Announcer:
Welcome to CME on ReachMD. This activity, entitled “Latest Clinical Advances in the Treatment of BRAF V600E-Mutated Metastatic Colorectal Cancer” is provided by AGILE and is supported by an independent educational grant from Merck KGaA, Darmstadt, Germany.
Prior to beginning the activity, please be sure to review the faculty and commercial support disclosure statements as well as the Learning Objectives.
Dr. Kopetz:
The BRAF V600E mutation occurs in approximately 10 to 15 percent of patients with metastatic colorectal cancer, and it’s associated with poor prognosis and quality of life. Subsequent lines of therapy are generally ineffective, leading to rapid disease progression and short overall survival. This is CME on ReachMD, and I’m your host, Dr. Scott Kopetz.
Dr. Van Cutsem:
I’m Eric Van Cutsem. I will be discussing the landscape of change that is occurring in the management of BRAF V600E-mutated metastatic colorectal cancer after first-line treatments.
Dr. Kopetz:
Dr. Van Cutsem, what have been the historical first- and second-line outcomes for patients with BRAF V600E-mutated metastatic colorectal cancer? And why have efforts using BRAF inhibitors failed to be effective in the past?
Dr. Van Cutsem:
This is a difficult-to-treat population. These patients have an aggressive tumor biology and aggressive behavior, and also patients with this mutation, they often do respond worse to standard cytotoxic regimens compared to patients with the BRAF V600E wild-type tumor. Having said that, in ESMO and NCCN guidelines, we came up with recommendations that fit patients – that probably the best treatment is to treat them with a triple FOLFOXIRI plus bevacizumab; in less fit patients, with the doublet FOLFOX plus bevacizumab; and then in second-line with the other doublet FOLFIRI plus an angiogenesis inhibitor. But even with the more aggressive approach with the triplet, the median survivals, the progression-free survival, and the response rates are usually lower in the BRAF V600E mutation compared to the wild-type patients, and the addition of an EGFR antibody to a cytotoxic doublet or triplet in this group of patients with a V600E mutation doesn’t add to the activity of the chemotherapy alone in this setting.
Dr. Kopetz:
And indeed, that’s an important point that I think we can continue to reiterate. So how has this understanding led to new therapeutic directions for these patients?
Dr. Van Cutsem:
Well, there were preclinical studies trying to understand much better the EGFR-RAS-BRAF-MEK pathway. This is an important pathway in colorectal cancer patients with this mutation. And in colorectal cancer patients, it was seen that there was no activity of a BRAF inhibitor alone. And then there were some preclinical data that looked at tackling the pathway at different levels because we have understood in the meantime that there are feedback loops, crosstalks. And then with inhibition of this pathway at different levels, EGFR, BRAF, and eventually also MEK, it was seen in colorectal cancer preclinical studies that the inhibition of the pathway led to a higher activity. This led to the development of the concept of tackling the EGFR-RAS-RAF-MEK-MAP kinase pathway at different levels.
Dr. Kopetz:
And that really set the stage for an explosion of studies that led to the BEACON trial, which was really designed to demonstrate and prove the activity of the EGFR and BRAF or the EGFR, BRAF, and MEK combination.
So Dr. Van Cutsem, now let’s focus on those initial findings of the BEACON study, looking at both the triplet with the MEK inhibitor as well as the doublet with the BRAF and EGFR alone that were tested in a second-line BRAF V600E-mutated metastatic colorectal cancer. Can you walk us through the study design and the results?
Dr. Van Cutsem:
We designed a randomized open-label phase 3 study in second-line or third-line in patients with a BRAF V600E mutation, so progressive after one or two prior regimens of chemotherapy, good general condition, good performance status, good organ function. And there was a randomization of the standard treatment FOLFIRI or irinotecan in combination with cetuximab first as a doublet encorafenib-cetuximab, first as a triplet of the BRAF inhibitor encorafenib, the MEK inhibitor binimetinib, and cetuximab. Six hundred sixty-five patients were included in this study and randomly assigned 1:1:1 for one of these three treatment arms. And primary endpoint of the trial was the survival of the triplet versus the control. And looking at the initial results, the first reports of the phase 3 studies, we’ve shown that the overall survival of triplet was 9 months versus 5.4 months for the control with the hazard ratio for survival of 0.52 and the confirmed overall response rate of 26% for the triplet versus 2% for the control arm. When we looked also at the activity of the doublet encorafenib-cetuximab, the median survival for encorafenib-cetuximab was 8.4 months versus the earlier mentioned 5.4 months for the control arm, and the hazard ratio for survival was 0.6 and the response rate for the doublet was 20%, again, compared to 2% for the control arm. What we also saw is that toxicity, although generally quite manageable, for the triplet was a bit higher than for the doublet. There were a bit more grade 3 adverse events. They occurred in 58% of patients with the triplet therapy and in 50% for the doublet therapy. And this compared favorably, if you look at the numerical differences but also at the type of adverse events, with control group where 61% of the patients had grade 3 adverse events. So based on these initial results, we concluded that the new targeted treatments with encorafenib, cetuximab plus or minus binimetinib were more active than cetuximab plus irinotecan-based chemotherapy in patients with a BRAF V600E mutation second- or third-line. And although formally speaking we could not compare the triplet versus the doublet, numerically, it seemed at the initial analysis that there was a small benefit for the triplet versus the doublet in this setting, but we concluded also that longer-term follow-up was needed to make these statements.
