Response rate and molecular correlates to encorafenib and binimetinib in BRAF-V600E mutant high-grade glioma.
Response rate and molecular correlates to encorafenib and binimetinib in BRAF-V600E mutant high-grade glioma.
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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。
DOI：
10.1158/1078-0432.ccr-23-3241
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发表时间：
2024
期刊：
影响因子：
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通讯作者：
Rudek,MichelleA
中科院分区：
文献类型：
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作者：
Schreck,KarisaC;Strowd,RoyE;Nabors,LouisB;Ellingson,BenjaminM;Chang,Michael;Tan,SzeK;Abdullaev,Zied;Turakulov,Rust;Aldape,Kenneth;Danda,Neeraja;Desideri,Serena;Fisher,Joy;Iacoboni,Michaella;Surakus,Trisha;Rudek,MichelleA
虽然只有不到5%的高级别胶质瘤（HGG）是BRAF-V600 E突变的，但这些肿瘤值得注意，因为BRAF靶向治疗对某些人群有效。本研究的目的是评估对恩可非尼与比尼替尼联合治疗复发性BRAF-V600突变HGG.Patients和MethodsIn此2期，开放标签，成人脑肿瘤协会（ABTC）试验（NCT 03973918），恩可非尼和比尼替尼以FDA批准的剂量在28天周期内连续给药。符合条件的患者需要有HGG或胶质母细胞瘤与BRAF-V600 E的改变，是复发后至少一个线的治疗，包括radiotherapy.ResultsFive患者之间登记2020年1月和行政终止2021年11月（由于关闭的ABTC）。入组的患者接受了2至40个月的治疗;目前有1名患者仍在接受治疗。中心确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，所有的肿瘤集群最密切的间变性多形性黄色星形细胞瘤（PXA）。在基线时，所有肿瘤的MAPK应答特征的转录谱相似，并且与该小群体中的应答不相关。治疗前、缓解期间和进展时在血浆样本中测量的循环肿瘤DNA显示检测BRAF-V600 E改变的可行性。在这个小系列中，Encorafenib和binimetinib在复发性BRAF-V600 E突变HGG患者中表现出积极的肿瘤反应，从而避免了治疗考虑。尽管毒性仍然是BRAF靶向治疗的一个问题，但在这些患者中未观察到新的安全性信号。
PurposeAlthough 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 MethodsIn 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 HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy.ResultsFive patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 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 that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (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 before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected.ConclusionsEncorafenib 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.