The Safety and Efficacy of Cetuximab Beta Plus Fruquintinib With or Without Immune Checkpoint Inhibitorrs in First-line Treatment of RAS/BRAF Wild Type Unresectable Metastatic Colorectal Cancer

NCT07257653 | Recruiting Phase 2 DMC

• 1 other identifier: concept
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Colorectal cancer is a malignant tumor ranking among the top four in incidence and the top three in causes of death globally . Chemotherapy combined with anti-EGFR or anti-VEGF monoclonal antibodies is currently the standard first-line treatment for advanced pMMR colorectal cancer. The inclusion of anti-EGFR or anti-VEGF targeted therapies has improved the overall survival of advanced colorectal cancer patients from 13 months in the era of fluorouracil monotherapy to the current 30 months. However, many patients refuse chemotherapy or cannot tolerate cytotoxic chemotherapeutic drugs, which often leads to poor prognosis in advanced colorectal cancer. Thus, in the treatment of advanced colorectal cancer, is it possible to achieve antitumor activity through the combination of targeted drugs while avoiding chemotherapy? Early clinical studies evaluated the possibility of combining anti-EGFR and anti-VEGF monoclonal antibodies. Subsequent large-scale Phase III clinical studies, such as PACCE , indicated that the combination of FOLFOX or FOLFIRI regimens with bevacizumab and panitumumab increased adverse reactions without providing survival benefits in the overall colorectal cancer population compared to the control group. Following this, the CAIRO2 clinical study added cetuximab to CapeOX combined with bevacizumab and still did not demonstrate survival benefits in the first-line treatment of advanced colorectal cancer, particularly in patients with RAS mutations. However, subgroup analyses suggested a certain survival advantage in patients with wild-type RAS who received combined targeted therapy. A recent clinical study (ECOG-ACRIN E7208) showed that in patients with KRAS wild-type advanced colorectal cancer, second-line use of irinotecan combined with cetuximab and ramucirumab significantly improved progression-free survival (PFS) and disease control rate (DCR) compared to cetuximab combined with irinotecan. These studies suggest that combining anti-EGFR and anti-VEGF monoclonal antibodies is a feasible approach for patients with wild-type RAS Certainly, in terms of anti-VEGF options, besides macromolecular anti-VEGFR monoclonal antibodies, small-molecule tyrosine kinase inhibitors targeting VEGF have also demonstrated significant antitumor activity in colorectal cancer. Studies have shown that fruquintinib significantly prolongs the survival of patients with advanced colorectal cancer, leading to its approval as a third-line treatment for colorectal cancer. On the other hand, immunotherapy targeting PD-1 and CTLA-4 has recently made significant progress in the treatment of colorectal cancer. For the pMMR type, which accounts for over 90% of advanced colorectal cancer cases, related clinical studies have confirmed that the combination of immunotherapy and targeted therapy has significant antitumor synergistic effects. These studies also indicate that immune checkpoint inhibitors can enhance the antitumor activity of anti-EGFR and anti-VEGF targeted therapies in pMMR advanced colorectal cancer. This study aims to evaluate the efficacy and safety of cetuximab combined with fruquintinib, with or without immune checkpoint inhibitors, as a first-line treatment for pMMR, RAS/BRAF wild-type metastatic colorectal cancer.

Conditions

Colorectal Neoplasms; RAS; BRAF; Cetuximabβ; Fruquintinib

Keywords

Colorectal cancer; Chemotherapy-free; KRAS/NRAS/BRAF wild-type; cetuximab combined with fruquintinib; with or without immune checkpoint inhibitors

Outcome Measures

Primary Outcomes (1)

• PFS

  PFS refers to the time from randomization (or the start of treatment) until the first observation of disease progression or death from any cause. The analysis is based on the full analysis set and the per-protocol set. The median PFS and its 95% CI were estimated using the Kaplan-Meier method, and survival curves were plotted.

  1 year

Secondary Outcomes (4)

• OS

  2 years

• ORR

  1 year

• DCR

  1 year

• DOR

  1 year

Study Arms (3)

Arm A

EXPERIMENTAL

Cetuximab β + Fruquintinib

Drug: Cetuximab β；Fruquintinib；

Arm B

EXPERIMENTAL

Cetuximab β + Fruquintinib + anti-PD1 antibody

Drug: Cetuximab β；Fruquintinib；anti-PD1 antibody；

Arm C

EXPERIMENTAL

Cetuximab β + Fruquintinib + anti-PD1/CTLA4 antibody

Drug: Cetuximab β；Fruquintinib；anti-PD1/CTLA4 antibody

Interventions

Cetuximab β；Fruquintinib； DRUG

Arm A：Cetuximab β（500mg/m2,iv,d1,q2w）+Fruquintinib(5mg, po, qd, 2w/1w)；

Arm A

Cetuximab β；Fruquintinib；anti-PD1 antibody； DRUG

Arm B：Cetuximab β (500mg/m2,iv,d1,q2w）+Fruquintinib（5mg, po, qd, 2w/1w）+Sintilimab（200mg, iv, d1, q3w）；

