Regorafenib Combined with BRAF/MEK Inhibitors for the Treatment of Refractory Melanoma Brain Metastases.

IF 4.5 2区医学 Q1 ONCOLOGY

Cancers Pub Date : 2024-12-05 DOI:10.3390/cancers16234083

Iris Dirven, Eden Pierre, An-Sofie Vander Mijnsbrugge, Manon Vounckx, Jolien I Kessels, Bart Neyns

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引用次数: 0

Abstract

Background: There are no active treatment options for patients with progressive melanoma brain metastases (MBM) failing immune checkpoint blockade (ICB) and BRAF/MEK inhibitors (BRAF/MEKi). Regorafenib (REGO), an oral multi-kinase inhibitor (incl. RAF-dimer inhibition), can overcome adaptive resistance to BRAF/MEKi in preclinical models.

Methods: This is a single-center retrospective case series of patients with refractory MBM treated with REGO plus BRAF/MEKi (compassionate use).

Results: A total of 22 patients were identified (18 BRAF-mutant, 4 NRAS^Q61-mutant; 19 with progressive MBM; 11 on corticosteroids). Thirteen BRAF^V600-mutant patients were progressing on BRAF/MEKi at the time of REGO association. BRAF-mutant patients received REGO (40-80 mg once daily) combined with BRAF/MEKi, NRAS-mutant patients were treated with REGO + MEKi (+low-dose BRAFi to mitigate skin-toxicity). Grade 3 TRAE included arterial hypertension (n = 4) and maculopapular rash (n = 3). There were no G4/5 TRAE. In BRAF-mutant patients, overall and intracranial objective response rates (overall ORR and IC-ORR) were 11 and 29%, and overall and intracranial disease control rates (overall DCR and IC-DCR) were 44 and 59%, respectively. In NRAS-mutant patients overall ORR and IC-ORR were 0 and 25% and overall DCR and IC-DCR were 25 and 50%, respectively. The median PFS and OS were, respectively, 7.1 and 16.4 weeks in BRAF-mutant and 8.6 and 10.1 weeks in NRAS-mutant patients.

Conclusions: In heavily pretreated patients with refractory MBM, REGO combined with BRAF/MEKi demonstrated promising anti-tumor activity with an acceptable safety profile. In BRAF^V600-mutant melanoma patients, responses cannot solely be attributed to BRAF/MEKi rechallenge. Further investigation in a prospective trial is ongoing to increase understanding of the efficacy.

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瑞非尼联合BRAF/MEK抑制剂治疗难治性黑色素瘤脑转移瘤

背景：对于免疫检查点阻断（ICB）和BRAF/MEK抑制剂（BRAF/MEKi）失败的进展性黑色素瘤脑转移（MBM）患者没有积极的治疗选择。Regorafenib （REGO）是一种口服多激酶抑制剂（包括raf二聚体抑制剂），在临床前模型中可以克服BRAF/MEKi的适应性耐药。方法：这是一项单中心回顾性病例系列研究，采用REGO + BRAF/MEKi（同情使用）治疗难治性MBM患者。结果：共鉴定出22例患者(braf突变体18例，nrasq61突变体4例；进行性MBM 19例；11人服用皮质类固醇)。在REGO关联时，13名brafv600突变患者的BRAF/MEKi治疗进展。BRAF突变患者接受REGO （40-80 mg，每日一次）联合BRAF/MEKi治疗，nras突变患者接受REGO + MEKi（+低剂量BRAFi以减轻皮肤毒性）治疗。3级TRAE包括动脉高血压（n = 4）和黄斑丘疹（n = 3），无G4/5级TRAE。在braf突变患者中，总体和颅内客观缓解率（总体ORR和IC-ORR）分别为11%和29%，总体和颅内疾病控制率（总体DCR和IC-DCR）分别为44%和59%。在nras突变患者中，总ORR和IC-ORR分别为0和25%，总DCR和IC-DCR分别为25和50%。braf突变患者的中位PFS和OS分别为7.1和16.4周，nras突变患者的中位PFS和OS分别为8.6和10.1周。结论：在重度预处理的难治性MBM患者中，REGO联合BRAF/MEKi显示出有希望的抗肿瘤活性和可接受的安全性。在brafv600突变的黑色素瘤患者中，反应不能仅仅归因于BRAF/MEKi再挑战。一项前瞻性试验的进一步调查正在进行中，以增加对疗效的了解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancers Medicine-Oncology

CiteScore

8.00

自引率

9.60%

发文量

5371

审稿时长

18.07 days

期刊介绍： Cancers (ISSN 2072-6694) is an international, peer-reviewed open access journal on oncology. It publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.