Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
BMC Cancer. 2024 Jan 30;24(1):147. doi: 10.1186/s12885-024-11820-x.
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.
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/m (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.
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.
ClinicalTrials.gov: NCT05566795. Registered on October 4, 2022.
小儿低级别胶质瘤（pLGG）本质上是一种单一通路疾病，大多数肿瘤由影响丝裂原活化蛋白激酶/细胞外信号调节激酶（MAPK）通路的基因组改变驱动，主要为 KIAA1549::BRAF 融合和 BRAF V600E 突变。这使得 pLGG 成为 MAPK 通路靶向治疗的理想候选者。I 型 BRAF 抑制剂 dabrafenib 与 MEK 抑制剂 trametinib 联合，已被美国食品和药物管理局批准用于治疗携带 BRAF V600E 突变的 pLGG 的全身治疗。然而，这种组合不被批准用于治疗携带 BRAF 融合的肿瘤患者，因为 I 型 RAF 抑制剂在这种情况下无效，并且可能会产生矛盾地增强肿瘤生长。II 型 RAF 抑制剂 tovorafenib（前身为 DAY101、TAK-580、MLN2480）在 2 期 FIREFLY-1 研究中显示出对 BRAF 改变的 pLGG 患者有良好的疗效和耐受性，根据神经肿瘤反应评估标准（RANO-HGG）的客观缓解率（ORR）为 67%。肿瘤反应与组织学亚型、BRAF 改变类型（融合与突变）、既往治疗线数和既往 MAPK 通路抑制剂的使用无关。
LOGGIC/FIREFLY-2 是一项在全球范围内进行的、随机、开放标签、多中心的 3 期试验，旨在评估 tovorafenib 单药治疗与当前标准治疗（SoC）化疗在需要一线全身治疗的、<25 岁、携带激活 RAF 改变的 pLGG 患者中的疗效、安全性和耐受性。患者按 1:1 随机分配至 tovorafenib 组或研究者选择的规定 SoC 化疗方案组。主要研究终点是根据 RANO-LGG 标准，由独立评审评估的两个治疗组之间的 ORR 比较。次要研究终点包括无进展生存期、缓解持续时间、安全性、神经功能和临床获益率的比较。
令人鼓舞的 tovorafenib 活性数据、CNS 穿透特性、强有力的科学依据，加上在 pLGG 患者中观察到的可管理的耐受性和安全性特征，促使 SIOPe-BTG-LGG 工作组提名 tovorafenib 用于该一线 3 期试验中与 SoC 化疗进行比较。该试验产生的疗效、安全性和功能反应数据可能为新诊断的 pLGG 确定新的标准治疗方法。
ClinicalTrials.gov：NCT05566795。于 2022 年 10 月 4 日注册。
