Anlotinib combined with benmelstobart as a chemo-free first-line treatment in advanced esophageal squamous cell carcinoma: an exploratory multicenter, single-arm phase II clinical trial

IF 27.7 1区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Molecular Cancer Pub Date : 2025-06-11 DOI:10.1186/s12943-025-02376-w

Xiangrui Meng, Xiuli Yang, Yonggui Hong, Wenkang Wang, Zhiye Zhang, Jin Xia, Yunfang Chen, Yue Zhou, Taiying Lu, Min Song, Zhengzheng Shan, Tao Wu, Weilong Wu, Ling Shen, Lulu Guan, Mingying Ma, Lisen Wang, Xi Luo, Dao Xin, Yihui Ma, Guozhong Jiang, Yu Qi, Binghua Jiang, Daoyu Zhang, Biao Hu, Xiaoying Wu, Zuofu Peng, Feng Wang

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引用次数: 0

Abstract

No combined antiangiogenic and PD-1/PD-L1 blockade therapy has been investigated as a chemo-free first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). This study evaluates the efficacy and safety of anlotinib combined with benmelstobart as a chemo-free treatment in previously untreated advanced ESCC, and identifies potential predictive biomarkers using next-generation sequencing (NGS). ALTER-E-003, a single-arm, open-label phase II trial, enrolled patients with advanced ESCC across five Chinese centers. Patients received oral anlotinib 12 mg daily on days 1–14 per three-week cycle, with benmelstobart 1200 mg infused on day 1 of each cycle for up to 24 months. Thereafter, patients received anlotinib maintenance therapy. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of response (DOR), and safety. NGS and fluorescent multiplex immunohistochemistry (mIHC) were performed on tumor specimens. Of 53 screened patients, 46 completed the study. The confirmed ORR was 56.5% (95% CI 41.1–71.1), and DCR was 91.3% (95% CI 79.2–97.6). Median PFS was 15.74 months (95% CI 9.03–21.91). Treatment-related adverse events occurred in 93.5% of patients, with 28.3% experiencing grade 3 or higher events. NGS revealed a novel predictive mutational signature (TP53+/FAT1+/NOTCH3-) that was associated with better ORR (65.6% versus 11.1%, P < 0.001), longer median PFS (17.91 versus 5.32 months, P = 0.005) and improved OS (P = 0.006). First-line anlotinib-benmelstobart combination demonstrated durable responses and acceptable safety in ESCC patients. Exploratory biomarker analyses identified a TP53+/FAT1+/NOTCH3- mutational signature potentially associated with improved outcomes, though further validation in randomized trials is warranted. NCT05038813.

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Anlotinib联合benmelstobart作为晚期食管鳞状细胞癌的无化疗一线治疗：一项探索性多中心单组II期临床试验

目前还没有研究联合抗血管生成和PD-1/PD-L1阻断治疗作为晚期食管鳞状细胞癌（ESCC）的无化疗一线治疗。本研究评估了anlotinib联合benmelstobart作为无化疗治疗先前未治疗的晚期ESCC的有效性和安全性，并使用下一代测序（NGS）确定了潜在的预测性生物标志物。ALTER-E-003是一项单臂、开放标签II期临床试验，在中国5个中心招募了晚期ESCC患者。患者在每3周周期的第1 - 14天每天口服安洛替尼12mg，并在每个周期的第1天输注benmelstobart 1200mg，持续长达24个月。此后，患者接受安洛替尼维持治疗。主要终点为客观缓解率（ORR）。次要终点包括无进展生存期（PFS）、总生存期（OS）、疾病控制率（DCR）、反应持续时间（DOR）和安全性。肿瘤标本行NGS和荧光多重免疫组化（mIHC）。在53名接受筛选的患者中，46名完成了研究。确诊ORR为56.5% (95% CI 41.1-71.1)， DCR为91.3% （95% CI 79.2-97.6）。中位PFS为15.74个月（95% CI 9.03-21.91）。93.5%的患者发生了与治疗相关的不良事件，其中28.3%发生了3级或更高级别的不良事件。NGS显示了一种新的预测性突变特征（TP53+/FAT1+/NOTCH3-），与更好的ORR（65.6%对11.1%,P < 0.001）、更长的中位PFS（17.91对5.32个月，P = 0.005）和改善的OS （P = 0.006）相关。在ESCC患者中，一线anlotinib-benmelstobart联合治疗显示出持久的疗效和可接受的安全性。探索性生物标志物分析发现TP53+/FAT1+/NOTCH3-突变特征可能与改善的结果相关，但需要在随机试验中进一步验证。NCT05038813。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Cancer 医学-生化与分子生物学

CiteScore

54.90

自引率

2.70%

发文量

224

审稿时长

2 months

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