BREAKWATER Trial Highlights ORR Boost in BRAF V600E mCRC

Microscopic image of colon cancer cell - Generated with Google Gemini AI

Treatment with encorafenib (Braftovi), cetuximab (Erbitux), and mFOLFOX6 chemotherapy (fluorouracil, leucovorin, and oxaliplatin) led to an increase in overall response rate (ORR) vs chemotherapy alone when given to patients with BRAF V600E–mutated metastatic colorectal cancer (mCRC), according to findings from the phase 3 BREAKWATER trial (NCT04607421) presented at the 2025 Gastrointestinal Cancer Symposium.¹

In the encorafenib plus cetuximab and chemotherapy arm (n = 110), the ORR was 60.9% (95% CI, 51.6%-69.5%) per blinded independent central review (BICR) compared with 40.0% (95% CI, 31.3%-49.3%) in the chemotherapy alone arm (n = 110; odds ratio, 2.443; 95% CI, 1.403-4.253; one-sided P = .0008).

The best responses in the experimental arm were complete response (CR; 2.7%), partial response (58.2%), stable disease (28.2%), progressive disease (PD; 2.7%) non-CR/non-PD (2.7%), and not evaluable (NE; 5.5%) compared with rates of 1.8%, 38.2%, 30.9%, 3.6%, 8.2%, and 17.3% in the control arm, respectively.

The median time to response in the encorafenib plus cetuximab and chemotherapy arm was 7.1 weeks (range, 5.7-53.7) vs 7.3 weeks (range, 5.4-48.0) in the chemotherapy arm, and the estimated duration of response (DOR) across groups were 13.9 months (range, 8.5-not evaluable [NE]) and 11.1 months (range, 6.7-12.7), respectively. The 6- and 12-month DOR rates were 68.7% and 22.4% in the experimental arm and 34.1% and 11.4% in the control arm, respectively.

For overall survival (OS), the median follow-up was 10.3 months (95% CI, 8.6-11.6) in the experimental arm and 9.8 months (95% CI, 7.5-11.3) in the control arm. The median OS was NE (95% CI, 19.8-NE) in the encorafenib plus cetuximab and mFOLFOX6 arm vs 14.6 months (95% CI, 13.4-NE) in the mFOLFOX6 alone arm, respectively (HR, 0.47; 95% CI, 0.318-0.691; P = .0000454). At the time of this analysis, the OS difference was not statistically significant.

“The response rate was certainly encouraging, but as part of the pre planned analysis, there was a fairly early interim look at overall survival, and I think that showed really impressive trends to improvement, where we saw an early separation of the survival curves,” explained Scott Kopetz, MD, PhD, FACP, in an interview with Targeted Oncology^TM.

Notably, the FDA granted the combination of encorafenib, cetuximab, and mFOLFOX6 for the treatment of patients with mCRC harboring a BRAF V600E mutation, as detected by an FDA-approved test, in December 2024.²

In the interview for Colorectal Cancer Awareness Month, Kopetz, deputy chair for Translational Research and a professor in the Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine; leader of the Department of Cancer Center Support Grant, GI Program; TRACTION medical director in the Division of Therapeutics Discovery Division; and associate vice president for Translational Integration at The University of Texas MD Anderson Cancer Center in Houston, further discussed the findings and take home points from the phase 3 BREAKWATER trial in metastatic colorectal cancer harboring BRAF V600E mutations.

Scott Kopetz, MD, PhD, FACP

Targeted Oncology: Please explain the background, methods, and design of the BREAKWATER trial.

Kopetz: The BREAKWATER study was a randomized phase 3 study that was run internationally. It was evaluating the efficacy of targeted therapy combined with chemotherapy in patients with metastatic BRAF V600E colorectal cancer. These were microsatellite stable patients that were randomized to 1 of 3 different arms. Encorafenib, cetuximab, and mFOLFOX6, which is the experimental arm, reported out. Additionally, an encorafenib and cetuximab arm will be reported later, and a control arm, or standard-of-care arm where the providers had the opportunity to utilize standard regimens, such as a FOLFOX, bevacizumab (Avastin), FOLFIRI regimen.

