加拿大多伦多大学Eric Bouffet团队研究了达拉菲尼联合曲美替尼治疗BRAF V600突变的复发性儿童低级别神经胶质瘤的疗效与安全性。这一研究成果发表在2023年9月20日出版的《新英格兰医学杂志》上。

在儿童低级别胶质瘤中检测到BRAF V600E突变与对标准化疗的较低缓解有关。在此前试验中，达拉菲尼（单药治疗和与曲美替尼联合治疗）对BRAF V600突变的复发性儿童低级别神经胶质瘤显示出疗效，这些发现值得进一步评估该联合治疗作为一线治疗。

在这项2期临床试验中，研究组将计划接受一线治疗的患有BRAF V600突变的儿童低级别神经胶质瘤患者以2:1的比例随机分配接受达拉菲尼加曲美替尼或标准化疗（卡铂加长春新碱）。主要结局为根据神经肿瘤缓解评估标准独立评估的总体缓解（完全或部分缓解）。还评估了临床获益（完全或部分缓解或疾病稳定≥24周）和无进展生存率。

共有110名患者接受了随机分组（73名接受达拉菲尼加曲美替尼治疗，37名接受标准化疗）。在18.9个月的中位随访中，47%的达拉菲尼加曲美替尼治疗的患者和11%的化疗患者出现了总体缓解（风险比为4.31；P<0.001）。86%接受了达拉菲尼加曲美替尼治疗的患者观察到了临床益处，接受化疗的患者中有46%（风险比为1.88）。达拉菲尼加曲美替尼的中位无进展生存期明显长于化疗（20.1个月vs.7.4个月；危险比为0.31；P<0.001）。47%接受达拉菲尼加曲美替尼治疗的患者和94%接受化疗的患者发生了3级或更高级别的不良事件。

研究结果表明，在患有BRAF V600突变的低级别神经胶质瘤的儿童患者中，与作为一线治疗的标准化疗相比，达拉菲尼加曲美替尼可显著提高疗效、延长无进展生存期和更好的安全性。

附：英文原文

Title: Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations

Author: Eric Bouffet, Jordan R. Hansford, Maria Luisa Garrè, Junichi Hara, Ashley Plant-Fox, Isabelle Aerts, Franco Locatelli, Jasper van der Lugt, Ludmila Papusha, Felix Sahm, Uri Tabori, Kenneth J. Cohen, Roger J. Packer, Olaf Witt, Larissa Sandalic, Ana Bento Pereira da Silva, Mark Russo, Darren R. Hargrave

Issue&Volume: 2023-09-20

Abstract:

Background

Detection of the BRAF V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with BRAF V600 mutations, findings that warrant further evaluation of this combination as first-line therapy.

Methods

In this phase 2 trial, patients with pediatric low-grade glioma with BRAF V600 mutations who were scheduled to receive first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus trametinib or standard chemotherapy (carboplatin plus vincristine). The primary outcome was the independently assessed overall response (complete or partial response) according to the Response Assessment in Neuro-Oncology criteria. Also assessed were the clinical benefit (complete or partial response or stable disease for ≥24 weeks) and progression-free survival.

Results

A total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive standard chemotherapy). At a median follow-up of 18.9 months, an overall response occurred in 47% of the patients treated with dabrafenib plus trametinib and in 11% of those treated with chemotherapy (risk ratio, 4.31; 95% confidence interval [CI], 1.7 to 11.2; P<0.001). Clinical benefit was observed in 86% of the patients receiving dabrafenib plus trametinib and in 46% receiving chemotherapy (risk ratio, 1.88; 95% CI, 1.3 to 2.7). The median progression-free survival was significantly longer with dabrafenib plus trametinib than with chemotherapy (20.1 months vs. 7.4 months; hazard ratio, 0.31; 95% CI, 0.17 to 0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of the patients receiving dabrafenib plus trametinib and in 94% of those receiving chemotherapy.

Conclusions

Among pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy as first-line therapy.

DOI: 10.1056/NEJMoa2303815

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2303815