BREAKWATER

During the 2025 annual ASCO GI meeting, Prof Scott Kopetz, medical oncologist at the MD Anderson Cancer Center in Houston, shared the first results of the randomized phase III BREAKWATER trial. In this video, Prof Kopetz shares the key take-aways from this presentation with Prof Em Eric Van Cutsem, digestive oncologist at the University Hospitals Leuven.

In BREAKWATER, 637 patients with BRAF^V600-mutant metastatic colorectal cancer (mCRC) who did not yet receive systemic therapy for their metastatic disease, were randomly assigned to receive, encorafenib plus cetuximab (EC), EC in combination with mFOLFOX6, or standard of care (SoC) therapy, consisting of mFOLFOX6, FOLFOXIRI, or CAPOX +/- bevacizumab. The study has two dual primary endpoints consisting of progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review (BICR). During ASCO GI 2025, results for ORR were presented.

Interestingly, adding EC to chemotherapy significantly improved the ORR from 40.0% with SoC to 60.9% with EC + mFOLFOX6 (OR[95%CI]: 2.443[1.403-4.253]). Responses to EC + mFOLOF6 were also more durable than what was seen in the control arm, with rates of patients with an ongoing response at 6 and 12 months of 68.7% vs. 34.1% and 22.4% vs. 11.4%, respectively. This benefit was seen across all investigated subgroups, irrespective of age, gender, ECOG performance status, the number of involved sites at baseline, tumor side and the presence of liver metastases. Importantly, an early interim analysis for overall survival (OS) shows a clear trend for a better OS with EC + mFOLFOX6 compared to SoC, with a 1-year OS rate of 79.5% and 66.1%, respectively. However, the corresponding p-value of 0.0000454 did not yet cross the very stringent threshold for significance at this interim analysis (p < 0.000000083).

The clinical benefit obtained with the addition of EC to mFOLFOX6 did not come at the cost of an excessive amount of added toxicity. The most notable differences in safety profile between mFOLFOX6 and SoC were a higher rate of grade ≥3 anemia (10.8% vs. 3.5%), grade ≥3 neutropenia (14.7% vs. 9.2%) and all-grade arthralgia (21.2% vs. 3.5%).

For Prof Kopetz and Prof Van Cutsem, these findings, which were simultaneously published in Nature Medicine, have the potential to be practice changing. However, some questions still need answering. For example, what would be the way to go in MSI-high patients with a BRAF^V600 mutation? Should we go for immunotherapy or EC + mFOLFOX6 in the first line treatment of these patients? Is it feasible to opt for EC + mFOLFO6 in patients who suffered a rapid relapse after adjuvant therapy with FOLFOX, or is it wiser to opt for EC alone, or a combination of EC with FOLFIRI in these patients? Further results of BREAKWATER and other studies will likely provide an answer to these and other questions in the years to come.