Editor’s Note: The 2025 ASCO Gastrointestinal Cancers Symposium (ASCO GI 2025) successfully concluded on January 25, showcasing the latest advances in gastrointestinal cancer research and treatment strategies. One of the most notable studies was the BREAKWATER trial (Abstract #16), which focused on BRAF V600E-mutant metastatic colorectal cancer (mCRC). This study demonstrated a significant improvement in response rates and durable efficacy, positioning EC + FOLFOX as a promising first-line treatment option for this high-risk patient group. The findings also provide further evidence for the role of precision medicine in mCRC, reinforcing the need to integrate targeted therapy into earlier treatment settings.To explore the study’s latest findings and clinical implications, Oncology Frontier invited Dr. Scott Kopetz from MD Anderson Cancer Center to provide an in-depth analysis of the results.
Oncology Frontier: Could you introduce the design and key findings of the BREAKWATER study?
Dr. Scott Kopetz: Based on findings from the BEACON phase III trial (NCT02928224), the combination of encorafenib (a BRAF inhibitor) and cetuximab (an anti-EGFR therapy) (EC) has already been approved for previously treated BRAF V600E-mutant mCRC. However, retrospective studies have indicated that standard first-line chemotherapy offers limited benefits for these patients, with a median progression-free survival (PFS) of around six months and overall survival (OS) barely exceeding one year. The BREAKWATER study (NCT04607421) was designed to explore more effective first-line treatment options to improve outcomes in this high-risk population.
BREAKWATER is a global, open-label, phase III randomized trial evaluating EC ± chemotherapy vs. standard-of-care (SOC) chemotherapy ± bevacizumab as a first-line treatment for BRAF V600E-mutant mCRC. The study assessed the efficacy and safety of EC + FOLFOX (oxaliplatin + leucovorin + 5-FU) vs. SOC chemotherapy, with key endpoints including objective response rate (ORR) (evaluated by blinded independent central review, BICR) and PFS, while OS was a key secondary endpoint. Additional secondary endpoints included duration of response (DOR) and time to response (TTR).
A total of 479 patients were randomized 1:1:1 into three arms: EC, EC+FOLFOX, and SOC. The baseline characteristics were well-balanced across groups, with a median age of 61 years, and ECOG performance status of 0-1. As of the data cutoff (December 22, 2023), the EC+FOLFOX arm demonstrated a clinically and statistically significant improvement in ORR compared to SOC chemotherapy. The ORR was 60.9% vs. 40.0% (OR = 2.443, one-sided p = 0.0008), reaching the co-primary endpoint. The response in the EC+FOLFOX arm was both rapid and durable.
Although OS data remains immature, early results indicate a promising survival benefit for EC+FOLFOX compared to SOC. The incidence of serious adverse events (SAEs) was similar between the two groups, occurring in 37.7% of EC+FOLFOX patients vs. 34.6% in the SOC arm, with no unexpected safety signals.
The BREAKWATER study confirms that EC + FOLFOX significantly improves response rates in BRAF V600E-mutant mCRC, demonstrating rapid and durable efficacy with a manageable safety profile.
Oncology Frontier: How do you evaluate the efficacy of EC+FOLFOX in the BREAKWATER study? What impact do you think these results will have on clinical practice?
Dr. Scott Kopetz: The BREAKWATER trial demonstrates that EC+FOLFOX provides a significant clinical benefit as a first-line treatment for BRAF V600E-mutant mCRC. Compared to standard chemotherapy, this regimen improved the ORR from 40% to 60% and significantly extended response duration. Early OS data also indicate a potential survival advantage.
From a clinical standpoint, these results support the use of EC+FOLFOX as a new first-line treatment option for BRAF V600E-mutant mCRC. Currently, BRAF-targeted therapy is mainly used in later treatment lines, but as more data accumulate, this regimen has the potential to redefine the standard of care in first-line settings.
Furthermore, the BREAKWATER study highlights the importance of precision medicine in oncology, demonstrating that targeted therapy combined with chemotherapy can not only improve response rates but also enhance long-term survival outcomes.
Oncology Frontier: What are the future research directions for EC + chemotherapy combinations following the BREAKWATER study?
Dr. Scott Kopetz: The BREAKWATER trial was designed with multiple study cohorts, and while we have reported findings from the EC+FOLFOX arm, data from the FOLFIRI-based cohort (irinotecan + leucovorin + 5-FU) have yet to be published. Future research will focus on evaluating whether irinotecan-based chemotherapy offers similar or superior clinical benefits compared to FOLFOX.
Additionally, this study aligns with the FDA’s Project FrontRunner initiative, which aims to accelerate the approval of novel cancer treatments in earlier treatment settings. With EC+FOLFOX already demonstrating superior ORR and DOR, long-term survival data will be the next critical focus.
Moving forward, we aim to assess the efficacy of EC-based regimens in different patient subgroups and explore potential combinations with emerging therapies, such as immunotherapy and BRAF-targeted treatments. These ongoing efforts will further refine treatment strategies for BRAF V600E-mutant mCRC, ensuring more effective and durable treatment options for patients.
About Dr. Scott Kopetz
Dr. Scott Kopetz is a medical oncologist and Deputy Chair for Translational Research at MD Anderson Cancer Center. He specializes in the multidisciplinary management and translational research of gastrointestinal cancers and serves as the Program Leader for the MD Anderson Cancer Center Gastrointestinal Cancer Center Support Grant (CCSG). He is also the Chair of the NCI Colon Cancer Task Force and Vice Chair of the NRG Oncology Colorectal Cancer Working Group (formerly NSABP/RTOG/GOG).
The BREAKWATER study represents a major advancement in the first-line treatment of BRAF V600E-mutant mCRC, highlighting the potential of EC+FOLFOX to improve patient outcomes. As more data become available, this regimen could reshape the standard of care, further demonstrating the power of precision medicine in oncology.
