Fruquintinib/Regorafenib Combined with Sintilimab ± Radiotherapy for Third-line Treatment of Metastatic Colorectal Cancer (FREST-CRC)

Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. Its early clinical manifestations are often subtle, leading to late-stage diagnosis in about 30% of cases with distant metastases. Liver metastases are widespread and associated with poor prognosis, especially in terms of response to immunotherapy. Despite advancements in first- and second-line treatments, third-line therapies for advanced CRC remain limited, emphasizing the need for novel strategies. This prospective study evaluates the efficacy of combined therapy involving Sintilimab, Fruquintinib/Regorafenib, and radiotherapy in advanced CRC. The study cohort comprises patients with non-liver metastatic advanced CRC and those with liver metastases, each receiving tailored treatment protocols. The primary objectives are to assess progression-free survival (PFS), overall survival (OS), and treatment response rates. Subgroup analyses will focus on liver metastases to delineate their impact on treatment outcomes. The rationale for this study stems from the intricate interplay between immunotherapy, targeted therapy, and radiotherapy in CRC management. Previous data suggest a negative correlation between liver metastases and immunotherapy efficacy, necessitating a comprehensive approach integrating multiple treatment modalities. Radiotherapy, particularly stereotactic body radiation therapy (SBRT), has shown promise in controlling liver tumors and modulating the tumor microenvironment, potentially enhancing immunotherapy responses. This study aims to provide valuable insights into optimizing third-line and subsequent therapies for advanced CRC by elucidating the efficacy and safety of this combined treatment approach. The findings may pave the way for personalized treatment strategies tailored to individual patient characteristics, ultimately improving clinical outcomes in this challenging disease setting.

Colorectal cancer (CRC) is a common malignant tumor, ranking second in incidence and mortality among malignant tumors after lung cancer. The early clinical symptoms of colorectal cancer are not obvious, and about 30% of patients have distant metastases (stage IV) at the time of diagnosis, commonly involving organs such as the liver and lungs. Surgery alone cannot cure it. First- and second-line targeted therapies for advanced colorectal cancer (mCRC) include monoclonal drugs targeting the epidermal growth factor receptor (EGFR), represented by cetuximab, suitable for RAS wild-type tumors, and monoclonal drugs targeting vascular endothelial growth factor (VEGF), represented by bevacizumab, suitable for RAS wild-type and mutated tumors. First- and second-line chemotherapy regimens for advanced colorectal cancer include continuous fluorouracil infusion or oral fluoropyrimidine combined with oxaliplatin (FOLFOX, XELOX regimen) or irinotecan (FOLFIRI, XELIRI regimen). The PFS of first-line treatment is about 10-12 months, and that of second-line treatment is about 6 months. However, after the failure of first- and second-line treatments for advanced colorectal cancer, the efficacy of third-line and subsequent treatments is not satisfactory. Although there is abundant data on third-line treatment for advanced colorectal cancer, the prognosis remains poor, with a median progression-free survival (PFS) of only 3.2-5.6 months. Effective third-line or subsequent treatment options are still lacking, and there is an urgent need to find new effective treatment methods. Approximately 70% of mCRC patients have liver metastases. Patients with liver metastases have a worse prognosis, and clinical benefits from immunotherapy are significantly less likely to be obtained. Liver metastases are significantly negatively correlated with the efficacy of immunotherapy. Subgroup analyses based on metastatic organs in studies such as REGNIVO and REGOTORI have shown that the efficacy of treatment in patients with liver metastases is significantly lower than that in patients without liver metastases. Adverse reactions to immunotherapy in patients with liver metastases are related to shortened overall survival (OS) and PFS. Stereotactic body radiation therapy (SBRT) is playing an increasingly important role in the treatment of liver metastases from colorectal cancer. The combination of radiotherapy and immunotherapy has become a hot topic in cancer treatment research. A preclinical study showed that radiotherapy can clinically control liver tumors and stimulate anti-tumor immunity. Liver radiotherapy can regulate the liver tumor microenvironment. This study aims to assess the efficacy of fruquintinib/regorafenib combined with sintilimab compared to fruquintinib/regorafenib alone in third-line treatment of non-liver metastatic advanced colorectal cancer, as well as the effectiveness of combined liver radiotherapy in third-line treatment of liver metastatic advanced colorectal cancer, ensuring that patients receive standard targeted therapy.

Eligibility Criteria:
Inclusion Criteria:

* ECOG PS 0-2
* Histologically confirmed metastatic colorectal adenocarcinoma (8th edition AJCC)
* RAS and BRAF gene mutations or wild type, MSS subtype
* Previously received standard first- and second-line systemic anti-tumor therapy
* At least one measurable lesion as defined by RECIST 1.1 criteria
* Access to tumor samples for biomarker assessment
* Expected survival of ≥3 months
* Normal function of major organ systems (within 14 days before enrollment)
* No systemic corticosteroid treatment within 7 days before treatment initiation, excluding physiological corticosteroid replacement therapy.
* Fertile males or females with the potential for pregnancy must use highly effective contraception methods during the trial.

Exclusion Criteria:

* Patients diagnosed with malignancies other than colorectal cancer within 3 years prior to enrollment.
* Participating in an interventional clinical study or receiving other investigational drugs or treatments with study devices within the past 4 weeks before enrollment.
* Previously received the following therapies: anti-PD-1, anti-PD-L1, or anti-PD-L2 drugs, or drugs targeting another T cell co-stimulatory or co-inhibitory receptor (e.g., CTLA-4, OX-40, CD137), fruquintinib, and regorafenib.
* Received traditional Chinese medicine or immune-modulating drugs with anti-tumor indications within the past 2 weeks before enrollment (excluding local use for controlling pleural effusion).
* Experienced active autoimmune diseases requiring systemic therapy within the past 2 years before enrollment. Replacement therapy is not considered systemic therapy.
* Diagnosed with immune deficiency or received systemic corticosteroid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of investigational treatment. After consultation with the sponsor, the use of physiological doses of corticosteroids may be approved.
* Received liver radiotherapy within the past 2 weeks before enrollment.
* Known presence of central nervous system metastases and/or carcinomatous meningitis.
* Received systemic corticosteroid therapy within 7 days before enrollment.