CONFERENCE UPDATE: ASCO 2025

Encorafenib + cetuximab + chemotherapy improves PFS and OS as first-line therapy in BRAF V600E-mutant mCRC: Results from the phase 3 BREAKWATER trial

ONCOLOGY GASTROENTEROLOGY & HEPATOLOGY
04 Sep 2025

STUDY DESIGN

BRAF V600E mutation occurs in approximately 8%-12% of patients with metastatic colorectal cancer (mCRC) and is associated with poor prognosis and limited response to standard chemotherapy-based regimens.1 Encorafenib is a highly selective, ATP-competitive BRAF inhibitor with prolonged pharmacodynamic activity.1 It has been approved for second- or later-line treatment of BRAF V600E-mutant mCRC.1 However, first-line treatment options specific to this aggressive molecular subtype remain limited.1

BREAKWATER is an ongoing, global, phase 3, open-label, randomized trial evaluating the efficacy and safety of encorafenib + cetuximab + chemotherapy as a first-line treatment for previously untreated patients with BRAF V600E-mutant mCRC.1 Eligible participants were adults aged ≥16 years with histologically confirmed metastatic colorectal adenocarcinoma harboring a BRAF V600E mutation, as determined by either local or central laboratory testing.1 All patients were systemically treatment-naïve in the metastatic setting and required measurable disease per RECIST v1.1.1 Additional eligibility criteria included an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate bone marrow, hepatic, and renal function to support protocol-defined treatment.1

A total of 637 patients were enrolled and initially randomized into three treatment arms: encorafenib + cetuximab + mFOLFOX6 (E+C+chemo), encorafenib + cetuximab (E+C) or standard chemotherapy ± bevacizumab (SOC).1 Following a protocol amendment, the E+C arm was closed.1 Subsequently, patients were randomized 1:1 to receive either E+C+chemo (n=236) or SOC treatment (n=243).1 Baseline demographics and disease characteristics were generally well-balanced across treatment arms.1

The dual primary endpoints were progression-free survival (PFS) and objective response rate (ORR).1 Overall survival (OS) was a key secondary endpoint.1

 

FINDINGS

Primary endpoints:
  • The dual primary endpoints were PFS and ORR1
  • At a median follow-up of 16.8 months, patients receiving E+C+chemo had significantly improved median PFS vs SOC (12.8 vs 7.1 months; HR=0.53; 95% CI: 0.407-0.677; p<0.0001), corresponding to a 47% reduction in the risk of progression or death1
  • PFS benefits with E+C+chemo were consistent across all prespecified subgroups, including age, sex, ECOG performance status, primary tumor location and number of metastatic sites1
  • ORR was higher in the E+C+chemo group (65.7%) compared with SOC (37.4%)1
  • A greater proportion of patients achieved a duration of response (DoR) >12 months with E+C+chemo (34.8%) compared to SOC (17.6%), corresponding to nearly a two-fold increase in durable responders with the triplet regimen1

Secondary endpoint:
  • The key secondary endpoint was OS which favored the E+C+chemo group1
  • Median OS was 30.3 months in the E+C+chemo group compared to 15.1 months in the SOC group (HR=0.49; 95% CI: 0.375-0.632; p<0.0001), reflecting a 51% reduction in the risk of death1
  • The OS benefit was consistent across all prespecified subgroups, mirroring the PFS findings and further supporting the generalizability of the treatment effect1

Safety:
  • The duration of treatment was nearly twice as long in the E+C+chemo group compared to SOC, which may account for the higher observed rates of adverse events1
  • Treatment-emergent adverse events (TEAEs) of any grade occurred in most patients across both groups1
  • Grade 3 or 4 TEAEs were reported in 81.5% (E+C+chemo group) and 66.8% (SOC group)1
  • Common AEs included nausea, anemia, diarrhea, and decreased appetite, but there was no substantial increase in treatment discontinuation1
  • The rate of grade 3 or 4 treatment-related adverse events (TRAEs) was 76.3% with E+C+chemo group vs. 58.5% with the SOC regimen1
  • The safety profile was consistent with known toxicities of each individual agents1
  • The addition of E+C to chemotherapy did not result in a substantial increase in chemotherapy dose reductions or treatment discontinuations compared to SOC1
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