A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation.
A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation.
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DOI：
10.1186/s12967-020-02680-7
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发表时间：
2021-01-06
影响因子：
7.4
通讯作者：
Ascierto PA
中科院分区：
文献类型：
--
作者：
Simeone E;Scognamiglio G;Capone M;Giannarelli D;Grimaldi AM;Mallardo D;Madonna G;Curvietto M;Esposito A;Sandomenico F;Sabbatino F;Bayless NL;Warren S;Ong S;Botti G;Flaherty KT;Ferrone S;Ascierto PA
在体外和小鼠模型中进行的研究表明，BRAF抑制剂通过抑制ERK增强IFN-α对BRAFV 600 E黑色素瘤细胞的作用。因此，维罗非尼和IFN-α联合治疗BRAFV 600 E黑色素瘤患者可能具有治疗获益; MEK抑制可能防止BRAF抑制剂耐药诱导的MAPK通路再激活。在一项I期研究中，晚期BRAFV 600突变型黑色素瘤成人患者接受了维罗非尼+ PEG-IFN-α-2b或维罗非尼+ cobimetinib + PEG-IFN-α-2b治疗，以评估联合治疗的安全性和IFN-α/β受体-1（IFNAR 1）的上调。8例患者接受了治疗;报告了59起不良事件，其中4起为严重不良事件（3起与研究治疗相关）。治疗前IFNAR 1在≤ 35%黑素瘤细胞上表达的患者的中位无进展生存期为12.0个月（范围：5.6-18.4个月），中位总生存期为31.0个月（范围：19.8-42.2个月），而治疗前IFNAR 1在> 35%的黑素瘤细胞上表达的患者的中位无进展生存期为4.0个月，（范围：0-8.8; p = 0.03），中位总生存期为5个月（p = 0.02）。治疗后，应答者具有更高水平的生长抑制基因，包括GAS 1和DUSP 1，以及参与代谢稳健免疫应答的基因，包括FAP。我们的研究支持vemurafenib + PEG-IFN-α-2b + cobimetinib组合的总体安全性。IFNAR 1表达水平与治疗反应相关，包括生存期。Vemurafenib + PEG-IFN-α-2b + cobimetinib在目前晚期黑色素瘤的治疗方案中很难找到一个利基，但我们推测我们的研究结果可能有助于确定对治疗特别敏感的受试者。试验注册：本研究注册于clinicaltrials.gov（NCT 01959633）。2013年10月10日注册，https://clinicaltrials.gov/ct2/show/NCT01959633
Studies carried out in vitro and in a mouse model have shown that BRAF inhibitors enhance the effects of IFN-α on BRAFV600E melanoma cells through the inhibition of ERK. Therefore, the combination of vemurafenib and IFN-α in patients with BRAFV600E melanoma may provide therapeutic benefits; MEK inhibition may prevent the reactivation of the MAPK pathway induced by BRAF inhibitor resistance. In a phase I study, adult patients with advanced BRAFV600-mutated melanoma were treated with vemurafenib + PEG-IFN-α-2b or vemurafenib + cobimetinib + PEG-IFN-α-2b, to assess the safety of the combination and the upregulation of IFN-α/β receptor-1 (IFNAR1). Eight patients were treated; 59 adverse events with four serious ones (three related to study treatments) were reported. Patients with a pre-treatment IFNAR1 expression on ≤ 35% melanoma cells had a median progression-free survival of 12.0 months (range: 5.6–18.4 months) and a median overall survival of 31.0 months (range: 19.8–42.2 months), while patients with a pre-treatment IFNAR1 expression on > 35% of melanoma cells had a median progression-free survival of 4.0 months (range: 0–8.8; p = 0.03), and a median overall survival of 5 months (p = 0.02). Following treatment, responders had higher levels of growth-suppressor genes, including GAS1 and DUSP1, and genes involved in a metabolically robust immune response, including FAP. Our study supports the overall safety of the vemurafenib + PEG-IFN-α-2b + cobimetinib combination. IFNAR1 expression levels correlated with response to treatment, including survival. Vemurafenib + PEG-IFN-α-2b + cobimetinib would have difficulty finding a niche in the current treatment scenario for advanced melanoma, but we speculate that our findings may contribute to identify subjects particularly responsive to treatment. Trial registration: The study was registered at clinicaltrials.gov (NCT01959633). Registered 10 October 2013, https://clinicaltrials.gov/ct2/show/NCT01959633
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