Purpose: While fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600 mutated HGG. Patients and methods: In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have high-grade glioma or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy including radiation. Results: Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2-40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed all tumors cluster most closely with anaplastic PXA. Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples prior to treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. Conclusions: Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

中文翻译：

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BRAF-V600E 突变型高级别胶质瘤中恩科拉非尼和 binimetinib 的缓解率和分子相关性

目的：虽然只有不到 5% 的高级别胶质瘤 (HGG) 存在 BRAF-V600E 突变，但这些肿瘤值得注意，因为 BRAF 靶向治疗对某些人群显示出疗效。本研究的目的是评估复发性 BRAF-V600 突变 HGG 成人患者对 encorafenib 与 binimetinib 联合治疗的反应。患者和方法：在这项 2 期开放标签成人脑肿瘤联盟 (ABTC) 试验 (NCT03973918) 中，恩科拉非尼和 binimetinib 按 FDA 批准的剂量在 28 天的周期中连续给药。符合条件的患者必须患有高级别胶质瘤或胶质母细胞瘤，并伴有 BRAF-V600E 改变，并且在至少一种治疗（包括放疗）后复发。结果：2020 年 1 月至 2021 年 11 月行政终止（由于 ABTC 关闭）期间入组了 5 名患者。入组患者接受2-40个月的治疗；目前，一名患者仍在接受治疗。集中测定的放射学缓解率为 60%，其中 1 例完全缓解，2 例部分缓解。甲基化分析显示所有肿瘤与间变性 PXA 最为接近。所有肿瘤的 MAPK 反应特征转录谱在基线时均相似，并且与这一小群体中的反应无关。在治疗前、反应期间和进展时在血浆样本中测量的循环肿瘤 DNA 显示了检测 BRAF-V600E 改变的可行性。没有检测到新的安全信号。结论：在本次小型系列研究中，恩科拉非尼和比尼美替尼在复发 BRAF-V600E 突变 HGG 患者中表现出阳性肿瘤反应，值得考虑治疗。尽管毒性仍然是 BRAF 靶向治疗的一个问题，但在这些患者中没有观察到新的安全信号。