between April 17, 2014, and July 25, 2018, 45 patients (31 with glioblastoma) were enrolled into the high-grade glioma cohort and 13 patients were enrolled into the low-grade glioma cohort. The results presented here are based on interim analysis 16 (data cutoff Sept 14, 2020). In the high-grade glioma cohort, median follow-up was 12·7 months (IQR 5·4–32·3) and 15 (33%; 95% CI 20–49) of 45 patients had an objective response by investigator assessment, including three complete responses and 12 partial responses. In the low-grade glioma cohort, median follow-up was 32·2 months (IQR 25·1–47·8). Nine (69%; 95% CI 39–91) of 13 patients had an objective response by investigator assessment, including one complete response, six partial responses, and two minor responses. Grade 3 or worse adverse events were reported in 31 (53%) patients, the most common being fatigue (five [9%]), decreased neutrophil count (five [9%]), headache (three [5%]), and neutropenia (three [5%]).

Interpretation

Dabrafenib plus trametinib showed clinically meaningful activity in patients withBRAFV600E mutation-positive recurrent or refractory high-grade glioma and low-grade glioma, with a safety profile consistent with that in other indications.BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma.




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