UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
National Center for Child Health and Development, Tokyo, Japan.
J Clin Oncol. 2023 Nov 20;41(33):5174-5183. doi: 10.1200/JCO.23.00558. Epub 2023 Aug 29.
V600 mutation is detected in 5%-10% of pediatric high-grade gliomas (pHGGs), and effective treatments are limited. In previous trials, dabrafenib as monotherapy or in combination with trametinib demonstrated activity in children and adults with relapsed/refractory V600-mutant HGG.
This phase II study evaluated dabrafenib plus trametinib in patients with relapsed/refractory V600-mutant pHGG. The primary objective was overall response rate (ORR) by independent review by Response Assessment in Neuro-Oncology criteria. Secondary objectives included ORR by investigator determination, duration of response (DOR), progression-free survival, overall survival (OS), and safety.
A total of 41 pediatric patients with previously treated V600-mutant HGG were enrolled. At primary analysis, median follow-up was 25.1 months, and 51% of patients remained on treatment. Sixteen of 20 discontinuations were due to progressive disease in this relapsed/refractory pHGG population. Independently assessed ORR was 56% (95% CI, 40 to 72). Median DOR was 22.2 months (95% CI, 7.6 months to not reached [NR]). Fourteen deaths were reported. Median OS was 32.8 months (95% CI, 19.2 months to NR). The most common all-cause adverse events (AEs) were pyrexia (51%), headache (34%), and dry skin (32%). Two patients (5%) had AEs (both rash) leading to discontinuation.
In relapsed/refractory V600-mutant pHGG, dabrafenib plus trametinib improved ORR versus previous trials of chemotherapy in molecularly unselected patients with pHGG and was associated with durable responses and encouraging survival. These findings suggest that dabrafenib plus trametinib is a promising targeted therapy option for children and adolescents with relapsed/refractory V600-mutant HGG.
V600 突变在 5%-10%的儿童高级别胶质瘤（pHGG）中被检测到，有效的治疗方法有限。在以前的试验中，达拉非尼单药或与曲美替尼联合治疗在复发/难治性 V600 突变的高级别胶质瘤患儿和成人中显示出活性。
这项 II 期研究评估了达拉非尼联合曲美替尼在复发/难治性 V600 突变 pHGG 患者中的应用。主要终点是通过独立的神经肿瘤反应评估标准（Response Assessment in Neuro-Oncology criteria）评估的总体缓解率（ORR）。次要终点包括研究者确定的 ORR、缓解持续时间（DOR）、无进展生存期、总生存期（OS）和安全性。
共纳入 41 例先前接受过治疗的 V600 突变 HGG 患儿。在首次分析时，中位随访时间为 25.1 个月，51%的患者仍在接受治疗。在这一复发/难治性 pHGG 人群中，20 例停药中有 16 例是由于疾病进展。独立评估的 ORR 为 56%（95%CI，40 至 72）。中位 DOR 为 22.2 个月（95%CI，7.6 个月至未达到[NR]）。报告了 14 例死亡。中位 OS 为 32.8 个月（95%CI，19.2 个月至 NR）。最常见的全因不良事件（AEs）为发热（51%）、头痛（34%）和皮肤干燥（32%）。有 2 例患者（5%）发生了导致停药的 AE（均为皮疹）。
在复发/难治性 V600 突变 pHGG 中，达拉非尼联合曲美替尼治疗与以前在未选择分子的 pHGG 患儿中进行的化疗试验相比，提高了 ORR，且与持久缓解和令人鼓舞的生存相关。这些发现表明，达拉非尼联合曲美替尼是一种有前途的针对复发/难治性 V600 突变 HGG 患儿的靶向治疗选择。
