A Randomized Trial of Encorafenib and Cetuximab Versus Irinotecan/Cetuximab or FOLFIRI /Cetuximab in Chinese Patients With BRAF V600E Mutant Metastatic Colorectal Cancer: The NAUTICAL Study

ABSTRACT Background Colorectal cancer (CRC) is a major health burden globally and in China, where 3%–5% of cases involve the BRAF V600E mutation, which is associated with aggressive disease and therefore a poor prognosis. Although the combination of encorafenib and cetuximab has demonstrated improved survival in BRAF V600E mutant metastatic CRC (mCRC), such treatments remain unavailable as chemotherapy‐free options in China. Methods The NAUTICAL CRC, a Phase II study in Chinese patients with BRAF V600E mutant metastatic CRC, includes a Safety Lead‐In (SLI) phase for tolerability assessment and a randomized phase comparing encorafenib/cetuximab vs. irinotecan‐based regimens, potentially bridging the treatment gap and evaluating safety, efficacy, and Quality of Life (QoL) outcomes in this Chinese population. Results No dose‐limiting toxicity was identified in the SLI phase ( N = 10). In the Randomized phase ( N = 97), the Doublet arm demonstrated superior progression‐free survival (PFS) of 4.2 months vs. 2.5 months in the Control arm (hazard ratio HR: 0.37, p = 0.0004) and longer overall survival (OS) of 11.6 months vs. 8.2 months (HR: 0.55). Treatment‐related adverse events were common but more severe in the Control arm. QoL measures consistently favored the Doublet arm, showing improved health status and reduced deterioration risk. Conclusions This NAUTICAL CRC Phase II study showed that the combination of encorafenib and cetuximab offers significant clinical benefits, improving PFS and OS, while providing manageable safety and important QoL advantages, making it a valuable treatment option for Chinese patients with previously treated BRAF V600E mutant mCRC. Trial Registration Clinical study registration number: NCT05004350