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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

  • 1Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450000, Henan, China.
  • 2Department of Oncology, The First Affiliated Hospital of Nanyang Medical College, Nanyang, Henan, China.
  • 3Department of Gastroenterology, Anyang Tumor Hospital, Anyang, Henan, China.
  • 4Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 5Department of Respiratory Oncology, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China.
  • 6Department of Oncology, Zhumadian Central Hospital, Zhumadian, Henan, China.
  • 7Department of Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 8Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 9Department of Thoracic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 10The Academy of Medical Science, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, China.
  • 11Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Nanjing, Jiangsu, China.
  • 12Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, China.
  • 13Alpha X (Beijing) Biotech CO., LTD, Beijing, China.
  • 14Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No. 1 Jianshe East Road, Zhengzhou, 450000, Henan, China. zzuwangfeng@zzu.edu.cn.
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June 11, 2025

Abstract

BACKGROUND

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).

METHODS

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.

RESULTS

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).

CONCLUSION

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.

TRIAL REGISTRATION

NCT05038813.

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