BREAKWATER
AN OPEN-LABEL, MULTICENTER, RANDOMIZED PHASE 3 STUDY OF FIRST-LINE ENCORAFENIB PLUS CETUXIMAB WITH OR WITHOUT CHEMOTHERAPY VERSUS STANDARD OF CARE THERAPY WITH A SAFETY LEAD-IN OF ENCORAFENIB AND CETUXIMAB PLUS CHEMOTHERAPY IN PARTICIPANTS WITH METASTATIC BRAF V600E-MUTANT COLORECTAL CANCER
Phase 3NCT04607421
- Population
- Previously untreated BRAF V600E-mutant metastatic colorectal cancer (excluding MSI-H/dMMR tumours unless ineligible for immune checkpoint inhibitors, and RAS-mutant tumours)
- Design
- Open-label, global, randomised phase 3 trial in previously untreated BRAF V600E-mutant metastatic colorectal cancer, preceded by a safety lead-in. Patients were randomised 1:1:1 to encorafenib plus cetuximab, encorafenib plus cetuximab plus mFOLFOX6, or investigator's choice of standard care; after a protocol amendment the encorafenib-plus-cetuximab arm stopped enrolling and allocation was 1:1 between the other two arms. Dual primary endpoints: objective response (first 110 patients in each of the two arms, reported in the Nature Medicine paper) and progression-free survival, both by blinded independent central review, comparing encorafenib plus cetuximab plus mFOLFOX6 with standard care; overall survival was the key secondary endpoint.
- Primary endpoint
- ORR, PFS
- Arms
- Standard of care (control, n = 243): Investigator's choice of mFOLFOX6, FOLFOXIRI or CAPOX, each with or without bevacizumab
- Encorafenib + cetuximab (experimental, n = 158): Encorafenib plus cetuximab
- Encorafenib + cetuximab + mFOLFOX6 (experimental, n = 236): Encorafenib plus cetuximab plus mFOLFOX6
- People
- Kopetz S
Δ ORR+20.9 pointsΔ median DOR+2.8 monthsOSHR 0.470 (95% CI 0.318–0.691)PFSHR 0.53 (95% CI 0.41–0.68)Δ median PFS+5.7 monthsOSHR 0.49 (95% CI 0.38–0.63)
Show the numbers
| Endpoint | Analysis | Encorafenib + cetuximab / Encorafenib + cetuximab + mFOLFOX6 | Standard of care | Effect |
|---|---|---|---|---|
| ORRObjective response rate analysis set (first 110 patients randomised to each of the two arms; 220 in total)Confirmed objective response rate by blinded independent central review, encorafenib + cetuximab + mFOLFOX6 versus standard care (first dual primary endpoint) | primaryKopetz 2025 | 60.9% | 40% | P=0.0008 (one-sided)Odds ratio 2.443 (95% CI 1.403 to 4.253; 99.8% CI 1.019 to 5.855); 95% CIs 51.6 to 69.5 and 31.3 to 49.3. Analysis set size and data cutoff are from the open-access Nature Medicine full text, not its abstract. |
| DORObjective response rate analysis set (first 110 patients randomised to each of the two arms)Median duration of response, encorafenib + cetuximab + mFOLFOX6 versus standard care (secondary endpoint) | primaryKopetz 2025 | median 13.9 months | median 11.1 months | Reported with the first analysis (Nature Medicine); no confidence intervals in the abstract. |
| OSPatients randomised to encorafenib + cetuximab + mFOLFOX6 or standard care (analysis population not stated in the abstract)Overall survival, first interim analysis (key secondary endpoint) | interimKopetz 2025 | — | — | HR 0.470 (95% CI 0.318–0.691)Reported with the response analysis. The repeated confidence interval was 0.166 to 1.322, so the survival difference was not yet statistically conclusive at this interim; no medians are given in the abstract. |
| PFSAll randomised patients in the two compared arms (stated in the full text, not in the abstract)Progression-free survival by blinded independent central review, encorafenib + cetuximab + mFOLFOX6 versus standard care (second dual primary endpoint) | primaryElez 2025 | median 12.8 months | median 7.1 months | HR 0.53 (95% CI 0.41–0.68)P<0.001The full text gives 95% CI 0.407 to 0.677 and medians with CIs (11.2 to 15.9 and 6.8 to 8.5 months). Population and data cutoff are from the Author accepted manuscript of the NEJM paper (PMC12197837, open access via Europe PMC). |
