A Phase III Study of First-line Anlotinib Combined With Benmelstobart in Patients With Advanced Esophageal Squamous Cell Carcinoma

A Randomized, Open-Label, Parallel-Controlled, Multicenter Phase III Clinical Trial to Evaluate the Safety and Efficacy of Anlotinib Hydrochloride Combined With Benmelstobart Versus Toripalimab Combined With Chemotherapy as First-Line Treatment for Advanced Esophageal Squamous Cell Carcinoma Harboring Specific Gene Mutations

A Randomized, Open-Label, Parallel-Controlled, Multicenter Phase III Clinical Trial to Evaluate the Safety and Efficacy of Anlotinib Hydrochloride Combined with Benmelstobart versus Toripalimab Combined with Chemotherapy as First-Line Treatment for Advanced Esophageal Squamous Cell Carcinoma Harboring Specific Gene Mutations

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced Esophageal Squamous Cell Carcinoma
• Intervention / Treatment: Drug: anlotinib combined with benmelstobart; Drug: Toripalimab Combined with Chemotherapy

• Study Type: Interventional
• Enrollment (Estimated): 578
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: feng wang; Phone Number: 0086-13938244776; Email: fengw010@163.com

Study Locations

• China
  • Henan
    • Zhengzhou, Henan, China
      • the First Affiliated Hospital of Zhengzhou University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• (1) Histologically or cytologically confirmed unresectable locally advanced, recurrent, or metastatic esophageal squamous cell carcinoma (excluding adenosquamous carcinoma); (2) No prior systemic therapy, or recurrence more than 6 months after completion of (neo)adjuvant therapy or definitive chemoradiotherapy; (3) Age: ≥18 years (calculated from the date of informed consent signature); ECOG PS score: 0-1; estimated life expectancy >3 months; (4) Presence of TP53 mutation or FAT1 mutation, and absence of NOTCH3 mutation; (5) At least one measurable lesion as confirmed by RECIST 1.1 criteria; measurable lesions should not have received prior local treatment such as radiotherapy (lesions within prior radiation fields may be selected as target lesions if progression is confirmed); (6) Adequate major organ function meeting the following criteria:
• Hemoglobin ≥90 g/L;
• Absolute neutrophil count (ANC) ≥1.5 × 10^9/L;
• Platelets ≥75 × 10^9/L;
• Total bilirubin ≤1.5 × upper limit of normal (ULN);
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if liver metastases present);
• Serum creatinine ≤1.5 × ULN or creatinine clearance ≥60 mL/min;
• Prothrombin time (PT), activated partial thromboplastin time (APTT), and international normalized ratio (INR) ≤1.5 × ULN (for patients not receiving anticoagulation);
• Thyroid-stimulating hormone (TSH) ≤ULN (if TSH abnormal, normal free T3 and free T4 are acceptable); (7) Women of childbearing potential must agree to use effective contraception during the study and for 6 months after study completion, with negative serum or urine pregnancy test within 7 days prior to enrollment; men must agree to use effective contraception during the study and for 6 months after study completion, see Section 5.4 for details; (8) Voluntary participation in this study with signed informed consent and good compliance.

Exclusion Criteria:

• (1) Other malignancies within 3 years prior to first dose or currently concurrent malignancies, except:Other malignancies treated with surgery alone with continuous disease-free survival (DFS) of ≥5 years;Cured cervical carcinoma in situ, non-melanomatous skin cancer, and superficial bladder tumors [Ta (non-invasive), Tis (carcinoma in situ), and T1 (tumor invades lamina propria)]; (2) Conditions affecting intravenous injection or blood collection, or factors affecting oral drug administration (e.g., inability to swallow, chronic diarrhea, intestinal obstruction); (3) Prior treatment-related adverse events not resolved to ≤Grade 1 per CTCAE v5.0, except Grade 2 alopecia, Grade 2 peripheral neuropathy, Grade 2 anemia, clinically non-significant and asymptomatic laboratory abnormalities, and hypothyroidism stable on hormone replacement therapy judged by investigator as having no safety risk; (4) Major surgery, significant traumatic injury within 4 weeks prior to first dose, or anticipated need for major surgery during study treatment (except protocol-required surgery), or presence of non-healing wounds or fractures. [Major surgery defined as Grade 3 or higher per National Surgical Classification Directory 2022]; (5) Esophageal squamous cell carcinoma with active bleeding from primary lesion within 2 months; hematemesis or melena with daily blood loss ≥2.5 mL within 3 months prior to screening, or any bleeding event ≥CTCAE Grade 3, or any bleeding signs or history regardless of severity judged by investigator as unsuitable for enrollment; (6) Arterial or venous thrombotic events within 6 months prior to first dose, including cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, or pulmonary embolism; (7) Active viral hepatitis with inadequate control. Eligible if: HBsAg-positive subjects: HBV DNA <2000 IU/mL (or 1×10⁴ copies/mL) or receiving anti-HBV treatment for ≥1 week prior to study with ≥1 log reduction in viral load, with willingness to continue anti-HBV therapy throughout study; HCV-infected subjects (HCV Ab or HCV RNA positive): judged by investigator as stable or receiving approved antiviral treatment at enrollment with plan to continue; (8) Active syphilis infection requiring treatment; (9) Active tuberculosis, history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, radiation pneumonitis requiring treatment, or symptomatic active pneumonia; (10) History of psychoactive substance abuse with inability to abstain, or psychiatric disorder; (11) Prior or planned allogeneic bone marrow or solid organ transplantation; (12) History of hepatic encephalopathy; (13) Significant cardiovascular disease, including any of the following:

