BREAKWATER Phase III: results for encorafenib and cetuximab plus mFOLFOX6 in first-line BRAF V600E–mutant metastatic colorectal cancer

ABSTRACT

The BREAKWATER Phase III study investigated encorafenib and cetuximab plus mFOLFOX6 versus chemotherapy with or without bevacizumab for the treatment of patients with previously untreated BRAF V600E – mutant metastatic colorectal cancer. The study showed significantly improved objective response rate by blinded independent central review, and significantly longer progression-free survival by blinded independent central review and overall survival in patients treated with first-line encorafenib and cetuximab plus mFOLFOX6 compared with chemotherapy with or without bevacizumab. The safety profiles were consistent with those known for each agent. These results led to the approval of encorafenib and cetuximab plus mFOLFOX6 for the treatment of BRAF V600E-mutant metastatic colorectal cancer, including in the first line. This paradigm shift in metastatic colorectal cancer highlights the importance for early genomic testing to identify patients who would benefit from this new treatment option. We discuss the results from BREAKWATER – including progression-free survival by blinded independent central review, overall survival, objective response rate by blinded independent central review in all participants, and safety – and the meaning of these results for clinical practice as a new treatment option and the need for earlier genomic testing.

Clinical Trial Registration: www.clinicaltrials.gov identifier is NCT04607421.

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1. Transcript

Josep Tabernero: : What is BRAF V600E-mutant colorectal cancer?

Scott Kopetz: : The BRAF V600E mutation is an activating mutation in the BRAF oncogene that’s found in about 1 in 10 colorectal cancers, depending on the setting. This is a mutation that we’ve known for many years is associated with more aggressive disease and poor prognosis compared to patients without this mutation in colorectal cancer [1].

Elena Élez: : The activity of BRAF inhibitors alone can be attenuated through the rapid pathway feedback activation of EGFR. Therefore, there is a value in a combined approach to circumvent this reactivation. The synergy of targeting BRAF simultaneously with EGFR inhibition has been shown in clinical trials, such as the BEACON study [2–6].

Josep Tabernero: : Actually, the BEACON was a Phase III study that evaluated the combination of encorafenib, a BRAF inhibitor, and cetuximab, an EGFR antibody, in patients who had BRAF V600E-mutant metastatic colorectal cancer and had progressed after previous treatment [6]. The BEACON study supported the synergy of encorafenib and cetuximab, also known as EC, in BRAF V600E-mutant colorectal cancer, and this combination was approved for its use in the second-line and later lines of therapy [7].

Scott Kopetz: : However, there was both preclinical and clinical need to really improve our first-line treatment for the BRAF V600E-mutant metastatic colorectal cancer, really acknowledging that our first-line therapy is not particularly active, and we need to prolong survival earlier in the treatment pathway, due to the limited efficacy that we see. So, this led us to the design and execution of the BREAKWATER study. Elena, can you share a little bit about the BREAKWATER Phase III study?

Elena Élez: : Sure, the BREAKWATER is an ongoing multi-part study. The first part of the study was a safety lead-in to assess the safety of the combination in a small number of participants, and the results of this portion have been reported previously [8,9]. The Phase III portion is evaluating EC, EC in combination with chemotherapy, [modified] FOLFOX6, versus chemotherapy, with or without bevacizumab as a control as a first-line treatment for BRAF V600E-mutant metastatic colorectal cancer [10,11]. EC in combination with another chemotherapy, namely FOLFIRI, is being evaluated in Cohort 3 of BREAKWATER.

Josep Tabernero: : Actually, this summary focuses on the EC plus modified FOLFOX6 arm, and the control arm from the Phase III portion of the BREAKWATER study. This Phase III portion of BREAKWATER enrolled patients with measurable BRAF V600E-mutant metastatic colorectal cancer who had not received pre-systemic treatment for the metastatic disease. The study excluded patients with symptomatic brain metastases, patients with RAS mutations, and patients with microsatellite instability-high/mismatch repair deficient tumors, unless a preexisting medical condition caused them to be ineligible to receive immune checkpoint inhibitors.