Arm B

Cetuximab β；Fruquintinib；anti-PD1/CTLA4 antibody DRUG

Arm C：Cetuximab β(500mg/m2,iv,d1,q2w）+Fruquintinib（5mg, po, qd, 2w/1w）+anti-PD1/CTLA4 antibody(5mg/kg, d1, q3w)

Arm C

Eligibility Criteria

• Age: 10 Years - 85 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• ）Subjects voluntarily join this study, sign the informed consent form, and demonstrate good compliance; 2) Age: 10-80 years old, ECOG PS score of 0-1. For patients aged 80-85, comprehensive functional assessments must be completed, and they may be enrolled if the investigator deems them tolerable, with an expected survival of over 3 months; 3) Histopathologically and/or cytologically confirmed, unresectable metastatic colorectal adenocarcinoma confirmed by MDT discussion (UICC/AJCC TNM staging system for colorectal cancer, 8th Edition, 2017); 4) At least one measurable lesion confirmed according to RECIST 1.1 criteria; 5) Adequate function of major organs, meeting the following criteria:
• Hematological examination standards (no blood transfusion or use of hematopoietic growth factors for correction within 7 days prior to screening):
• Hemoglobin (HGB) ≥ 90 g/L;
• Absolute neutrophil count (NEUT) ≥ 1.5 × 10⁹/L;
• Platelet count (PLT) ≥ 75 × 10⁹/L;
• Biochemical tests must meet the following criteria:
• Total bilirubin (TBIL) ≤ 1.5 × ULN (≤ 3 × ULN for subjects with Gilbert's syndrome);
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. If with liver metastases, ALT and AST ≤ 5 × ULN;
• Serum creatinine (CR) ≤ 1.5 × ULN or creatinine clearance rate (CCR) ≥ 50 ml/min.
• Coagulation function or thyroid function tests must meet the following criteria:
• Prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (without anticoagulant therapy);
• Thyroid-stimulating hormone (TSH) ≤ ULN; if abnormal, T3 and T4 levels should be assessed (FT3 and FT4 may be substituted if T3/T4 are unavailable at the center). Subjects may be enrolled if T3 and T4 levels are normal.
• Echocardiogram assessment: Left ventricular ejection fraction (LVEF) ≥ 50%.
• Hepatitis B surface antigen (HBsAg) negative. If HBsAg positive, hepatitis B virus deoxyribonucleic acid (HBV-DNA) must be \< 2500 copies/mL or 500 IU/mL for enrollment.
• HCV antibody negative or HCV-RNA negative subjects may enroll; if HCV-RNA positive, subjects must have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN to enroll. Subjects with co-infection of hepatitis B and hepatitis C are excluded (positive for HBsAg or HBcAb, and positive for HCV antibody).

You may not qualify if:

• Presence of MSI-H/dMMR patients.
• Concurrent diseases and medical history:
• Diagnosis of or concurrent other malignancies within the past 3 years. The following conditions are eligible for enrollment:
• Cured cervical carcinoma in situ, non-melanoma skin cancer, and superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ), and T1 (tumor invading the basement membrane)\];
• Multiple factors affecting oral medication (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, etc.);
• History or tendency of gastrointestinal bleeding or perforation within 4 weeks prior to enrollment;
• Patients with active inflammatory bowel disease within 4 weeks prior to enrollment;
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage;
• Unresolved toxicities from any prior antitumor therapy exceeding CTCAE Grade 1 (excluding alopecia and oxaliplatin-induced neurotoxicity ≤ Grade 2);
• Major surgical treatment, incisional biopsy, or significant traumatic injury within 28 days prior to the start of study treatment (excluding gastrointestinal endoscopic biopsy);
• Symptoms of active bleeding within 1 week prior to screening, without significant improvement or control;
• Patients with any bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to study initiation, or presence of unhealed wounds, ulcers, or fractures;
• Arterial/venous thrombotic events within 6 months, such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and pulmonary embolism;
• History of psychoactive drug abuse with inability to abstain;
• Patients with any severe and/or uncontrolled diseases, including:

Sponsors & Collaborators

• Zhejiang University: lead

Study Sites (1)

Second Affiliated Hospital Zhejiang University College of Medicine, Hangzhou, Zhejiang Province 310999

Hangzhou, Zhejiang, China

RECRUITING

MeSH Terms

Conditions

Colorectal Neoplasms

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Kefeng Ding, PhD

  Second Affiliated Hospital, School of Medicine, Zhejiang University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kefeng Ding, PhD

CONTACT

86-571-87784720; dingkefeng@zju.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Arm A: Cetuximab β + Fruquintinib Arm B: Cetuximab β + Fruquintinib + anti-PD1 antibody Arm C: Cetuximab β + Fruquintinib + anti-PD1/CTLA4 antibody

Study Record Dates

• First Submitted: November 20, 2025
• First Posted: December 2, 2025
• Study Start: October 21, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: December 2, 2025

Record last verified: 2025-11

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)