美国纽约大学健康中心癌症中心Jeffrey S Weber团队研究了mRNA-4157联合派姆单抗治疗高危黑色素瘤患者对预后的影响。该项研究成果发表在2024年1月18日出版的《柳叶刀》杂志上。

检查点抑制剂是IIB-IV期切除的黑色素瘤的标准辅助治疗，但许多患者会复发。该研究旨在评估mRNA-4157（V940），一种新的基于信使核糖核酸的个性化新抗原疗法，与派姆单抗单药治疗切除的高危黑色素瘤相比，联合派姆单抗是否能提高无复发生存率和无远处转移生存率。

研究组对来自美国和澳大利亚完全切除的高危皮肤黑色素瘤患者进行了mRNA-4157联合派姆单抗与派姆单抗单药治疗的开放标签、随机临床2b期辅助研究。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加派姆单抗或派姆单抗单药治疗。mRNA-4157在3周周期内肌肉内给药（最多9剂）和派姆单抗静脉注射（最多18剂）。主要终点是意向治疗人群的无复发生存率。

2019年7月18日至2021年9月30日，157名患者被分配接受mRNA-4157加派姆单抗联合治疗（n=107）或派姆单抗单药治疗（n=50）；中位随访时间分别为23个月和24个月。与单药治疗相比，联合治疗的无复发生存期更长（复发或死亡的危险比[HR]为0.561；双侧p=0.053），复发或死亡事件率较低（107例中有24例[22%]，50例中有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）。

大多数与治疗相关的不良事件为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，无mRNA-4157相关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。

研究结果表明，在切除的高危黑色素瘤患者中，与派姆单抗单一疗法相比，佐剂mRNA-4157加派姆单抗延长了无复发生存期，并显示出可控的安全性。

附：英文原文

Title: Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study

Author: Jeffrey S Weber, Matteo S Carlino, Adnan Khattak, Tarek Meniawy, George Ansstas, Matthew H Taylor, Kevin B Kim, Meredith McKean, Georgina V Long, Ryan J Sullivan, Mark Faries, Thuy T Tran, C Lance Cowey, Andrew Pecora, Montaser Shaheen, Jennifer Segar, Theresa Medina, Victoria Atkinson, Geoffrey T Gibney, Jason J Luke, Sajeve Thomas, Elizabeth I Buchbinder, Jane A Healy, Mo Huang, Manju Morrissey, Igor Feldman, Vasudha Sehgal, Celine Robert-Tissot, Peijie Hou, Lili Zhu, Michelle Brown, Praveen Aanur, Robert S Meehan, Tal Zaks

Issue&Volume: 2024-01-18

Abstract:

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.

DOI: 10.1016/S0140-6736(23)02268-7

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)02268-7/abstract