Weber Jeffrey S, Carlino Matteo S, Khattak Adnan, Meniawy Tarek, Ansstas George, Taylor Matthew H, Kim Kevin B, McKean Meredith, Long Georgina V, Sullivan Ryan J, Faries Mark, Tran Thuy T, Cowey C Lance, Pecora Andrew, Shaheen Montaser, Segar Jennifer, Medina Theresa, Atkinson Victoria, Gibney Geoffrey T, Luke Jason J, Thomas Sajeve, Buchbinder Elizabeth I, Healy Jane A, Huang Mo, Morrissey Manju, Feldman Igor, Sehgal Vasudha, Robert-Tissot Celine, Hou Peijie, Zhu Lili, Brown Michelle, Aanur Praveen, Meehan Robert S, Zaks Tal
Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, NY, USA.
Westmead and Blacktown Hospitals, Melanoma Institute Australia, Sydney, NSW, Australia.
Lancet. 2024 Feb 17;403(10427):632-644. doi: 10.1016/S0140-6736(23)02268-7. Epub 2024 Jan 18.
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 ClinicalTrials.gov, NCT03897881.
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.
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.
检查点抑制剂是IIB-IV期可切除黑色素瘤的标准辅助治疗方法，但许多患者会复发。我们的研究旨在评估新型基于信使核糖核酸（mRNA）的个体化新抗原疗法mRNA-4157（V940）联合帕博利珠单抗，与帕博利珠单抗单药治疗相比，在可切除的高危黑色素瘤患者中是否能改善无复发生存期和无远处转移生存期。
我们在美国和澳大利亚的研究地点招募了完全切除的高危皮肤黑色素瘤患者，开展了一项开放标签、随机、2b期辅助研究，比较mRNA-4157联合帕博利珠单抗与帕博利珠单抗单药治疗。完全切除黑色素瘤（IIIB-IV期）的患者按2:1分配，接受开放标签的mRNA-4157联合帕博利珠单抗或帕博利珠单抗单药治疗。mRNA-4157通过肌肉注射给药（最大九剂），帕博利珠单抗通过静脉注射给药（最大18剂），每3周为一个周期。主要终点是意向性治疗人群的无复发生存期。这项正在进行的试验已在ClinicalTrials.gov注册，注册号为NCT03897881。
从2019年7月18日至2021年9月30日，157例患者被分配接受mRNA-4157联合帕博利珠单抗联合治疗（n = 107）或帕博利珠单抗单药治疗（n = 50）；中位随访时间分别为23个月和24个月。联合治疗组的无复发生存期长于单药治疗组（复发或死亡的风险比[HR]为0·561[95%CI 0·309 - 1·017]；双侧p = 0·053），复发或死亡事件发生率较低（107例中的24例[22%]对比50例中的20例[40%]）；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25%的患者和单药治疗组18%的患者发生≥3级治疗相关不良事件，未发生与mRNA-4157相关的4 - 5级事件。联合治疗组（37例[36%]）和单药治疗组（18例[36%]）的免疫介导不良事件发生率相似。
对于可切除的高危黑色素瘤患者，辅助性mRNA-4157联合帕博利珠单抗比帕博利珠单抗单药治疗延长了无复发生存期，且安全性可控。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有益。
Moderna与美国新泽西州拉威市默克公司的子公司默克夏普&多贺美合作。
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