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. 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 , . 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 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. 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. Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

中文翻译：

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个体化新抗原疗法 mRNA-4157 (V940) 加派姆单抗与派姆单抗单药疗法在切除黑色素瘤中的比较 (KEYNOTE-942)：一项随机 2b 期研究

检查点抑制剂是 IIB-IV 期切除黑色素瘤的标准辅助治疗，但许多患者会复发。我们的研究旨在评估 mRNA-4157 (V940)（一种基于 mRNA 的新型个体化新抗原疗法）与派姆单抗 (pembrolizumab) 联合治疗，与派姆单抗 (pembrolizumab) 单药治疗相比，是否能改善切除的高危黑色素瘤的无复发生存期和无远处转移生存期。我们对来自美国和澳大利亚的完全切除高危皮肤黑色素瘤的患者进行了一项开放标签、随机、2b 期辅助研究，研究对象为 mRNA-4157 加派姆单抗与派姆单抗单一疗法。完全切除黑色素瘤（IIIB-IV 期）的患者按照 2:1 的比例分配接受开放标签 mRNA-4157 加派姆单抗或派姆单抗单药治疗。 mRNA-4157 肌肉注射（最多 9 剂），派姆单抗静脉注射（最多 18 剂），周期为 3 周。主要终点是意向治疗人群的无复发生存期。这项正在进行的试验注册于， 。从2019年7月18日到2021年9月30日，157名患者被分配接受mRNA-4157加派姆单抗联合疗法（n=107）或派姆单抗单药疗法（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]，0·561 [95% CI 0·309–1·017]；双侧 p=0·053），且复发率较低或死亡事件率（107 中的 24 [22%] 50 中的 20 [40%]）； 18 个月无复发生存率为 79% (95% CI 69·0–85·6) 对比 62% (46·9–74·3)。大多数与治疗相关的不良事件为 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≥3 级治疗相关不良事件，没有 mRNA-4157 相关的 4-5 级事件。联合治疗组 (37 [36%]) 和单一治疗组 (18 [36%]) 的免疫介导不良事件发生率相似。与派姆单抗单药治疗相比，辅助 mRNA-4157 加派姆单抗可延长切除高危黑色素瘤患者的无复发生存期，并且显示出可控的安全性。这些结果证明基于 mRNA 的个体化新抗原疗法在辅助治疗中可能是有益的。 Moderna 与 Merck Sharp & Dohme（美国新泽西州拉韦市 Merck & Co 的子公司）合作。