Department of Medical Oncology, Vrije Universiteit Brussel (VUB)/University Hospital of Brussels (UZ Brussel), Brussels.
Department of Medical Oncology, AZ Sint-Jan Hospital Bruges, Bruges, Belgium.
Melanoma Res. 2024 Aug 1;34(4):366-375. doi: 10.1097/CMR.0000000000000977. Epub 2024 May 27.
Melanoma patients failing all approved treatment options have a poor prognosis. The antimelanoma activity of regorafenib (REGO), a multitargeted kinase inhibitor, has not been investigated in this patient population. The objective response rate and safety of REGO treatment in advanced melanoma patients was investigated retrospectively. Twenty-seven patients received REGO treatment. All patients had progressed on anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibition and BRAF/MEK inhibitors (in case of a BRAF V600 mutation). REGO was administered in continuous dosing and combined (upfront or sequentially) with nivolumab ( n = 5), trametinib ( n = 8), binimetinib ( n = 2), encorafenib ( n = 1), dabrafenib/trametinib ( n = 9), or encorafenib/binimetinib ( n = 7). The best overall response was partial response (PR) in five patients (18.5%) and stable disease in three patients (11.1%). Three of seven (42.8%) BRAF V600mut patients treated with REGO in combination with BRAF/MEK inhibitors obtained a PR (including regression of brain metastases in all three patients). In addition, PR was documented in a BRAF V600mut patient treated with REGO plus anti-PD-1, and a NRASQ61mut patient treated with REGO plus a MEK inhibitor. Common grade 3-4 treatment-related adverse events included arterial hypertension ( n = 7), elevated transaminase levels ( n = 5), abdominal pain ( n = 3), colitis ( n = 2), anorexia ( n = 1), diarrhea ( n = 1), fever ( n = 1), duodenal perforation ( n = 1), and colonic bleeding ( n = 1). Median progression-free survival was 11.0 weeks (95% confidence interval, 7.1-14.9); median overall survival was 23.1 weeks (95% confidence interval, 13.0-33.3). REGO has a manageable safety profile in advanced melanoma patients, in monotherapy as well as combined with BRAF/MEK inhibitors or PD-1 blocking monoclonal antibodies. The triplet combination of REGO with BRAF/MEK inhibitors appears most active, particularly in the BRAF V600mut patients.
所有已批准的治疗方案均失败的黑色素瘤患者预后不良。regorafenib（REGO）是一种多靶点激酶抑制剂，尚未在该患者人群中进行抗黑色素瘤活性研究。本研究回顾性调查了晚期黑色素瘤患者接受 REGO 治疗的客观缓解率和安全性。27 例患者接受了 REGO 治疗。所有患者均在接受抗程序性细胞死亡蛋白 1（PD-1）和抗细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）检查点抑制剂以及 BRAF/MEK 抑制剂（如果存在 BRAF V600 突变）治疗后进展。REGO 持续剂量给药，联合（ upfront 或序贯）使用 nivolumab（n=5）、trametinib（n=8）、binimetinib（n=2）、encorafenib（n=1）、dabrafenib/trametinib（n=9）或 encorafenib/binimetinib（n=7）。最佳总体缓解为 5 例患者（18.5%）部分缓解（PR）和 3 例患者（11.1%）疾病稳定。3 例接受 REGO 联合 BRAF/MEK 抑制剂治疗的 BRAF V600mut 患者获得 PR（包括所有 3 例患者脑转移瘤消退）。此外，在接受 REGO 联合抗 PD-1 治疗的 1 例 BRAF V600mut 患者和接受 REGO 联合 MEK 抑制剂治疗的 1 例 NRAS Q61mut 患者中也观察到 PR。常见的 3-4 级治疗相关不良事件包括动脉高血压（n=7）、转氨酶升高（n=5）、腹痛（n=3）、结肠炎（n=2）、厌食（n=1）、腹泻（n=1）、发热（n=1）、十二指肠穿孔（n=1）和结肠出血（n=1）。中位无进展生存期为 11.0 周（95%置信区间：7.1-14.9）；中位总生存期为 23.1 周（95%置信区间：13.0-33.3）。REGO 在晚期黑色素瘤患者中具有可管理的安全性特征，无论是单药治疗还是与 BRAF/MEK 抑制剂或 PD-1 阻断单克隆抗体联合治疗。REGO 与 BRAF/MEK 抑制剂的三联组合似乎最有效，尤其是在 BRAF V600mut 患者中。
