Nature Medicine | Tovorafenib为治疗儿童低级别胶质瘤带来新希望
学术经纬约 6 分钟2023年11月，美国国家儿童医学中心的 Lindsay Kilburn 医生领衔的团队发表于 Nature Medicine 上题为 The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial 的文章，报道了Tovorafenib对复发/难治性儿童低级别胶质瘤的 II期临床实验结果，实验结果表明Tovorafenib可能是治疗携带BRAF突变的复发/难治性儿童低级别胶质瘤的有效疗法。
这个名为FIREFLY-1的临床试验，是一个多国合作、多中心、单臂、II期临床试验，评估Tovorafenib在治疗BRAF基因改变的复发/难治性儿童低级别胶质瘤（pLGG）中的疗效和安全性。在没有对照组的临床试验中，所有参与者都接受试验性疗法，而不是将其与标准治疗或安慰剂进行比较。这种设计常见于早期药物开发阶段，尤其是当研究新药物或治疗方法对于特定疾病的效果时。这类试验通常被称为“单臂试验”（single-arm trials），因为只有一个“臂”或治疗组。在这种设计中，研究者通常会将所观察到的效果与历史数据或已知的疾病自然进程进行比较，而不是直接与另一种治疗方法相比较。
根据神经肿瘤学高级别胶质瘤反应评估(RANO-HGG)标准，可评估患者的总缓解率(ORR)为67%，其中完全缓解率为17%，部分缓解率为49%， 临床获益率为93%。这个数据表明，大多数接受tovorafenib治疗的患者都有明显的肿瘤缩小或稳定。缓解持续时间(DOR)中位数为16.6个月。这意味着一半以上的患者在治疗后至少持续了16.6个月的肿瘤缩小或稳定。反应时间(TTR)中位数为3.0个月，表明患者在开始治疗后平均约3个月内就能观察到肿瘤反应。
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*本文由深圳市拾玉儿童公益基金会“儿童肿瘤前沿”团队编译或约稿，文中图表均源引自文献原文。本文著作权归文章作者所有，欢迎个人转发分享，未经允许禁止转载，作者拥有所有法定权利，违者必究。如需转载，请留言或联系[email protected]。本文旨在分享儿童肿瘤科研前沿成果，不是治疗方案推荐。如需获得疾病治疗方案指导，请前往正规医院就诊。
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原文摘要（Abstract）
BRAF genomic alterations are the most common oncogenic drivers in pediatric low-grade glioma (pLGG). Arm 1 (n = 77) of the ongoing phase 2 FIREFLY-1 (PNOC026) trial investigated the efficacy of the oral, selective, central nervous system-penetrant, type II RAF inhibitor tovorafenib (420 mg m-2 once weekly; 600 mg maximum) in patients with BRAF-altered, relapsed/refractory pLGG. Arm 2 (n = 60) is an extension cohort, which provided treatment access for patients with RAF-altered pLGG after arm 1 closure. Based on independent review, according to Response Assessment in Neuro-Oncology High-Grade Glioma (RANO-HGG) criteria, the overall response rate (ORR) of 67% met the arm 1 prespecified primary endpoint; median duration of response (DOR) was 16.6 months; and median time to response (TTR) was 3.0 months (secondary endpoints). Other select arm 1 secondary endpoints included ORR, DOR and TTR as assessed by Response Assessment in Pediatric Neuro-Oncology Low-Grade Glioma (RAPNO) criteria and safety (assessed in all treated patients and the primary endpoint for arm 2, n = 137). The ORR according to RAPNO criteria (including minor responses) was 51%; median DOR was 13.8 months; and median TTR was 5.3 months. The most common treatment-related adverse events (TRAEs) were hair color changes (76%), elevated creatine phosphokinase (56%) and anemia (49%). Grade ≥3 TRAEs occurred in 42% of patients. Nine (7%) patients had TRAEs leading to discontinuation of tovorafenib. These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG.
DOI: 10.1038/s41591-023-02668-y