Cetuximab and vemurafenib plus liposomal irinotecan (II), leucovorin and fluorouracil for BRAF ^V600E -mutated advanced colorectal cancer (IMPROVEMENT2): A multicenter, open-label, randomized controlled trial.

TPS316 Background: Current first-line treatment regimen for advanced colorectal cancer with BRAF V600E gene mutation is chemotherapy combined with anti-angiogenic drug, but the efficacy is somewhat limited. Theoretically, targeting BRAF V600E mutation is an effective treatment strategy and has achieved success in lung cancer and melanoma. However, the objective response rate (ORR) is below 5% in colorectal cancer, suggesting that BRAF V600E mutation in colorectal cancer may have different feedback regulation mechanisms compared to other cancer types. Combining chemotherapy (such as 5-fluorouracil plus irinotecan) with BRAF/EGFR targeted therapy may potentially achieve good efficacy. Subsequently, we conducted the IMPROVEMENT (NCT03727763) study, which showed an objective response rate (ORR) of 85% and a disease control rate of 100% with this regimen, significantly higher than those with chemotherapy combined with anti-angiogenic drug. The recent BREAKWATER study showed similar trends. To further validate the efficacy and safety of this regimen, we designed a randomized controlled trial. Methods: IMPROVEMENT2 (NCT06603376) is a multicenter, open-label, randomized controlled trial in patients with histologically or cytologically confirmed advanced colorectal cancer. Adult patients who are previously untreated in the metastatic setting, have a confirmed BRAF V600E mutation, measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and Eastern Cooperative Oncology Group performance status of 0-1 are eligible. Patients who received previous treatment in the adjuvant setting but experienced metastasis or recurrence within 12 months are permitted. A total of 75 eligible patients will be randomly assigned (2:1) to receive liposomal irinotecan(Ⅱ) 60 mg/m 2 , leucovorin 400 mg/m 2 , fluorouracil 2800 mg/m 2 , and cetuximab 500 mg/m 2 on day 1 of each 14-day cycle plus oral vemurafenib 720 mg twice daily, or liposomal irinotecan(Ⅱ) 60 mg/m 2 , leucovorin 400 mg/m 2 , fluorouracil 2800 mg/m 2 , and bevacizumab 5 mg/kg on day 1 of each 14-day cycle. Treatment will be continued until disease progression or unacceptable toxicity. The primary endpoint is ORR per RECIST 1.1 by blinded independent central review (BICR). Key secondary endpoints are depth of response, progression-free survival per RECIST 1.1 by BICR, overall survival, and safety. The study is actively enrolling patients. Clinical trial information: NCT06603376 .