FOLFOX Chemotherapy Combined With Fruquintinib and Serplulimab as First-Line Conversion Therapy for Initially Unresectable pMMR/MSS Colorectal Cancer

Exploratory Clinical Study of FOLFOX Chemotherapy Combined With Fruquintinib and Serplulimab as First-Line Conversion Therapy for Initially Unresectable pMMR/MSS Colorectal Cancer

To evaluate the efficacy and safety of immune checkpoint inhibitor-based combination therapy with targeted therapy and chemotherapy in patients with locally advanced unresectable or metastatic colorectal cancer.

1.1 Overview of Colorectal Cancer Colorectal cancer (CRC) is the third most common malignancy worldwide and a leading cause of cancer-related mortality. In China, CRC incidence and mortality continue to rise, with a high proportion of patients diagnosed at advanced stages. While radical surgery remains the cornerstone of curative treatment, many patients present with unresectable disease, and long-term survival remains poor.

Immune checkpoint inhibitors targeting PD-1/PD-L1 have transformed cancer therapy; however, their benefit in CRC is largely confined to dMMR/MSI-H tumors, which account for only 10-15% of cases. The majority of CRC patients with pMMR/MSS disease derive little benefit from immunotherapy alone.

1.2 Conversion Therapy in Colorectal Cancer Conversion therapy aims to downstage initially unresectable tumors through systemic treatment, enabling surgical resection. In metastatic CRC, successful conversion followed by radical resection can significantly improve long-term survival, with 5-year survival rates reaching 30-50% in selected patients.

1.3 Immunotherapy and Targeted Therapy in pMMR/MSS CRC pMMR/MSS tumors are considered "cold tumors" with low tumor mutational burden and limited immune cell infiltration. Multiple trials have shown minimal efficacy of PD-1 inhibitors alone in this population. Combination strategies incorporating chemotherapy and anti-angiogenic agents may enhance immune response and improve outcomes.

1.4 Serplulimab Serplulimab is a fully humanized anti-PD-1 IgG4 monoclonal antibody with high affinity, slow dissociation, low immunogenicity, and favorable safety characteristics. It has been approved in China for multiple indications including lung cancer and esophageal squamous cell carcinoma, with demonstrated survival benefits.

1.5 Fruquintinib Fruquintinib is a highly selective small-molecule VEGFR inhibitor targeting VEGFR-1, -2, and -3. It inhibits tumor angiogenesis with high potency and manageable toxicity. Fruquintinib has been approved for metastatic colorectal cancer refractory to standard therapies.

1.6 Rationale for This Study Based on strong preclinical and clinical evidence supporting the synergistic effects of immunotherapy, anti-angiogenic therapy, and chemotherapy, this study is the first to explore serplulimab combined with fruquintinib and FOLFOX chemotherapy as first-line conversion therapy in pMMR/MSS colorectal cancer.

Inclusion Criteria:

• Age 18-75 years;
• Histologically confirmed adenocarcinoma of colorectal cancer, initially unresectable locally advanced or metastatic/recurrent disease;
• Expected survival ≥12 weeks;
• No prior systemic antitumor therapy for colorectal cancer;
• Confirmed pMMR by IHC or MSS/MSI-L by PCR or NGS;
• ECOG PS 0-1;
• At least one measurable lesion per RECIST v1.1;
• Adequate organ and bone marrow function;
• Controlled viral hepatitis status as specified;
• Signed written informed consent.

Exclusion Criteria:

• Prior immune checkpoint inhibitor therapy;
• CNS or leptomeningeal metastases;
• Uncontrolled cardiovascular disease or hypertension;
• Active autoimmune disease requiring systemic therapy;
• Active infection including tuberculosis;
• Recent major surgery;
• Pregnancy or lactation;
• Any condition deemed by investigators to compromise safety or study compliance.