Encorafenib/Cetuximab Plus Chemo Viable for Continued Study in BRAF V600E–Mutated mCRC

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Scott Kopetz, MD, discussed the key objectives of the phase 3 BREAKWATER trial being done in patients with BRAF V600E–mutated mCRC, the recently reported safety and efficacy data observed with encorafenib plus cetuximab and chemotherapy, and the importance of conducting biomarker research to further personalize treatment in these patients.

Scott Kopetz, MD

Scott Kopetz, MD

Data from the safety lead-in portion of the phase 3 BREAKWATER trial (NCT04607421) showed that encorafenib (Braftovi) plus cetuximab (Erbitux) paired with mFOLFOX6 or FOLFIRI had an acceptable safety profile and produced response rates that compared favorably with historical data of first-line chemotherapy in patients with BRAF V600E–mutated metastatic colorectal cancer (mCRC), according to Scott Kopetz, MD.1 He added that these data support the regimen’s continued evaluation in this patient population for the phase 3 portion of the trial.

In September 2021, the FDA approved encorafenib plus cetuximab for use in adult patients with BRAFV600E–mutated mCRC based on findings from the phase 3 BEACON CRC trial (NCT02928224).2 With the phase 3 trial, investigators sought to further evaluate the potential synergistic effects of the targeted regimen when combined with cytotoxic chemotherapy backbones. 

Data from the safety-lead in portion of the research were presented at the 2023 Gastrointestinal Cancers Symposium and showed that the regimen had a low rate of dose-limiting toxicities, with only 1 patient in the FOLFIRI cohort experiencing grade 4 neutropenia that lasted for more than 7 days. Treatment-emergent adverse effects (TEAEs) occurred in both the mFOLFOX6 (n = 27) and FOLFIRI (n = 30) cohorts; the rates of grade 3 or higher TEAEs were 77.8% and 50.0%, respectively. Moreover, 18.5% of those receiving mFOLFOX6 vs 20.0% of those receiving FOLFIRI experienced TEAEs that led to discontinuation of any drug.

In the frontline setting, an overall response rate (ORR) of 75.0% (95% CI, 46.8%-91.1%) was seen with encorafenib/cetuximab plus FOLFIRI (n = 12) vs 68.4% (95% CI, 46.0%-84.6%) with encorafenib/ cetuximab plus mFOLFOX6 (n = 19).2 In the second-line setting, these rates were 44.4% (95% CI, 24.6%-66.3%) in the FOLFIRI arm (n = 18) and 37.5% (95% CI, 13.7%-69.4%) in the mFOLFOX6 arm (n = 8).

“These are small numbers, but [they] do [provide us with] enthusiasm [in] that this combination may provide benefit for [these] patients, said Kopetz, who is a professor in the Department of Gastrointestinal (GI) Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, TX. [The data] support the continued enrollment of the phase 3 portion of the BREAKWATER study.”

In an interview with OncLive®, Koptez discussed the key objectives of the phase 3 BREAKWATER trial being done in patients with BRAF V600E–mutated mCRC, the recently reported safety and efficacy data observed with encorafenib plus cetuximab and chemotherapy, and the importance of conducting biomarker research to further personalize treatment in these patients.

OncLive®: Could you speak to the rationale for the BREAKWATER trial?

Kopetz: Patients with BRAF V600E–mutated mCRC have an aggressive tumor [that is] dependent on tumor signaling through the MAPK pathway. Prior work has demonstrated that BRAF inhibition combined with EGFR inhibition blunts tumor feedback mechanisms and improves survival in patients. The combination of encorafenib and cetuximab is a standard of care in second- and third-line [settings]. The hope is that the combination of targeted therapies and cytotoxic chemotherapies can improve the outcomes of these patients, as we have seen with other targeted therapies that synergize well with cytotoxics.

What is the trial design and the key objectives of the research?

The large, randomized, international, phase 3 BREAKWATER study is designed to look at the combination of mFOLFOX6 or FOLFIRI backbone combined with encorafenib and cetuximab [vs] either [a second experimental arm] of encorafenib and cetuximab alone or with a control arm of chemotherapy alone. [The study was performed in] patients [with] previously untreated metastatic disease and a BRAF V600E mutation. The study has 2 components: the safety lead-in, and the [ongoing] randomized phase 3 portion of the study [evaluating] overall survival [OS] and progression-free survival [PFS].

What did the data from the safety lead-in portion of the research show?

[Updated] safety data demonstrate that encorafenib and cetuximab can be combined with both mFOLFOX6 and FOLFIRI with an acceptable safety profile. [The rates of] TRAEs [leading to discontinuation] were approximately 20% in both arms and [were] favorable [compared] with those [observed with] either targeted therapy or cytotoxic chemotherapy alone.

What efficacy data were reported during the meeting?

Efficacy results from these [2 safety] cohorts have also been reported. Although these are small [cohorts with] approximately 30 patients in each, response rates in the first-line setting were between 68% and 75%. [These rates are] favorable compared with historic data [showing] that patients with BRAF V600E–mutated mCRC generally have lower response rates with cytotoxic chemotherapy. [These findings] also compare favorably with the response rate [observed] with encorafenib and cetuximab. Encouragingly, this [regimen] is also associated with prolonged PFS. Both in the first and second line, and with a FOLFOX and a FOLFIRI backbone, we’re seeing the median PFS exceeding 10 months.

What was learned from the circulating tumor DNA (ctDNA) profiling done during the treatment phase of the trial?

Additional biomarker data [were] also reported. One of the emerging [areas of interest] is looking at ctDNA. In patients who have a BRAF V600E mutation, we have a [way to look] at that mutated DNA in circulation and are able to track how that changes with treatment. More than two-thirds of patients treated with chemotherapy combined with encorafenib and cetuximab had complete clearance of their BRAF V600E–mutant DNA in circulation; that is an encouraging sign of efficacy. That doesn’t mean that these tumors are completely eradicated, but that the amount of disease has been driven down below the limits of detection.

What is your take-home message regarding this research?

We’re excited by both the safety and efficacy data from this safety lead-in [portion of the research]. We recognize that this population needs new and innovative strategies. By bringing targeted therapies to [earlier] lines of therapy and combining with the cytotoxic chemotherapy, we hope to harness the biological synergy that may exist with these combinations and improve outcomes [in terms of] responses, PFS, and OS for these patients.

What other data from the meeting would you like to highlight?

We’re always encouraged to see progress made in CRC [treatment]. We are learning more about ctDNA and are encouraged by that progress; this continues to be relevant [theme] for CRC. [Additionally], [we saw] results [from the] phase 3 SUNLIGHT study [NCT04737187,] which showed that bevacizumab [Avastin] combined with trifluridine/tipiracil [TAS-102; Lonsurf] improves OS in a more refractory patient population.


  1. Kopetz S, Yoshino T, Kim T, et al. BREAKWATER safety lead-in (SLI): Encorafenib (E) + cetuximab (C) + chemotherapy for BRAFV600E metastatic colorectal cancer (mCRC). J Clin Oncol. 2023;41(suppl 4):119. doi:10.1200/JCO.2023.41.3_suppl.119
  2. FDA expands Lilly’s Erbitux (cetuximab) label with combination of Braftovi (encorafenib) for the treatment of BRAF V600E mutation-positive metastatic colorectal cancer (CRC) after prior therapy. News release. Eli Lilly and Company. September 29, 2021. Accessed February 3, 2023. https://investor.lilly.com/news-releases
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