本文由小咖机器人翻译整理

期刊来源：Lancet

原文链接：https://doi.org/10.1016/S0140-6736(23)02268-7

摘要内容如下：

背景

检查点抑制剂是IIB-IV期切除黑色素瘤的标准辅助治疗，但许多患者复发。我们的研究旨在评估mRNA-4157（V940）（一种新型的基于mRNA的个体化新抗原疗法）联合pembrolizumab与pembrolizumab单药治疗相比，是否能提高切除的高危黑色素瘤患者的无复发生存率和无远处转移生存率。

方法

我们进行了一项开放标签、随机、2B期辅助研究，在来自美国和澳大利亚的完全切除的高危皮肤黑色素瘤患者中进行了mRNA-4157联合pembrolizumab与pembrolizumab单药治疗的比较。完全切除的黑色素瘤（IIIB-IV期）患者以2:1的比例接受开放标签mRNA-4157联合pembrolizumab或pembrolizumab单药治疗。在3周的周期中，肌肉注射（最多9剂）和静脉注射pembrolizumab（最多18剂）给予mRNA-4157。主要终点是意向治疗人群的无复发生存率。这项正在进行的试验在ClinicalTrials.gov，NCT03897881上注册。

调查结果

从2019年7月18日至2021年9月30日，157名患者被分配接受mRNA-4157联合pembrolizumab联合治疗（n=107）或pembrolizumab单药治疗（n=50）；中位随访时间分别为23个月和24个月。联合治疗与单药治疗相比，无复发生存期更长（复发或死亡的风险比[HR]为0.561[95%CI 0.309-1.017]；双侧P=0.053），具有较低的复发或死亡事件发生率（24[22%]/107 vs 20[40%]/50）；18个月无复发生存率分别为79%（95%CI 69.0-85.6）和62%（46.9-74.3）。大多数治疗相关不良事件为1-2级。联合治疗组中25%的患者和单药治疗组中18%的患者发生了≥3级治疗相关不良事件，未发生mRNA-4157相关的4-5级事件。联合治疗组（37[36%]）和单药治疗组（18[36%]）的免疫介导不良事件发生率相似。

解释

与pembrolizumab单药治疗相比，辅助mRNA-4157联合pembrolizumab延长了切除的高危黑色素瘤患者的无复发生存期，并显示出可控制的安全性。这些结果提供了基于mRNA的个体化新抗原治疗可能在辅助环境中有益的证据。

英文原文如下：

Abstracts

BACKGROUND  Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.

METHODS  We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.

FINDINGS  From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.

INTERPRETATION  Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.

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