A Phase II Study of Sintilimab Combined With Ipilimumab N01, Cetuximab and Dabrafenib in Patients With Microsatellite-Stable, BRAF V600E-Mutated Metastatic Colorectal Cancer

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.

Inclusion Criteria:

1. Provided written informed consent.

2. Age ≥ 18 years.

3. Histologically or pathologically confirmed colorectal adenocarcinoma.

4. Documented microsatellite stable (MSS) and BRAF V600E mutation by prior genomic testing.

5. Locally advanced unresectable disease or distant metastasis.

6. No prior treatment with BRAF/MEK/ERK inhibitors, EGFR inhibitors, or immune checkpoint inhibitors (ICI).

7. Presence of measurable target lesions per RECIST 1.1.

8. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1.

9. Adequate organ function, based on the following laboratory values obtained within 7 days prior to Cycle 1 Day 1:

   1. Hemoglobin ≥ 9.0 g/dL.
   2. Absolute neutrophil count ≥ 1,500/mm³ (≥ 1.5 × 109/L).
   3. Platelet count ≥ 80,000/mm³ (≥ 80 × 109/L).
   4. Serum total bilirubin ≤ 1.5 × upper limit of normal (ULN).
   5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN.
   6. Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min.

10. Willing and able to comply with study procedures and visit schedule.

Exclusion Criteria:

1. Received any approved or investigational systemic anti-tumor therapy within 4 weeks prior to enrollment.
2. Underwent any surgery or invasive procedure within 4 weeks prior to study initiation (exceptions include venous catheter placement and paracentesis/drainage).
3. Multiple primary malignancies (exceptions include completely resected basal cell carcinoma, stage I squamous cell carcinoma, carcinoma in situ, intramucosal carcinoma, superficial bladder cancer, or any other cancer that has been in complete remission for at least 3 years).
4. Presence of severe comorbidities or serious medical conditions.
5. Pregnant or breastfeeding females.
6. The investigator deems the patient unsuitable for participation in this study.