A phase III BREAKWATER study has met one of its dual primary endpoints demonstrating a statistically significant and clinically relevant benefit in objective response rate (ORR) by blinded independent central review with encorafenib plus cetuximab plus mFOLFOX6 versus standard-of-care (SOC) in first-line treatment for patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC).
Prespecified analyses of mature progression-free survival (PFS) and overall survival (OS) data are planned. The findings were presented at the 2025 ASCO GI Cancer Symposium along with a simultaneous publication by Dr. Scott Kopetz of the University of Texas MD Anderson Cancer Center in Houston, TX, US and colleagues on 25 January 2025 in the Nature Medicine.
The authors wrote in the background that BRAF V600E mutations occur in 8-12% of mCRCs; the presence of these mutations has emerged as a distinct subtype that is characterised by poor prognosis compared with wild-type disease and resistance to standard chemotherapy regimens. Encorafenib plus cetuximab is approved for previously treated BRAF V600E-mutated mCRC based on results from the BEACON study. However, there are currently no first-line activation pathway-targeted treatments indicated for patients with BRAF V600E-mutated mCRC.
BREAKWATER is a phase III study evaluating encorafenib plus cetuximab with or without standard mFOLFOX6 chemotherapy versus SOC, investigator’s choice of chemotherapy with or without bevacizumab for the first-line treatment of patients with BRAF V600E-mutated mCRC. Data from the safety lead-in portion demonstrated encouraging response rates and PFS of encorafenib and cetuximab with chemotherapy (mFOLFOX6 or FOLFIRI).
The study team reported in the paper published in the Nature Medicine one of the dual primary endpoints, ORR and the first interim analysis of OS, duration of response (DoR), time to response and safety in the encorafenib plus cetuximab plus mFOLFOX6 and SOC arms from the phase III portion.
The second dual primary endpoint, PFS, is event driven; the required number of events needed for analysis had not yet been achieved and will be reported later. Additional planned secondary endpoints not reported are progression after next line of therapy, patient-reported outcomes, pharmacokinetics and biomarker endpoints.
BREAKWATER met one of dual primary endpoints of ORR, demonstrating significant and clinically relevant improvement with encorafenib plus cetuximab plus mFOLFOX6, 60.9% versus 40.0% with SOC (odds ratio 2.443, 95% confidence interval [CI] 1.403-4.253; 99.8% CI 1.019-5.855; one-sided p = 0.0008).
Median DoR was 13.9 versus 11.1 months. The percentage of patients with a DoR beyond 6 or 12 months approximately doubled in the encorafenib plus cetuximab plus mFOLFOX6 arm compared with the SOC arm.
At this first interim analysis of OS, the hazard ratio was 0.47 (95% CI 0.318-0.691; repeated CI 0.166-1.322). However, 16.9% of patients in the encorafenib plus cetuximab plus mFOLFOX6 arm and 29.6% of patients in the SOC arm had an event at data cut-off for this first interim analysis and did not achieve the prespecified statistical significance.
Serious adverse event rates were 37.7% versus 34.6%. The safety profiles were consistent with those known for each agent. Patients in the encorafenib plus cetuximab plus mFOLFOX6 arm had a longer duration of treatment and maintained high relative dose intensities. The addition of encorafenib plus cetuximab to chemotherapy was generally tolerable without significant increase in chemotherapy dose reduction or discontinuation.
BREAKWATER is ongoing and once the required number of events specified in the protocol have occurred, the primary analysis of PFS, the other dual primary endpoint, will be conducted and subsequently reported. Future biomarker analyses of the BREAKWATER study may shed light on the resistance mechanism by comparing chemotherapy plus targeted therapy versus chemotherapy or targeted therapy alone.
The authors commented that BREAKWATER excluded patients with MSI-H or dMMR tumours unless ineligible to receive immune checkpoint inhibitors due to a preexisting medical condition. Pembrolizumab has shown clinical benefit as a first-line therapy for MSI-H or dMMR mCRC. SEAMARK is an ongoing phase II study evaluating first-line encorafenib plus cetuximab with pembrolizumab versus pembrolizumab alone in patients with BRAF V600E-mutated and MSI-H/dMMR mCRC.
The phase III portion of BREAKWATER only investigated encorafenib plus cetuximab in combination with mFOLFOX6. The safety lead-in portion evaluated encorafenib plus cetuximab plus mFOLFOX6 or FOLFIRI in a small number of patients and showed encouraging results. BREAKWATER is further evaluating encorafenib plus cetuximab plus FOLFIRI versus FOLFIRI with or without bevacizumab in the ongoing cohort III portion.
The authors concluded that BREAKWATER showed substantially improved clinical benefit with encorafenib plus cetuximab plus mFOLFOX6 as a first-line treatment for patients with BRAF V600E-mutated mCRC. These encouraging data support this regimen to potentially become the new SOC in patients with BRAF V600E-mutated mCRC.
References
- Abstract 16: Kopetz S, Yoshino T, Van Cutsem E, et al. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. 2025 ASCO GI Cancer Symposium; 23-25 January 2025, San Francisco, CA, USA.
- Kopetz S, Yoshino T, Van Cutsem E, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nature Medicine; Published online 25 January 2025. DOI: https://doi.org/10.1038/s41591-024-03443-3