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
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...
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| Published in | Molecular cancer Vol. 24; no. 1; pp. 175 - 13 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
England
BioMed Central Ltd
11.06.2025
BioMed Central BMC |
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| 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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| AbstractList | 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. 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. 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).BACKGROUNDNo 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.METHODSALTER-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).RESULTSOf 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.CONCLUSIONFirst-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.TRIAL REGISTRATIONNCT05038813. 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. 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. Keywords: Anlotinib, Benmelstobart, Esophageal squamous cell carcinoma, Next-generation sequencing, TP53+/FAT1+/NOTCH3-, PD-L1 |
| ArticleNumber | 175 |
| Audience | Academic |
| Author | Guan, Lulu Yang, Xiuli Wu, Weilong Zhang, Daoyu Jiang, Guozhong Shan, Zhengzheng Ma, Yihui Peng, Zuofu Jiang, Binghua Chen, Yunfang Hong, Yonggui Song, Min Luo, Xi Xia, Jin Ma, Mingying Zhang, Zhiye Meng, Xiangrui Xin, Dao Wang, Feng Wang, Wenkang Wu, Tao Wang, Lisen Hu, Biao Shen, Ling Lu, Taiying Wu, Xiaoying Qi, Yu Zhou, Yue |
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| Keywords | PD-L1 TP53+/FAT1+/NOTCH3 Benmelstobart Esophageal squamous cell carcinoma Anlotinib Next-generation sequencing |
| Language | English |
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| Snippet | 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... Background No combined antiangiogenic and PD-1/PD-L1 blockade therapy has been investigated as a chemo-free first-line treatment for advanced esophageal... Abstract Background No combined antiangiogenic and PD-1/PD-L1 blockade therapy has been investigated as a chemo-free first-line treatment for advanced... |
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| SubjectTerms | Adult Aged Anlotinib Antineoplastic Combined Chemotherapy Protocols - administration & dosage Benmelstobart Biomarkers, Tumor Cancer Chemotherapy Clinical trials Esophageal cancer Esophageal Neoplasms - drug therapy Esophageal Neoplasms - mortality Esophageal Neoplasms - pathology Esophageal squamous cell carcinoma Esophageal Squamous Cell Carcinoma - drug therapy Esophageal Squamous Cell Carcinoma - genetics Esophageal Squamous Cell Carcinoma - mortality Esophageal Squamous Cell Carcinoma - pathology Female Humans Indoles - administration & dosage Ipilimumab Male Middle Aged Mutation Neoplasm Staging Next-generation sequencing PD-L1 Quinolines - administration & dosage Squamous cell carcinoma TP53+/FAT1+/NOTCH3 Treatment Outcome |
| Title | 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 |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/40500695 https://www.proquest.com/docview/3218153414 https://pubmed.ncbi.nlm.nih.gov/PMC12153090 https://doaj.org/article/f4d1a5d3f66c4bbf861f43c45795e134 |
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