Encorafenib/Cetuximab Plus mFOLFOX6 Provides New SOC for BRAF V600E+ mCRC

Scott Kopetz, MD, PhD, FACP

Following its FDA approval in December 2024, the combination of encorafenib (Braftovi) plus cetuximab (Erbitux) plus mFOLFOX6 (leucovorin, fluorouracil, and oxaliplatin) has emerged as a new mainstay treatment for patients with BRAF V600E–mutated metastatic colorectal cancer (mCRC), supported by early survival signals and improved response rates in the phase 3 BREAKWATER trial (NCT04607421), according to Scott Kopetz, MD, PhD, FACP.1

Updated findings from BREAKWATER reported at the 2025 Gastrointestinal Cancers Symposium showed that the overall response rate (ORR) with encorafenib plus cetuximab and chemotherapy (n = 110) was 60.9% (95% CI, 51.6%-69.5%) per blinded independent central review (BICR) vs 40.0% (95% CI, 31.3%-49.3%) with chemotherapy alone (n = 110; odds ratio [OR], 2.443; 95% CI, 1.403-4.253; one-sided P = .0008).2

Moreover, results from an interim analysis of overall survival (OS) showed that, at a median follow-up of 10.3 months (95% CI, 8.6-11.6), the median OS was not estimable (NE; 95% CI, 19.8 to NE) vs 14.6 months (95% CI, 13.4-NE) in the encorafenib/cetuximab arm vs standard of care (SOC) arm, respectively.

“I’m pleased that this is now a new SOC for this patient population,” Kopetz said in an interview with OncLive®. “We look forward to seeing [data read out for] the other coprimary end point of PFS, as well as the mature OS [data] at future meetings. We have already seen encouraging survival signals, but [statistical] significance has not yet been established.”

During the interview, Kopetz highlighted the rationale for evaluating encorafenib plus cetuximab in BRAF V600E–mutated mCRC, the design of the BREAKWATER study, and key efficacy and safety data with this regimen.

Kopetz is the deputy chair for Translational Research and professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

OncLive: What was the rationale for evaluating encorafenib plus cetuximab in previously treated BRAF V600E-mutant mCRC?

Kopetz: Patients with BRAF V600E–mutated mCRC have poor prognoses. This is a subgroup where the normal SOC does not work well compared with other molecular subtypes. This was the rationale for really taking BRAF V600E–directed therapy with encorafenib and cetuximab and combining that with standard-of-care chemotherapy in the BREAKWATER study.

What were the methods, eligibility criteria, and end points of this study?

The BREAKWATER study is an international, randomized, phase 3 study. [It was] initially designed as a 3-arm study evaluating a SOC arm of investigator’s choice of chemotherapy vs a combination of mFOLFOX6 plus encorafenib and cetuximab, or a chemotherapy-free arm of encorafenib and cetuximab. There were 2 coprimary end points in the study: overall response rate [ORR] and progression-free survival [PFS]. The patient population included previously untreated patients who displayed a BRAF V600E mutation.

What key efficacy data from BREAKWATER were reported at the 2025 Gastrointestinal Cancers Symposium? Did any patient subgroups experience more benefit with this combination?

This study was conducted as part of the FDA’s Project FrontRunner, which is designed to use an early readout—in this case, response rate—to help support an accelerated approval in mCRC.

At the 2025 Gastrointestinal Cancers Symposium, we reported the ORR data and an interim analysis of OS. The data showed that, indeed, the ORR was higher [in the encorafenib plus cetuximab arm] at 60.9% vs 40% for the control [arm]. The odds ratio was 2.4 with a [one-sided] P-value of .008. Importantly, this ORR was associated with a higher duration of response [DOR], both in terms of the median DOR and the 6- and 12-month time frame. At 6 months, the DOR was more than twice in the experimental arm than in the control arm [at 68.7% and 34.1%, respectively]. [The 12-month DOR in the experimental arm] was also more than twice [that of the] control arm, [at 22.4% and 11.4%, respectively.]

This combination was associated with activity across all of the usual prognostic groups, sightedness, extent of location of disease, age, and region, which showed that a higher ORR was seen universally.

As a result of the ORR [data from BREAKWATER], in accordance with the [FDA’s Project FrontRunner], the regimen received approval from the FDA in December 2024.

What do the interim OS findings from BREAKWATER suggest about the long-term survival benefit of encorafenib plus cetuximab in mCRC?

OS [was a] key secondary end point, and [we were] mandated to evaluate it as part of the regulatory plan. As this was an interim [analysis], a very small amount of alpha was expended on this, meaning that the study had to exceed a P value of 8 x 10–8 for the data to be considered statistically significant. Impressively, the HR for OS was 0.47, with a P value of 5 x 10–5.

Although [this interim analysis showed] a compelling early trend [in favor of encorafenib and cetuximab], it did not meet its prespecified [statistical significance]. We look forward to more mature and full survival data later.

What should be known about the agent’s safety profile?

The safety data was very commensurate with what was expected from the individual agents. [Treatment with] encorafenib increased [the incidence of] some low-grade arthralgias, low-grade rashes, and a slightly higher rate of anemia. Overall, the differences in treatment-emergent adverse effects were not statistically or meaningfully different, and there were no differences in the rate of treatment interruptions or discontinuations of the chemotherapy component between treatment arms.

References

1. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed April 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-encorafenib-cetuximab-and-mfolfox6-metastatic-colorectal-cancer-braf
2. Kopetz S, Yoshino T, Van Cutsem E, et al. BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer. J Clin Oncol. 2025;43(4):16. doi:10.1200/JCO.2025.43.4_suppl.16