| OSAll randomised patients in the two compared arms (stated in the full text, not in the abstract)Overall survival, updated interim analysis (key secondary endpoint) | interimElez 2025 | median 30.3 months | median 15.1 months | HR 0.49 (95% CI 0.38–0.63)P<0.001The full text states that 242 deaths (81.5% of the 297 expected for the final analysis) had occurred and gives 95% CI 0.375 to 0.632 for the hazard ratio (Author accepted manuscript of the NEJM paper (PMC12197837, open access via Europe PMC)). |
| Endpoint | Analysis | Encorafenib + cetuximab / Encorafenib + cetuximab + mFOLFOX6 | Standard of care | Effect |
|---|---|---|---|---|
| ORRObjective response rate analysis set (first 110 patients randomised to each of the two arms; 220 in total)Confirmed objective response rate by blinded independent central review, encorafenib + cetuximab + mFOLFOX6 versus standard care (first dual primary endpoint) | primaryKopetz 2025 | 60.9% | 40% | P=0.0008 (one-sided)Odds ratio 2.443 (95% CI 1.403 to 4.253; 99.8% CI 1.019 to 5.855); 95% CIs 51.6 to 69.5 and 31.3 to 49.3. Analysis set size and data cutoff are from the open-access Nature Medicine full text, not its abstract. |
| DORObjective response rate analysis set (first 110 patients randomised to each of the two arms)Median duration of response, encorafenib + cetuximab + mFOLFOX6 versus standard care (secondary endpoint) | primaryKopetz 2025 | median 13.9 months | median 11.1 months | Reported with the first analysis (Nature Medicine); no confidence intervals in the abstract. |
| OSPatients randomised to encorafenib + cetuximab + mFOLFOX6 or standard care (analysis population not stated in the abstract)Overall survival, first interim analysis (key secondary endpoint) | interimKopetz 2025 | — | — | HR 0.470 (95% CI 0.318–0.691)Reported with the response analysis. The repeated confidence interval was 0.166 to 1.322, so the survival difference was not yet statistically conclusive at this interim; no medians are given in the abstract. |
| PFSAll randomised patients in the two compared arms (stated in the full text, not in the abstract)Progression-free survival by blinded independent central review, encorafenib + cetuximab + mFOLFOX6 versus standard care (second dual primary endpoint) | primaryElez 2025 | median 12.8 months | median 7.1 months | HR 0.53 (95% CI 0.41–0.68)P<0.001The full text gives 95% CI 0.407 to 0.677 and medians with CIs (11.2 to 15.9 and 6.8 to 8.5 months). Population and data cutoff are from the Author accepted manuscript of the NEJM paper (PMC12197837, open access via Europe PMC). |
| OSAll randomised patients in the two compared arms (stated in the full text, not in the abstract)Overall survival, updated interim analysis (key secondary endpoint) | interimElez 2025 | median 30.3 months | median 15.1 months | HR 0.49 (95% CI 0.38–0.63)P<0.001The full text states that 242 deaths (81.5% of the 297 expected for the final analysis) had occurred and gives 95% CI 0.375 to 0.632 for the hazard ratio (Author accepted manuscript of the NEJM paper (PMC12197837, open access via Europe PMC)). |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 0.47 | 0.318–0.691 |
| PFS | 0.53 | 0.41–0.68 |
| OS | 0.49 | 0.38–0.63 |
- Encorafenib + cetuximab + mFOLFOX6 (experimental)
- Standard of care (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Encorafenib + cetuximab + mFOLFOX6 | Standard of care |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 9 | 63.8% | 57.0% |
| 17 | 42.8% | 34.6% |
| 26 | 27.3% | 19.7% |
| 35 | 17.5% | 11.2% |
- Encorafenib + cetuximab + mFOLFOX6 (experimental)
- Standard of care (control)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Encorafenib + cetuximab + mFOLFOX6 | Standard of care |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 8 | 64.8% | 45.8% |
| 16 | 42.0% | 21.0% |
| 24 | 27.3% | 9.6% |
| 32 | 17.7% | 4.4% |
Appears in
Sources
Kopetz S, Yoshino T, Van Cutsem E, Eng C, Kim TW, Wasan HS, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025;31(3):901-908.
Elez E, Yoshino T, Shen L, Lonardi S, Van Cutsem E, Eng C, et al. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med. 2025;392(24):2425-2437.