BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer.
Authors: Kopetz Scott , Yoshino Takayuki , Van Cutsem Eric , Eng Cathy , Kim Tae Won , Wasan Harpreet Singh , Desai Jayesh , Ciardiello Fortunato , Yaeger Rona , Maughan Timothy S. , Beyzarov Elena , Zhang Xiaoxi , Ferrier Graham , Zhang Xiaosong , Tabernero Josep 
Published: January 2025

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Background:
Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study (NCT02928224). Historically, first-line (1L) treatment of BRAF V600E-mutant mCRC with chemotherapy (chemo) regimens has had limited efficacy.BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating 1L EC with or without chemo vs standard of care (SOC; chemo with or without bevacizumab). Reported here are the primary analysis of objective response rate by blinded independent central review (ORR by BICR; dual primary endpoint [EP]), the first interim analysis of overall survival (OS; key secondary EP), other secondary EPs, and safety for the EC+FOLFOX (oxaliplatin, leucovorin, and 5-FU) vs SOC arms.
Methods:
Eligible patients (pts) had untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0-1. Pts were randomized 1:1:1 to receive EC, EC+FOLFOX, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs were ORR (assessed in the first 110 pts randomized to each of the EC+FOLFOX and SOC arms) and progression-free survival by BICR (EC+FOLFOX vs SOC); OS was a key secondary EP (EC+FOLFOX vs SOC), other secondary EPs included response duration and time to response (TTR).
Results:
Four hundred seventy-nine pts were randomized to the EC+FOLFOX and SOC arms (EC+FOLFOX: n=236; SOC: n=243). Baseline demographics and disease characteristics were similar across arms (median age: 61.0 years; male: 50.5%; ECOG PS 0: 54.3%). At data cutoff (Dec 22, 2023), the EC+FOLFOX arm demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR vs the SOC arm, 60.9% vs 40.0%, odds ratio=2.443, one-sided
P
-value=0.0008, meeting this dual primary EP. The response observed with EC+FOLFOX was rapid and durable. OS data were immature but indicated a sustained survival benefit with EC+FOLFOX vs SOC arm. Serious treatment-emergent adverse events (EC+FOLFOX: n=231; SOC: n=228) occurred in 37.7% vs 34.6% of pts in the respective arms. The safety profile was consistent with that known for each agent.
Conclusions:
BREAKWATER demonstrated a substantially improved response rate that was rapid and durable with EC+FOLFOX in BRAF V600E-mutant mCRC with manageable toxicities and no new safety signals.
Clinical trial information: NCT04607421
.

EC+FOLFOXn=110
SOCn=110

ORR by BICR % (95% CI)
60.9 (51.6, 69.5)
40.0 (31.3, 49.3)

Odds ratio (95% CI)
P
-value
a

2.443 (1.348, 4.380) 0.0008

n=67

n=44

Estimated median response duration by BICR (95% CI), mo
13.9 (8.5, NE)
11.1 (6.7, 12.7)

Pts with a response duration of ≥6 mo, n (%)Pts with a response duration of ≥12 mo, n (%)
46 (68.7)15 (22.4)
15 (34.1)5 (11.4)

Median TTR by BICR (range), weeks
7.1 (5.7-53.7)
7.3 (5.4-48.0)

n=236

n=243

OS (95% CI), mo
NE (19.8, NE)
14.6 (13.4, NE)

Hazard ratio (95% CI)
0.47 (0.318, 0.691)

a
One-sided α=0.001.

NE, not estimable.