Scott Kopetz: : In the EC plus [modified] FOLFOX6 arm, that dosing was encorafenib, 300 milligrams orally once daily, the cetuximab was given at the standard every two-week dose of 500 milligrams per meter squared IV, and then modified FOLFOX6 administered, again, every 2 weeks on a 28-day cycle, using the 85 milligram per meter squared oxaliplatin dose, leucovorin, and 5-FU bolus and infusion, as is typical for this regimen. In the control arm, patients were allowed to receive modified FOLFOX6, FOLFOXIRI, or CAPOX, all with or without bevacizumab.

Elena Élez: : In these two arms, the median age was 61 years, 49% of participants were female, and 42% had an Eastern Cooperative Oncology Group performance status of 1. The majority of participants had tumors that were on the right, and most were microsatellite stable/proficient mismatch repair [11]. So, Dr. Tabernero, what were the efficacy results for encorafenib, cetuximab plus [modified] FOLFOX6?

Josep Tabernero: : The proportion of participants who had their tumor shrink, also known as the objective response rate, was substantially higher with the EC plus modified FOLFOX6 arm versus the control arm, actually 66% versus 37%. The respective 95% confidence intervals were 59 to 71, and 32 to 44. At a median follow-up of 17 months and 10 months for EC plus modified FOLFOX6 versus control, respectively, the risk of progression or death was reduced by 47% with EC plus modified FOLFOX6 versus control, and the median time to progression was significantly longer, 13 months versus 7 months. The p-value was less than 0.001, supporting that this difference was statistically significant [10].

Scott Kopetz: : At a median follow-up of 22 months for both arms, the risk of death was halved with EC plus [modified] FOLFOX6 versus control, and the median survival time was double in the EC plus [modified] FOLFOX6 arm compared to the control arm, going from 30 months, with a confidence interval of 22 to not evaluable, versus 15 months for the control. And likewise, this p-value is also less than 0.001, supporting that this difference was both clinically and statistically significant [10].

Elena Élez: : Furthermore, when looking at subgroups, such as age, sex, and presence of liver metastasis, the clinical benefit of EC [plus modified] FOLFOX6 versus control was consistent. Across all subgroups, the hazard ratios and corresponding 95% confidence intervals were below 1 for both progression-free survival and overall survival. However, as subgroups were small, interpretation of this data should be cautious [10]. Josep, what was the safety profile for EC [plus modified] FOLFOX6?

Josep Tabernero: : The most common side effects were nausea, anemia, diarrhea, decreased appetite, and vomiting; however, most of these side effects were of grade 1 or 2. The most common grade 3 or 4 side effects were neutrophil count decrease, 19% in the EC plus modified FOLFOX6 arm, and 17% in the control arm, so very similar; lipase increase 17% and 6%, respectively; neutropenia 15% and 10%, respectively; and anemia 15% and 4%, respectively. Importantly, no new side effects were reported that were unexpected [10].

Scott Kopetz: : The addition of EC to chemotherapy, modified FOLFOX6, did not substantially increase the proportion of patients who discontinued the chemotherapy portion of treatment due to side effects when compared to the control arm who received the chemotherapy with or without bevacizumab. There was 21% in the EC plus [modified] FOLFOX6 arm, and 17% in the control arm [10]. Elena, what is meaningful about this data for patients with BRAF V600E-mutant metastatic colorectal cancer?

Elena Élez: : This result from BREAKWATER has led to the approval of EC [plus modified] FOLFOX6 to treat BRAF V600E-mutant metastatic colorectal cancer in any line, including in the first line. This upfront treatment is practice-changing and is now a standard of care for these patients.

Josep Tabernero: : Furthermore, this paradigm shift in BRAF V600E-mutant metastatic colorectal cancer poses the importance of early genomic testing. Identifying genomic mutations early, such as BRAF V600E mutations, can ensure that patients receive upfront targeted therapies and have the opportunity to achieve improved outcomes earlier in the treatment pathway.

