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Scott Kopetz, MD, PhD, The University of Texas MD Anderson Cancer Center, Houston, TX, explains the rationale for initiating the Phase III BREAKWATER (NCT04607421) trial. This Phase III trial was built on the success of the Phase III BEACON (NCT02928224) study which demonstrated that encorafenib plus cetuximab performed better than the standard of care (SOC) in second- and third-line settings in treating patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). The activity of this combination demonstrated superior results in the second-line setting compared to third-line. Combining this insight with the results from the Phase II ANCHOR-CRC (NCT03693170) trial, which examined first-line data of the targeted therapy encorafenib plus binimetinib plus cetuximab alone, initiated the rationale to investigate targeted therapy as first-line treatment for patients with BRAF V600E-mCRC. The Phase III BREAKWATER trial is investigating SOC chemotherapy alone or combined with encorafenib plus cetuximab, as well as encorafenib plus cetuximab alone in patients with BRAF V600E-mCRC. The primary endpoint is progression-free survival (PFS) with the key secondary endpoint of overall survival (OS). This interview took place at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.