背景:小儿低度胶质瘤(pLGG)本质上是一种单通路疾病,大多数肿瘤由影响丝裂原活化蛋白激酶/ERK(MAPK)途径的基因组改变驱动,主要是KIAA1549::BRAF融合和BRAFV600E突变。这使得pLGG成为MAPK途径靶向治疗的理想候选者。I型BRAF抑制剂,Dabrafenib,与MEK抑制剂联合使用,曲美替尼,已被美国食品和药物管理局批准用于BRAFV600E突变的pLGG的全身治疗。然而,该组合未被批准用于治疗有BRAF融合的肿瘤患者,因为I型RAF抑制剂在这种情况下无效,并且可能矛盾地促进肿瘤生长.II型RAF抑制剂,托沃拉非尼(前身为DAY101,TAK-580,MLN2480),在2期FIREFLY-1研究中,在BRAF改变的pLGG患者中显示出有希望的活性和良好的耐受性,神经肿瘤学高级别胶质瘤(RANO-HGG)标准的客观缓解率(ORR)为67%。肿瘤反应独立于组织学亚型,BRAF改变类型(融合与突变),先前治疗路线的数量,和之前使用MAPK通路抑制剂。
方法:LOGIC/FIREFLY-2是双臂,随机化,开放标签,多中心,全球,评估疗效的3期试验,安全,托沃拉非尼单药治疗的耐受性和耐受性<25岁的pLGG患者的现行标准治疗(SoC)化疗具有激活的RAF改变,需要一线全身治疗。患者以1:1的比例随机分配给托沃拉非尼,每周一次,剂量为420mg/m2(不超过600mg),或研究者选择预先指定的SoC化疗方案。主要目的是比较两个治疗组之间的ORR,根据RANO-LGG标准通过独立审查进行评估。次要目标包括无进展生存期的比较,响应的持续时间,安全,神经功能,和临床受益率。
结论:有希望的托沃拉非尼活性数据,中枢神经系统渗透特性,强有力的科学理由加上pLGG患者的可管理的耐受性和安全性导致SIOPe-BTG-LGG工作组在这项一线3期试验中提名托沃拉非尼与SoC化疗进行比较.功效,安全,和从试验生成的功能响应数据可以定义用于新诊断的pLGG的新SoC治疗。
背景:ClinicalTrials.gov:NCT05566795。2022年10月4日注册。
BACKGROUND: Pediatric low-grade glioma (pLGG) is essentially a single pathway disease, with most tumors driven by genomic alterations affecting the mitogen-activated protein kinase/ERK (MAPK) pathway, predominantly KIAA1549::BRAF fusions and BRAF V600E mutations. This makes pLGG an ideal candidate for MAPK pathway-targeted treatments. The type I BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, has been approved by the United States Food and Drug Administration for the systemic treatment of BRAF V600E-mutated pLGG. However, this combination is not approved for the treatment of patients with tumors harboring BRAF fusions as type I RAF inhibitors are ineffective in this setting and may paradoxically enhance tumor growth. The type II RAF inhibitor, tovorafenib (formerly DAY101, TAK-580, MLN2480), has shown promising activity and good tolerability in patients with BRAF-altered pLGG in the phase 2 FIREFLY-1
study, with an objective response rate (ORR) per Response Assessment in Neuro-Oncology high-grade glioma (RANO-HGG) criteria of 67%. Tumor response was independent of histologic subtype, BRAF alteration type (fusion vs. mutation), number of prior lines of therapy, and prior MAPK-pathway inhibitor use.
METHODS: LOGGIC/FIREFLY-2 is a two-arm, randomized, open-label, multicenter, global, phase 3
trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs. current standard of care (SoC) chemotherapy in patients < 25 years of age with pLGG harboring an activating RAF alteration who require first-line systemic therapy. Patients are randomized 1:1 to either tovorafenib, administered once weekly at 420 mg/m2 (not to exceed 600 mg), or investigator\'s choice of prespecified SoC chemotherapy regimens. The primary objective is to compare ORR between the two treatment arms, as assessed by independent review per RANO-LGG criteria. Secondary objectives include comparisons of progression-free survival, duration of response, safety, neurologic function, and clinical benefit rate.
CONCLUSIONS: The promising tovorafenib activity data, CNS-penetration properties, strong scientific rationale combined with the manageable tolerability and safety profile seen in patients with pLGG led to the SIOPe-BTG-LGG working group to nominate tovorafenib for comparison with SoC chemotherapy in this first-line phase 3
trial. The efficacy, safety, and functional response data generated from the
trial may define a new SoC treatment for newly diagnosed pLGG.
BACKGROUND: ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.