Scott Kopetz: : Thank you for listening.

Funding Statement

This podcast was funded by Pfizer. The BREAKWATER study that is discussed in this article is sponsored by Pfizer and was conducted with support from ONO Pharmaceutical, Merck KGaA, Darmstadt, Germany, and Eli Lilly and Company. Writing support was provided by Eleanor Porteous, MSc, of Nucleus Global, an Inizio company, and was funded by Pfizer.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14796694.2025.2579882.

Disclosure statement

Scott Kopetz reports stock and other ownership interests with Lylon, Lutris, MolecularMatch, and Navire; consulting or advisory roles for AbbVie, Amal Therapeutics, AstraZeneca/MedImmune, Bayer Health, Bicara Therapeutics, Boehringer Ingelheim, Boston Biomedical, Carina Biotech, Daiichi Sankyo, EMD Serono, Endeavor BioMedicines, Flame Biosciences, Genentech, Gilead Sciences, GSK, HalioDx, Holy Stone Healthcare, Inivata, Ipsen, Iylon, Jacobio, Jazz Pharmaceuticals, Lilly, Lutris, Merck, Mirati Therapeutics, Natera, Novartis, Numab, Pfizer, Pierre Fabre, Redx Pharma, Repare Therapeutics, Servier, and Xilis; and research funding from Amgen, Array BioPharma, Biocartis, Daiichi Sankyo, EMD Serono, Genentech/Roche, Guardant Health, Lilly, MedImmune, Novartis, and Sanofi.

Josep Tabernero reports consulting or advisory roles for Array BioPharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, Daiichi Sankyo, F. Hoffmann-La Roche, Genentech, HalioDx, Hutchison MediPharma, Ikena Oncology, Inspirna Inc., IQVIA, Lilly, Menarini, Merck Serono, Merus, Mirati Therapeutics, MSD, NeoPhore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seagen Inc., Servier, Taiho Pharmaceutical, Tessa Therapeutics, and TheraMyc; and other relationships with Amgen, Array Biopharma, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Cancer Research UK, Celgene, Debiopharm, F. Hoffman-La Roche, Fundación Científica de la Asociación Española Contra el Cáncer, Genentech, HalioDX, Hutchinson Medipharma, Imedex, Janssen-Cilag, MedImmune, Medscape, Menarini, Merck Health KGaA, MJH Life Sciences, MSD, Merus, Mirati, Novartis, Oniria Therapeutics, PeerView Institute for Medical Education, Pfizer, PharmaMar, Physicans’ Education Resource, Sanofi-Aventis, Servier, and Taiho Pharmaceutical.

Elena Élez reports research funding from Pfizer (Inst); consultancy for Agenus, Boehringer Ingelheim, Cureteq, GlaxoSmithKline, Janssen, MSD, Nordic Group BV, Novartis, Pfizer, Repare Therapeutics, RIN Institute Inc., Rottapharm Biotech, Seagen, Takeda; speaker engagement/scientific advisor for Amgen, Merck, Pierre Fabre, sanofi aventis, servier; scientific advisory board for Bayer, F. Hoffmann-La Roche; speaker for Bristol-Myers Squibb Company, Lilly, Medscape, Pfizer; invited speaker for Organon & Co.

Reviewer Disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Scott Kopetz is an investigator of the study, contributed to the interpretation of the results, critically reviewed the article, agreed to the journal to which the article was submitted, and takes responsibility and is accountable for the contents of the article.

Josep Tabernero is an investigator of the study, contributed to the interpretation of the results, critically reviewed the article, agreed to the journal to which the article was submitted, and takes responsibility and is accountable for the contents of the article.

Elena Élez is an investigator of the study, contributed to the interpretation of the results, critically reviewed the article, agreed to the journal to which the article was submitted, and takes responsibility and is accountable for the contents of the article.

All authors were involved in the recording of the podcast.

Pfizer had a role in the study design, data collection and analysis of BREAKWATER, and in the decision to publish and the preparation of this article in collaboration with the authors.