BREAKWATER
Trial question
What is the role of encorafenib plus cetuximab with chemotherapy in the management of patients with BRAF V600E-mutated metastatic CRC?
Study design
Multi-center
Open label
RCT
Population
Characteristics of study participants
49.0% female
51.0% male
N = 479
479 patients (237 female, 242 male).
Inclusion criteria: adult patients with untreated BRAF V600E-mutated metastatic CRC.
Key exclusion criteria: previous receipt of systemic treatment for metastatic disease; previous receipt of a BRAF or EGFR inhibitor; symptomatic brain metastases; MSI-H, dMMR tumors; KRAS mutation.
Interventions
N=236 EC+mFOLFOX6 (oral encorafenib 300 mg/day plus intravenous cetuximab 500 mg/m² once every 2 weeks, along with oxaliplatin, leucovorin, and fluorouracil once every 2 weeks in a 28-day cycle).
N=243 standard care (investigator's choice of chemotherapy).
Primary outcome
Median progression-free survival
12.8 months
7.1 months
12.8 months
9.6 months
6.4 months
3.2 months
0.0 months
EC+mFOLFOX6
Standard
care
Significant
increase ▲
Significant increase in median progression-free survival (12.8 months vs. 7.1 months; HR 1.89, 95% CI 1.47 to 2.44).
Secondary outcomes
Significant increase in median overall survival (30.3 months vs. 15.1 months; HR 2.04, 95% CI 1.59 to 2.63).
Safety outcomes
No significant difference in adverse events.
Conclusion
In adult patients with untreated BRAF V600E-mutated metastatic CRC, EC+mFOLFOX6 was superior to standard care with respect to median progression-free survival.
Reference
Elena Elez, Takayuki Yoshino, Lin Shen et al. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med. 2025 May 30. Online ahead of print.
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