Multicenter, nonrandomized clinical trial to evaluate the efficacy and toxicity of a combination of targeted therapy and chemotherapy in the second-line treatment of patients with metastatic inoperable colorectal cancer.

TPS247 Background: BRAF mutation found in 8-10% of colorectal cancers (CRC). BRAF mutation in tumor determines poor prognosis and low sensitivity to available treatments. Therapy with BRAF inhibitors in combination with anti-EGFR antibodies with or without MEK inhibitors as second and subsequent lines of treatment allows for objective response rates (ORR 20-30%), progression-free survival (PFS) 3-4.5 months. We hypothesized that addition of irinotecan and anti-EGFR antibodies to dabrafenib and trametinib combination may represent an effective second-line therapy for patients with metastatic BRAF V600E- mutated colorectal cancer. Methods: This phase 2 non-randomized, open-label, multicenter prospective study is designed to evaluate the efficacy and safety of irinotecan in combination with dabrafenib + trametinib and cetuximab or panitumumab in patients with mCRC who have BRAF mutation and one previous line of treatment. It is possible to include patients with MSI or dMMR if they have received first-line immune checkpoint therapy. Main inclusion criteria are: patients with histologically confirmed mCRC, who BRAF mutation, adequate hematopoietic function and vital signs, and measurable disease according to RECIST v1.1, absence of grade 2 or higher toxicity from previous line of treatment. The primary endpoint is Objective Response Rate (ORR), secondary endpoints are Progression-free survival (PFS), time to objective response, duration of response (DOR), disease control rate, overall survival (OS), Incidence of adverse events (NCI CTCAE 5.0), Incidence of adverse events grade 3-4, frequency of dose reductions and drug withdrawals, biomarker studies to assess the causes of resistance. Statistical hypothesis: null hypothesis - objective response rate 20%, alternative hypothesis - objective response rate 50%. To accept the alternative hypothesis, with a first-order error of 0.05 and 90% power, 23 patients should be included. Enrollment began in January 2025 and is ongoing. Clinical trial information: NCT06967155 .