Sintilimab in Combination with Cetuximab and Chemotherapy As First-line Treatment for RAS/BRAF Wild-type Advanced Colorectal Cancer: an Open-label, Non-comparative, Phase 1b/2 Dose Escalation and Expansion Trial
In 2018, global cancer incidence reached 18.1 million new cases, with 9.6 million cancer-related deaths. Colorectal cancer ranked as the third most common malignancy by incidence. Data from the U.S. NIH SEER database indicate a five-year survival rate for colorectal cancer of approximately 65%. Specifically, the survival rate is 90% for localized (non-metastatic) cases, 71% for regional (lymph node metastasis) cases, and only 14% for advanced metastatic cases. According to the China Society of Clinical Oncology (CSCO) guidelines, first-line therapy for advanced colorectal cancer typically involves chemotherapy combined with targeted agents, such as bevacizumab or cetuximab, yielding a median survival of 20-30 months. Prognosis is generally better for RAS wild-type patients compared to those with RAS mutations. In subsequent lines of therapy, chemotherapy combined with targeted therapy results in remission for approximately 22% of patients, although overall survival rarely exceeds 12 months. Basic research has demonstrated that cetuximab, when combined with chemotherapy, enhances the infiltration of NK cells, cytotoxic T cells, and other immune cells into the tumor microenvironment. In head and neck cancer, an increase in PD-1+ and TIM-3+ tumor-infiltrating lymphocytes (TILs) during cetuximab treatment was negatively correlated with treatment response. Blocking these immune checkpoints may improve cetuximab-based immunotherapy by reversing CD8+ TIL dysfunction, potentially enhancing clinical outcomes. The cetuximab-chemotherapy regimen increases tumor immunogenicity by inducing tumor cell death and antigen release. When combined with immune checkpoint inhibitors, cetuximab may convert cold tumors into hot tumors, thus synergistically improving tumor cell elimination. Additionally, cetuximab has been shown to activate tumor-promoting M2 macrophages, particularly CD163-positive macrophages in colorectal cancer, which produce high levels of Fc-γ receptors and PD-L1, supporting the theoretical basis for combining cetuximab with immune checkpoint inhibitors in colorectal cancer treatment. In patients with locally advanced colorectal cancer, immune checkpoint inhibitors like PD-1 and CTLA-4 inhibitors have shown preliminary efficacy. The NICHE study reported a 100% pathological response in MSI-H patients and a 27% response in MSS-type patients, indicating potential benefits and safety of immunotherapy in both MSI-H sensitive and MSS/pMMR populations. For first-line treatment of advanced colorectal cancer, the BBCAPX Phase II study showed that sintilimab combined with CapeOX and bevacizumab resulted in an objective response rate (ORR) of 84% and a 100% disease control rate in RAS-mutant, MSS-type metastatic colorectal cancer (mCRC) patients. Similarly, the AIO-KRK-0216 study found that a combination of Avelumab (PD-L1), cetuximab, and chemotherapy produced an ORR of 79.5% in first-line MSS-type metastatic colorectal cancer. In later-line therapy, the REGONIVO Phase II study reported a 36% ORR for PD-1 monoclonal antibody combined with anti-angiogenesis agents (chemotherapy, targeted therapy) in metastatic colorectal cancer, with a 33% ORR for MSS-type patients. The median progression-free survival (PFS) was 7.9 months, though median overall survival (OS) had not been reached.
• Sign a written informed consent before implementing any trial-related procedures.
• Age between 18 and 75 years old.
• No gender restrictions.
• Histologically or cytologically confirmed inoperable or recurrent metastatic colorectal cancer (AJCC 8th edition, Stage IV).
• No prior systemic antitumor treatment, or at least 6 months since the completion of adjuvant therapy.
• At least one measurable lesion as per the RECIST 1.1 criteria for solid tumors.
• Tumor tissue with both RAS and BRAF mutations being wild-type. 8.Tumor tissue with PD-L1 CPS ≥1, TPS ≥1%, or CD8+ TILs ≥2%. 9.ECOG performance status score of 0 or 1. 10.Expected survival time \>3 months. 11.Sufficient organ function and bone marrow compensation function are required, and the subjects must meet the following laboratory criteria:
⁃ .Neutrophil Absolute Count (ANC) ≥ 1.5 x 10\^9/L, provided that granulocyte colony-stimulating factor has not been used in the past 14 days.
⁃ .Platelet count ≥ 90 x 10\^9/L, provided that no blood transfusion has been received in the past 14 days.
⁃ .Hemoglobin \> 9 g/dL, provided that no blood transfusion or erythropoiesis-stimulating agents have been used in the past 14 days.
⁃ .Total bilirubin ≤ 1.5× Upper Limit of Normal (ULN); or total bilirubin \> ULN but direct bilirubin ≤ ULN.
⁃ .Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5× ULN (patients with liver metastasis are allowed to have ALT or AST ≤ ULN).
⁃ .Serum creatinine ≤ 1.5× ULN, and creatinine clearance (calculated using the Cockcroft-Gault formula) ≥ 60 ml/min.
⁃ .Normal coagulation function, defined as International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5× ULN.
⁃ .Normal thyroid function, defined as thyroid-stimulating hormone (TSH) within the normal range. If baseline TSH is outside the normal range, subjects with normal total T3 (or FT3) and FT4 levels may also be included.
⁃ .Normal myocardial enzyme levels (subjects with isolated laboratory abnormalities that the investigator determines to have no clinical significance may still be eligible for inclusion). (Optional) 12.For female subjects of reproductive potential, a urine or serum pregnancy test must be performed within 3 days prior to the first dose of study medication (Cycle 1, Day 1), and the result must be negative. If the urine pregnancy test result cannot be confirmed as negative, a blood pregnancy test is required. Non-reproductive-aged females are defined as those who are at least 1 year postmenopausal or have undergone surgical sterilization or hysterectomy.
⁃ If there is a risk of pregnancy, all subjects (male and female) must use a contraceptive method with a failure rate of less than 1% throughout the treatment period and for 120 days after the last dose of study drug (or for 180 days after the last dose of chemotherapy).