一项评估维莫非尼联合考比替尼和聚乙二醇干扰素（VEMUPLINT）治疗携带 V600BRAF 突变的晚期黑色素瘤患者的单中心 I 期研究。
A monocentric phase I study of vemurafenib plus cobimetinib plus PEG-interferon (VEMUPLINT) in advanced melanoma patients harboring the V600BRAF mutation.
机构信息
Istituto Nazionale Tumori-IRCCS-Fondazione G Pascale, Naples, Italy.
Istituto Nazionale Tumori Regina Elena, IRCCS, Rome, Italy.
出版信息
J Transl Med. 2021 Jan 6;19(1):17. doi: 10.1186/s12967-020-02680-7.
BACKGROUND
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.
PATIENTS AND METHODS
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).
RESULTS
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.
CONCLUSION
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.
背景
体外和小鼠模型研究表明，BRAF 抑制剂通过抑制 ERK 增强 BRAFV600E 黑色素瘤细胞中 IFN-α 的作用。因此，BRAFV600E 黑色素瘤患者中维莫非尼联合 IFN-α 治疗可能提供治疗益处；MEK 抑制可防止 BRAF 抑制剂耐药引起的 MAPK 通路的再激活。
患者和方法
在一项 I 期研究中，晚期 BRAFV600 突变黑色素瘤的成年患者接受维莫非尼联合 PEG-IFN-α-2b 或维莫非尼联合 cobimetinib 联合 PEG-IFN-α-2b 治疗，以评估联合用药的安全性和 IFN-α/β 受体-1（IFNAR1）的上调情况。
结果
共 8 例患者接受治疗；报告了 59 例不良事件，其中 4 例为严重不良事件（3 例与研究治疗相关）。治疗前黑色素瘤细胞中 IFNAR1 表达水平≤35%的患者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 IFNAR1 表达水平＞35%的患者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，应答者的生长抑制基因水平较高，包括 GAS1 和 DUSP1，以及代谢活跃的免疫反应基因，包括 FAP。
结论
我们的研究支持维莫非尼联合 PEG-IFN-α-2b 联合 cobimetinib 治疗的总体安全性。IFNAR1 表达水平与治疗反应相关，包括生存。维莫非尼联合 PEG-IFN-α-2b 联合 cobimetinib 在晚期黑色素瘤的当前治疗方案中可能难以找到一席之地，但我们推测我们的发现可能有助于确定对治疗特别敏感的患者。
试验注册
该研究在 clinicaltrials.gov 上注册（NCT01959633）。于 2013 年 10 月 10 日注册，https://clinicaltrials.gov/ct2/show/NCT01959633。
Zotero 插件