Delving Into the Braftovi Plus Erbitux FDA Approval for BRAF+ mCRC

Treatment with Braftovi (encorafenib) and Erbitux (cetuximab) plus chemotherapy demonstrated responses in patients with metastatic colorectal cancer with a BRAF V600E mutation, according to Dr. Cathy Eng, co-Director of GI Oncology; co-leader of the GI Cancer Research Program and director of the Young Adult Cancers Program at Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, located in Nashville, Tennessee.

These responses were generated in patients studied on the BREAKWATER trial which investigated the combination, ultimately leading to the treatment combinations United States Food and Drug Administration (FDA) approval in this population in December 2024. In order to further five into this regulatory approval, Eng sat down for an interview with CURE.

She also currently serves as the David H. Johnson Endowed Chair in Surgical and Medical Oncology; a professor of Medicine, Hematology and Oncology; and director for Strategic Relations, at Vanderbilt University Medical Center.

CURE: Can you please provide some background information on the breakwater study and the investigative combination that was evaluated?

Eng: Just to give you some perspective of our metastatic colorectal cancer patient population, the presence of the BRAF V600E mutation has historically been associated with a poor prognosis in our MSI-stable patient population.

Previously, the addition of Braftovi, a BRAF inhibitor, plus Erbitux, an anti-EGFR inhibitor, in the previously treated setting, had already received FDA approval. This was based on improved overall survival compared with standard chemotherapy in the second or third-line setting. That survival was about 9.3 months, leading to the FDA approval of the doublet of Braftovi and Erbitux to provide a more tailored approach to our BRAF-mutated patients.

Now, these patients tend to have very metastatic disease, and we obviously want to help them as much as possible because they can become very symptomatic if not treated early on. So, how can we improve upon that original FDA indication? That is the purpose of the BREAKWATER trial.

The purpose of the BREAKWATER trial is to take that doublet of Braftovi and Erbitux and look at it in combination with chemotherapy to see if it's actually better than chemotherapy alone. The original study design also included one arm with the doublet by itself, but that was eventually discontinued. The main portion of the trial really focuses on chemotherapy with the FOLFOX or FOLFIRI (fluorouracil, leucovorin, oxaliplatin or irinotecan) backbone plus Braftovi and Erbitux. Is that better than standard chemotherapy?

You should be aware that a FOLFOXIRI arm was also added, and that trial has finished enrollment. We don't have those results yet. So, the purpose of the BREAKWATER FDA's new indication is the addition of chemotherapy in treatment-naive patients with a BRAF V600E mutation in their metastatic colorectal carcinoma, using oxaliplatin-based therapy (FOLFOX) or FOLFIRI plus Braftovi and Erbitux.

It showed an improved response rate, as well as, at the interim analysis, what looks like improved overall survival. So that is the new recent indication. The response rate was quite high, 60% versus 40%, so we are quite impressed with that. Once again, we are really trying to provide our best options for these patients who have a much more aggressive tumor type, which historically has resulted in poor overall survival.

What is the importance of this FDA approval for patients with this specific subset of colorectal cancer?

It's really important for our providers at all centers. This is now a primary option that should be considered for all patients with the BRAF V600E mutation. I presume it will eventually also receive EMA (European) approval, as well as international approval in general.

Really, chemotherapy plus Braftovi and Erbitux can make a significant difference, versus just waiting for the second or third-line setting to utilize the doublet. If you can utilize [the doublet] in the first-line setting, I think it's completely appropriate, and it has resulted in improved response rates, and at least based on the interim overall survival data presented at ASCO GI in 2025, we believe that this is the best approach at this time.

Once again, the FOLFOXIRI backbone has completed enrollment. We do not have those final results, but I wouldn't be surprised if they are very similar. This is because the whole intent is: can the addition of chemotherapy to the doublet improve the overall outcomes?

With the objective response rate being approximately 61% in the treatment arm, how should patients interpret that number in terms of expected benefits or symptom improvement?

Well, in my experience, this often leads to patients having very diffuse disease, and they can be very symptomatic, whether due to tumor pain, loss of appetite, or generalized weakness. So, a response rate of 60.9% versus 40% — a difference of approximately 21% — could obviously significantly improve the quality of life for our patients, I believe.

If you are reducing the tumor burden, this may potentially reduce tumor pain, at least based on my own anecdotal experience with my patients who participated in this original trial.

Can you explain how this treatment may differ from what's been available in the past?

Historically, for BRAF V600E mutated tumor types, we would normally just provide them with standard chemotherapy, whether it's a 5-FU-based treatment with either oxaliplatin or irinotecan, or, if you want to be very aggressive, a FOLFIRI regimen.

There was some earlier data suggesting that the FOLFIRI regimen, which is a very aggressive regimen and has the highest response rate of all the chemotherapy regimens, might be the best option. However, the data for that trial was not specifically powered for the BRAF mutation.

It is really hard to definitively say whether that is the best approach. I always make sure to assess your patient, look at their performance status, look at their other comorbidities, and decide whether it is appropriate to proceed with FOLFOX or FOLFIRI versus the more aggressive FOLFIRI regimen. So, getting back to your question, just standard chemotherapy would typically be offered to these patients.

How do these medications work together, and what should patients expect in terms of treatment, scheduling and monitoring?

Well, the schedule doesn't change; it's still every two weeks, aligning with the standard chemotherapy schedule. So, that's not an issue. Obviously, whenever you have a combination of drugs, you're more likely to experience some additional toxicities, but I think none of these toxicities were unexpected.

We are very well aware that with any EGFR therapy, you are likely to develop a rash. So, I want to emphasize the importance of educating the patient early on about skin care and photosensitivity, so some hypersensitivity to sunlight. All of our patients on any chemotherapy during the summer and spring months should wear sunscreen, as they are more prone to sunburn. Additionally, there can be a higher potential for diarrhea. So, it's really important, once again, to focus on the supportive management of these patients with anti-nausea and anti-diarrheal medications.

Because the regimen is every two weeks, I would highly encourage physicians to really ensure they evaluate patients for any treatment-related toxicities and address them early on. However, the benefit of this regimen, I think, far exceeds any potential toxicities, as long as the patient communicates well with you, and you follow these patients closely.

Since this approval is based on early results from the BREAKWATER trial, what are some next steps in confirming long term benefits within this population?

I would just say, you know, stay tuned. There will be updates regarding this trial. And, you know, at the end of the day, we obviously want to continue to follow these patients’ long term and analyze any additional data to ensure that we are sharing this information with patients and their providers to optimize the overall benefit for our patient population.

As I stated, there is still an additional arm, the FOLFIRI-based arm, for which we are still awaiting results as well. So, I look forward to seeing those results.

This really emphasized the importance of molecular testing. The BRAF V600E mutation affects less than 10% of our patient population, about 9% I would say. The majority of individuals are currently being tested, but it's not 100%. I think when healthcare professionals meet a new patient, they tend to provide very standard chemotherapy regimens and then just order the next generation sequencing as needed.

I would say as soon as you meet any new patient, get the next-generation sequencing completed, definitely for both blood and tissue. The blood turnaround time for next-generation sequencing is very short, usually seven to ten days.

There is no reason why you can't start chemotherapy for one cycle if you feel the patient is very symptomatic and needs immediate treatment, but make sure you order those next-generation sequencing tests early on so you can have those results quickly. Then, if the patient has the BRAF V600E mutation, you can incorporate the addition of Braftovi and Erbitux or panitumumab, depending on your location in the country regarding the EGFR component.

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