Cobimetinib Plus Gemcitabine: An Active Combination in KRAS G12R-Mutated Pancreatic Ductal Adenocarcinoma Patients in Previously Treated and Failed Multiple Chemotherapies.

Journal of Pancreatic Cancer Pub Date : 2021-10-13 eCollection Date: 2021-01-01 DOI:10.1089/pancan.2021.0006
Bach Ardalan, Jose Azqueta, Danny Sleeman
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引用次数: 5

Abstract

Purpose: The KRAS proto-oncogene is involved in the RAS/MAPK pathway. KRAS is present in the wild type or mutated forms. The oncogene KRAS is frequently mutated in various cancers. At the time that amino acid glycine is mutated, KRAS protein acquires oncogenic properties that result in the tumor cell growth, proliferation, and cancer progression. There has been limited understanding of the different mutations at codon 12. The consequences of such mutations is not fully understood. Various G12X mutations in pancreatic cancer patients have been examined, with the most common mutations being G12D (40%), G12V (30%), and G12R (15-20%). Now we are understanding that G12X mutations in the KRAS are not all equal. Methods: In a single-arm exploratory study, we accrued 13 KRAS-G12X-mutated pancreatic patients (KRAS G12D, G12V, and G12R). They were divided into two groups: group 1 consisted of seven patients with G12D and G12V and group 2 included six patients with the KRAS G12R mutation. All patients were treated with the combination of gemcitabine at 1250 mg/m2 intravenous weekly for 3 weeks and oral cobimetinib 20 mg b.i.d. for 3 weeks. This was followed by a week of rest before the initiation of the next cycle. Results: In the first cohort, seven patients were on treatment, all of whom progressed and died within the 2 months of the study. In the second cohort, one of six patients achieved partial response, and five achieved stable disease. Median progression-free survival was 6 months (9% confidence interval 3.0-9.3 months) and overall survival has been reached at 8 months. Common adverse reactions included rash, fatigue, nausea, and vomiting (grades 2 and 3). Cancer antigen CA19-9 decreased by >50% in all group 2 patients. Conclusion: Our pancreatic cancer patients were heavily pretreated (all had received FOLFIRINOX and gemcitabine/nab-paclitaxel) before the entry into our trial. Upon entry into our trial, all patients were treated with the combination of gemcitabine and oral cobimetinib. Therefore, this constituted the second exposure of the patients to gemcitabine. This study illustrates a new discovery, which can potentially target 15-20% of pancreatic cancer patients and allow for a significant improvement in their prognosis. We will be conducting randomized phase II trials to substantiate our findings.

Abstract Image

Cobimetinib +吉西他滨:KRAS g12r突变的胰腺导管腺癌患者先前治疗和多次化疗失败的有效组合
目的:KRAS原癌基因参与RAS/MAPK通路。KRAS存在于野生型或突变形式中。致癌基因KRAS在各种癌症中经常发生突变。当氨基酸甘氨酸发生突变时,KRAS蛋白获得致癌特性,导致肿瘤细胞生长、增殖和癌症进展。人们对密码子12的不同突变了解有限。这种突变的后果尚不完全清楚。研究了胰腺癌患者的各种G12X突变,其中最常见的突变是G12D (40%), G12V(30%)和G12R(15-20%)。现在我们了解到KRAS中的G12X突变并不都是一样的。方法:在一项单臂探索性研究中,我们收集了13例KRAS- g12x突变的胰腺患者(KRAS G12D, G12V和G12R)。他们被分为两组:1组包括7名G12D和G12V患者,2组包括6名KRAS G12R突变患者。所有患者联合吉西他滨1250mg /m2静脉注射,每周3周,口服cobimetinib 20mg b.d,连续3周。接下来是一个星期的休息,然后才开始下一个周期。结果:在第一队列中,7例患者接受治疗,所有患者在研究的2个月内进展并死亡。在第二个队列中,6名患者中有1名达到部分缓解,5名达到病情稳定。中位无进展生存期为6个月(9%置信区间为3.0-9.3个月),总生存期为8个月。常见的不良反应包括皮疹、疲劳、恶心和呕吐(2级和3级)。所有2组患者的癌抗原CA19-9下降>50%。结论:我们的胰腺癌患者在进入我们的试验之前进行了大量的预处理(所有患者都接受了FOLFIRINOX和吉西他滨/nab-紫杉醇)。在进入我们的试验时,所有患者都接受吉西他滨和口服哥比美替尼的联合治疗。因此,这构成了患者对吉西他滨的第二次暴露。这项研究说明了一个新的发现,它可以潜在地针对15-20%的胰腺癌患者,并允许他们的预后显著改善。我们将进行随机II期试验来证实我们的发现。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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