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

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.