What were the key findings from the trial and their significance for patients with BRAF V600E–mutated metastatic colorectal cancer?

The study was a unique new design as part of the FDA project front runner, which had dual primary end points of overall response rate and progression-free survival. The design is part of an initiative to move experimental therapies into the first-line treatment more rapidly to benefit more patients, and as a result, the design is for accelerated approval on the basis of an early look at the response rate and durability of response, that is then converted to a full approval of a regimen based on the other co primary end point of progression-free survival.

In the BREAKWATER study, we saw that the encorafenib and cetuximab arm compared with standard of care was associated with a higher response rate, 60.9% vs 40%, so that was an odds ratio of 2.4 and a P value of .0008. This met the pre-specified end point, was clinically and statistically significant, and importantly, the duration of response was meaningful. We saw that the responses occurred early and were durable, and the duration of response at 6 and 12 months with the experimental arm was double that of the control arm.

Overall, how did the addition of encorafenib to cetuximab and chemotherapy perform in terms of efficacy compared with existing first-line treatments?

The response rate was certainly encouraging, but as part of the pre-planned analysis, there was a fairly early interim look at overall survival, and I think that showed really impressive trends to improvement, where we saw an early separation of the survival curves. The median was not reached in the experimental arm and was 14.3 months in the control arm. The hazard ratio was 0.47 for overall survival, so a really large effect was seen there. The P value was 4.5 x 10^-5.

Now, this was a very early interim and so the amount of alpha that was allotted to this first interim look was very small, and to claim statistical significance at this first look, we needed to have a P value less than 8 x 10^-8. At the current point, we cannot claim that this was statistically significantly different, but certainly [there is] a compelling trend, and we look forward to further updates for the survival data to follow.

Were there any notable safety findings in the trial?

The safety was as expected with individual agents. We know that encorafenib/cetuximab is associated with some arthralgias and rash. These were mostly grade 1 and 2, and there was some increase in anemia, also a kind of a class effect of the regimens. But these were all consistent and very manageable...and no differences in the chemotherapy discontinuation or interruption rates between the 2 arms and the overall safety profile was very manageable.

What do these findings suggest about the importance of targeting BRAF V600E mutations in colorectal cancer, and how might this inform future research?

This is a very encouraging finding that sets a new standard of care for the therapy. This is also supported by the fact that the FDA has recently approved this regimen, so we now have a new standard of care, first-line therapy for this population. I think that really suggests a kind of meaningful improvement in the efficacy. We are continuing to build upon this and understand how tumors are evolving resistance, and we look forward to not only further updates on progression-free survival and overall survival for this population, but also showing better understanding of the molecular features of resistance and thinking about new therapies to follow.

What are the main implications of the findings?

It is exciting to have this new option for patients. I think it does have implications on how we practice in the first line. This really shows us that because patients in the control arm did have access to BRAF therapies on crossover, [it shows that] doing these treatments together in the first line improves outcome, as opposed to sequential administration. That is an important point—that how we administer these certainly makes a difference.

Also, a very practical point is that it tells us that we need to know the BRAF mutation status along with [microsatellite instability] and KRAS status in these patients when they are newly diagnosed. For some patients, that sometimes is a limitation, and that information is not always available. It is a practice pattern that we will need to shift to where we utilize faster turnaround time assays, for example, liquid biopsies, where those are accessible. But I think also changing our pattern, in my practice, is giving a dose or 2 of just FOLFOX alone while we wait for the molecular testing to come back, and then we can appropriately target the right therapies and provide precision treatments for the patients in first line. I am just excited that we have new options for patients, and we look forward to getting more updates on this study in the future.

REFERENCES:

1. 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(supp 4):16. doi:10.1200/JCO.2025.43.4_suppl.16

2. FDA grants accelerated approval to encorafenib with cetuximab and mFOLFOX6 for metastatic colorectal cancer with a BRAF V600E mutation. FDA. December 20, 2024. Accessed February 28, 2025. https://tinyurl.com/3tymxnvj