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 (18BRAF-mutant, 4NRASQ61-mutant; 19 with progressive MBM; 11 on corticosteroids). ThirteenBRAFV600-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. InBRAF-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. InNRAS-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 inBRAF-mutant and 8.6 and 10.1 weeks inNRAS-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. InBRAFV600-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.
背景：对于免疫检查点阻断（ICB）和BRAF/MEK抑制剂（BRAF/MEKi）治疗失败的进展性黑色素瘤脑转移（MBM）患者，目前尚无有效的治疗选择。瑞戈非尼（REGO）是一种口服多激酶抑制剂（包括RAF二聚体抑制作用），临床前模型显示其可克服对BRAF/MEKi的适应性耐药。方法：本研究是一项单中心回顾性病例系列分析，纳入接受REGO联合BRAF/MEKi（同情用药）治疗的难治性MBM患者。结果：共纳入22例患者（18例BRAF突变，4例NRAS Q61突变；19例存在MBM进展；11例使用皮质类固醇）。其中13例BRAF V600突变患者在联合REGO时正处于BRAF/MEKi治疗进展期。BRAF突变患者接受REGO（每日一次40–80 mg）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级治疗相关不良事件包括动脉高血压（n=4）和斑丘疹（n=3）。未发生4/5级治疗相关不良事件。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，总体ORR和IC-ORR分别为0%和25%，总体DCR和IC-DCR分别为25%和50%。BRAF突变患者的中位无进展生存期（PFS）和总生存期（OS）分别为7.1周和16.4周，NRAS突变患者分别为8.6周和10.1周。结论：在经深度治疗的难治性MBM患者中，REGO联合BRAF/MEKi显示出有前景的抗肿瘤活性和可接受的安全性。对于BRAF V600突变黑色素瘤患者，治疗反应不能完全归因于BRAF/MEKi的再次使用。目前正在进行前瞻性试验以进一步探究其疗效。
肿瘤(癌症)患者之家