  1. New York Heart Association (NYHA) Class II or greater heart failure or left ventricular ejection fraction (LVEF) <50% by echocardiography;
  2. History of clinically significant ventricular arrhythmia (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes) or arrhythmia requiring continuous antiarrhythmic medication;
  3. Unstable angina pectoris;
  4. Myocardial infarction within 12 months;
  5. Fridericia-corrected QT interval (QTcF) >450 msec for males or >470 msec for females (if abnormal, three consecutive measurements ≥2 minutes apart, use average);
  6. Congenital long QT syndrome or family history;
  7. History of deep vein thrombosis, pulmonary embolism, or other serious thromboembolism within 3 months prior to randomization (implanted port or catheter-related thrombosis, or superficial venous thrombosis not considered "serious");
  8. Current use or recent use (within 7 days prior to study treatment) of aspirin (>325 mg/day), dipyridamole, ticlopidine, clopidogrel, or cilostazol; (14) Active or uncontrolled severe infection (≥CTCAE Grade 2); (15) Renal failure requiring hemodialysis or peritoneal dialysis; (16) History of immunodeficiency, including HIV positivity or other acquired or congenital immunodeficiency disorders; (17) Use of immunosuppressants or systemic or absorbable topical corticosteroids for immunosuppressive purposes within 7 days prior to first dose (except prednisone ≤10 mg daily or equivalent); (18) Epilepsy requiring treatment; (19) Tumor-related symptoms and treatment:
  1. Cytotoxic chemotherapy, immunotherapy within 3 weeks, or radiotherapy or small molecule targeted therapy within 2 weeks prior to first dose, or within 5 half-lives of drug (whichever is shorter) from last treatment; (prior radiotherapy: target lesions should not be within radiation field, or if within field, progression must be confirmed);
  2. Traditional Chinese medicines with anti-tumor indications approved by NMPA within 2 weeks prior to first dose (including Compound Cantharis Capsules, Kang'ai Injection, Kanglaite Capsules/Injection, Aidi Injection, Brucea Javanica Oil Injection/Capsules, Xiaoaiping Tablets/Injection, Huachansu Capsules, etc.);
  3. Imaging evidence of significant tumor invasion into adjacent organs (aorta or trachea) with increased risk of bleeding or fistula; ulcerative ESCC with increased bleeding risk due to proximity to vessels;
  4. Known complete esophageal obstruction requiring interventional relief;
  5. Post-esophageal or tracheal stent placement;
  6. Uncontrolled pleural effusion, pericardial effusion, or moderate to severe ascites requiring repeated drainage (investigator judgment);
  7. Known spinal cord compression, carcinomatous meningitis, or brain metastasis with symptoms or symptom control <4 weeks; (20) Known hypersensitivity to study drug excipients; (21) Prior treatment with anlotinib hydrochloride or other anti-angiogenic agents, or any anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibody; (22) Participation in other interventional clinical trials with investigational drug use within 4 weeks prior to first dose; (23) Pregnancy, lactation, or planned pregnancy during study period; (24) Any condition that, in the opinion of the investigator, would pose significant safety risk to the subject or interfere with completion of the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Anlotinib Hydrochloride Combined with Benmelstobart	Drug: anlotinib combined with benmelstobart; Benmelstobart injection 1200 mg will be diluted in 250 mL normal saline (0.9% sodium chloride) and administered via intravenous infusion over 60 ± 10 minutes on Day 1 of each 21-day cycle until disease progression, unacceptable toxicity, or a maximum of 24 months. Anlotinib hydrochloride capsules 12 mg will be administered orally once daily before breakfast at approximately the same time each day on a schedule of 2 weeks on and 1 week off in 21-day cycles until disease progression or unacceptable toxicity.
Active Comparator: Toripalimab in Combination with Chemotherapy	Drug: Toripalimab Combined with Chemotherapy; Induction Phase (maximum 6 cycles):Toripalimab injection 240 mg will be administered intravenously over 60 minutes on Day 1 of each 21-day cycle after dilution in 100 mL normal saline (0.9% sodium chloride). Chemotherapy regimen will be determined prior to randomization based on individual patient characteristics. Patients will receive one of the following chemotherapy regimens per local treatment standards: Cisplatin 60-75 mg/m² intravenously on Day 1 plus paclitaxel 150-175 mg/m² intravenously over >3 hours, both administered every 3 weeks; or cisplatin 60-75 mg/m² intravenously on Day 1 plus fluorouracil 700-850 mg/m² daily by continuous intravenous infusion over 24 hours on Days 1-5, repeated every 3 weeks. Maintenance Phase :Toripalimab injection 240 mg will be administered intravenously over 60 minutes on Day 1 of each 21-day cycle after dilution in 100 mL normal saline (0.9% sodium chloride).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PFS	The time from randomization to the first occurrence of disease progression or death due to any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1.	about 2 years
OS	The time from randomization to death due to any cause.	about 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ORR	The percentage of subjects with complete response (CR) or partial response (PR) as determined by the investigator according to RECIST 1.1.	about 2 years
DCR	The percentage of subjects with complete response (CR), partial response (PR), or disease stabilization (SD) for ≥6 weeks as determined by the investigator according to RECIST 1.1.	about 2 years
DOR	The time from the first documented confirmed objective response to disease progression or death due to any cause, whichever occurs first, as determined by the investigator according to RECIST v1.1.	about 2 years
AE	The incidence and severity of adverse events, with severity graded according to the NCI CTCAE v5.0 scale.	about 2 years

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Zhengzhou University

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): June 1, 2029

Study Registration Dates

• First Submitted: February 25, 2026
• First Submitted That Met QC Criteria: February 26, 2026
• First Posted (Actual): March 3, 2026

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 26, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Therapeutics; Drug Therapy
• Other Study ID Numbers: TQB2450-ALTN-Ⅲ-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No