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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02824-y

摘要内容如下：

瑞戈非尼在不可切除的肝细胞癌（UHCC）患者中具有抗肿瘤活性，并具有潜在的免疫调节作用，这表明其与免疫检查点抑制剂联合应用可能对UHCC患者具有临床意义。多中心、单组、2期Renobate试验测试了Regorafenib-Nivolumab作为UHCC的一线治疗。42名患者接受了每4周480mg的nivolumab和每天80mg的瑞戈非尼（3周服用/1周停用方案）。主要终点是研究者根据实体瘤疗效评价标准（RECIST）1.1版评估的客观缓解率（ORR）。次要终点包括安全性、无进展生存期（PFS）和总生存期（OS）。根据RECIST 1.1版，ORR为31.0%，达到主要终点。最常见的不良事件是掌跖红觉障碍综合征（38.1%）、脱发（26.2%）和皮疹（23.8%）。中位无进展生存期为7.38个月。1年总生存率为80.5%，未达到中位总生存率。外周血单个核细胞的探索性单细胞RNA测序分析显示，长期应答者表现出T细胞受体库的多样化，在MKI67+增殖的CD8+T细胞中代表免疫治疗反应性的基因的富集，以及M1导向的单核细胞极化的更高概率。我们的数据支持Regorafenib-Nivolumab联合作为UHCC一线治疗的进一步临床开发，并提供了关于免疫生物标志物反应的初步见解。ClinicalTrials.gov标识符：NCT04310709。

英文原文如下：

Abstracts

Regorafenib has anti-tumor activity in patients with unresectable hepatocellular carcinoma (uHCC) with potential immunomodulatory effects, suggesting that its combination with immune checkpoint inhibitor may have clinically meaningful benefits in patients with uHCC. The multicenter, single-arm, phase 2 RENOBATE trial tested regorafenib-nivolumab as front-line treatment for uHCC. Forty-two patients received nivolumab 480 mg every 4 weeks and regorafenib 80 mg daily (3-weeks-on/1-week-off schedule). The primary endpoint was the investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). ORR per RECIST version 1.1 was 31.0%, meeting the primary endpoint. The most common adverse events were palmar-plantar erythrodysesthesia syndrome (38.1%), alopecia (26.2%) and skin rash (23.8%). Median PFS was 7.38 months. The 1-year OS rate was 80.5%, and the median OS was not reached. Exploratory single-cell RNA sequencing analyses of peripheral blood mononuclear cells showed that long-term responders exhibited T cell receptor repertoire diversification, enrichment of genes representing immunotherapy responsiveness in MKI67+ proliferating CD8+ T cells and a higher probability of M1-directed monocyte polarization. Our data support further clinical development of the regorafenib-nivolumab combination as front-line treatment for uHCC and provide preliminary insights on immune biomarkers of response. ClinicalTrials.gov identifier: NCT04310709 .

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