本文由小咖机器人翻译整理

期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02942-7

摘要内容如下：

程序性死亡-1（PD-1）抑制剂被批准用于治疗伴有DNA错配修复缺陷（DMMR）的妇科癌症，尽管反应的预测指标仍然难以捉摸。我们在35名患有DMMR子宫癌或卵巢癌的患者中进行了Nivolumab的单组2期研究。共同主要终点包括客观缓解率（ORR）和24周无进展生存期（PFS24）。次要终点包括总生存期（OS）、疾病控制率（DCR）、缓解持续时间（DOR）和安全性。探索性终点包括生物标志物和反应的分子相关性。ORR为58.8%（97.5%可信区间（CI）:40.7-100%），PFS24比率为64.7%（97.5%单侧CI:46.5-100%），满足预先指定的终点。DCR为73.5%（95%CI:55.6-87.1%）。中位随访时间为42.1个月（8.9-59.8个月），中位OS未达到。一年总生存率为79%（95%CI:60.9-89.4%）。32名患者（91%）出现治疗相关不良事件（TRAE），包括关节痛（n=10，29%）、疲劳（n=10，29%）、疼痛（n=10，29%）和瘙痒（n=10，29%）；大多数为1级或2级。10名患者（29%）报告了3级或4级TRAE；未发生5级事件。探索性分析显示，功能失调（CD8+PD-1+）或终末功能失调（CD8+PD-1+TOX+）T细胞的存在及其与程序性死亡配体-1（PD-L1）+细胞的相互作用与PFS24独立相关。PFS24与MEGF8或SETD1B体细胞突变相关。该试验很早就达到了其共同的主要终点（ORR和PFS24），我们的研究结果强调了与DMMR癌症中PD-1阻断反应相关的几个遗传和肿瘤微环境参数，为其在更大的队列中的验证提供了理论基础。

英文原文如下：

Abstracts

Programmed death-1 (PD-1) inhibitors are approved for therapy of gynecologic cancers with DNA mismatch repair deficiency (dMMR), although predictors of response remain elusive. We conducted a single-arm phase 2 study of nivolumab in 35 patients with dMMR uterine or ovarian cancers. Co-primary endpoints included objective response rate (ORR) and progression-free survival at 24 weeks (PFS24). Secondary endpoints included overall survival (OS), disease control rate (DCR), duration of response (DOR) and safety. Exploratory endpoints included biomarkers and molecular correlates of response. The ORR was 58.8% (97.5% confidence interval (CI): 40.7-100%), and the PFS24 rate was 64.7% (97.5% one-sided CI: 46.5-100%), meeting the pre-specified endpoints. The DCR was 73.5% (95% CI: 55.6-87.1%). At the median follow-up of 42.1 months (range, 8.9-59.8 months), median OS was not reached. One-year OS rate was 79% (95% CI: 60.9-89.4%). Thirty-two patients (91%) had a treatment-related adverse event (TRAE), including arthralgia (n = 10, 29%), fatigue (n = 10, 29%), pain (n = 10, 29%) and pruritis (n = 10, 29%); most were grade 1 or grade 2. Ten patients (29%) reported a grade 3 or grade 4 TRAE; no grade 5 events occurred. Exploratory analyses show that the presence of dysfunctional (CD8+PD-1+) or terminally dysfunctional (CD8+PD-1+TOX+) T cells and their interaction with programmed death ligand-1 (PD-L1)+ cells were independently associated with PFS24. PFS24 was associated with presence of MEGF8 or SETD1B somatic mutations. This trial met its co-primary endpoints (ORR and PFS24) early, and our findings highlight several genetic and tumor microenvironment parameters associated with response to PD-1 blockade in dMMR cancers, generating rationale for their validation in larger cohorts.ClinicalTrials.gov identifier: NCT03241745 .

-----------分割线---------

点击链接：https://www.mediecogroup.com/community/user/vip/categories/ ，成为医咖会员，获取12项专属权益。