A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer
Colorectal cancer (CRC) is the second leading cause of cancer-related death globally. BRAF V600E mutations occur in approximately 12% of metastatic CRC (mCRC) patients, conferring an extremely poor prognosis with a median overall survival (OS) of only 11 months for standard chemotherapy. Most BRAF V600E-mutant mCRC are microsatellite stable (MSS) and do not benefit from single-agent PD-1/PD-L1 inhibition. Preclinical and clinical evidence indicates that BRAF inhibition in combination with EGFR blockade can induce DNA damage, trigger a deficient mismatch repair (dMMR) phenotype, and increase tumor mutational burden (TMB), thereby sensitizing MSS tumors to immune checkpoint inhibition. This provides a strong rationale for combining BRAF/EGFR inhibitors with anti-PD-1 and anti-CTLA-4 immunotherapy. This is a single-arm, open-label, Phase II clinical trial. The primary objective is to evaluate the efficacy and safety of the triplet combination of sintilimab (anti-PD-1), ipilimumab N01 (anti-CTLA-4), cetuximab (anti-EGFR), and dabrafenib (BRAF inhibitor) in patients with MSS, BRAF V600E-mutant mCRC.
• Provided written informed consent.
• Age ≥ 18 years.
• Histologically or pathologically confirmed colorectal adenocarcinoma.
• Documented microsatellite stable (MSS) and BRAF V600E mutation by prior genomic testing.
• Locally advanced unresectable disease or distant metastasis.
• No prior treatment with BRAF/MEK/ERK inhibitors, EGFR inhibitors, or immune checkpoint inhibitors (ICI).
• Presence of measurable target lesions per RECIST 1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.
• Adequate organ function, based on the following laboratory values obtained within 7 days prior to Cycle 1 Day 1:
∙ Hemoglobin ≥ 9.0 g/dL.
‣ Absolute neutrophil count ≥ 1,500/mm³ (≥ 1.5 × 109/L).
‣ Platelet count ≥ 80,000/mm³ (≥ 80 × 109/L).
‣ Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN).
‣ Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN.
‣ Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min.
⁃ Willing and able to comply with study procedures and visit schedule.