Dr. Kopetz:
Thank you, and I think these initial results are really very encouraging and provided that initial prespecified look at the overall survival endpoint.
For those of us just joining us, this is CME on ReachMD. I’m Dr. Scott Kopetz, and I’m here today with Dr. Eric Van Cutsem. Together we’re discussing the changing landscape of treatment for BRAF V600E-mutated metastatic colorectal cancer.
So with this interim data from BEACON – the trend in superior outcomes for the triplet – with additional updated analysis, how did that message change?
Dr. Van Cutsem:
Well in longer follow-up, we had some further refinements of the data, and the updated survival analysis, it was clear that the doublet seems to be as good as the triplet. Indeed, the overall survival for the doublet encorafenib-cetuximab was 9.3 months versus 5.9 months for the control arm. And when we look at the triplet median overall survival, it’s identical; the curves overlap completely. It was also 9.3 months versus 5.9 months for the control arm, and the hazard ratio for survival were, respectively, 0.61 and 0.60. So, it seems that with the longer-term follow-up, there was no extra benefit if we look at all comers in the trial for the triplet versus the doublet compared to the standard treatment. However, when we look at further subgroup analysis, the forest plots, we can see that the patients with the poorer performance status, but still an ECOG PS 1, at least three organs involved with metastasis, patients with a higher baseline CRP, or patients with partially resected or unresected disease, that these patients seem to have a bit more benefit – numerically more benefit. There was no statistical difference for the triplet versus the doublet, so we have to look into the future because there are clearly some patients who needed the triplet. But having said that, today the approved treatment by FDA as well as EMA in Europe is a doublet encorafenib-cetuximab for patients with with BRAF V600E mutation who are treated with chemotherapy.
Dr. Kopetz:
It really is the new standard of care for these patients, and as you say, it’s really been adopted by many regulatory agencies. But I’m still intrigued by this potential that there are a subgroup of patients that derive some benefit with the addition of the MEK inhibitor, and I think we have to be careful because there is some slightly higher GI toxicity and some anemia that’s related to the to the known on-target toxicities of the MEK inhibitor.
So now that we have an understanding of outcomes from the BEACON trial, it may be a good time to introduce some of the first-line trials such as the ANCHOR trial in BRAF V600E-mutated metastatic colorectal cancer. Can you share what we know about the ANCHOR trial and subsequent first-line efforts?
Dr. Van Cutsem:
The ANCHOR trial is a first-line treatment of patients with BRAF V600E mutation where we looked at the activity and safety in patients of these triplets in the first-line treatment, so patients not pretreated with chemotherapy. We have reported at ESMO GI recently the first results of this first cohort in this trial, around 40 patients showing that close to 50% of patients had an objective response. This trial includes around 100 patients in the non-randomized setting. It is planned to see whether it’s feasible to treat these patients in the first-line in order to design an upcoming randomized phase 3 trial in patients with metastatic disease.
Dr. Kopetz:
I think we’ll learn a lot from the ANCHOR study, but also the idea of how to combine this with chemotherapy, I think, is a compelling question as well. And this so-called BREAKWATER study, as the name has now been laid to the upcoming phase 3 study with chemotherapy, I think, will really provide a good opportunity to match aggressive therapy with an aggressive disease.
As we come to the close of our discussion today, Dr. Van Cutsem, what are your key take-home messages for your colleagues?
Dr. Van Cutsem:
Well, there is an important take-home message after this experience. One, we are making progress in the field of personalized treatment. The subgroup of patients with a BRAF V600E mutation are a challenging subgroup of patients. It’s clear that we have a new standard treatment. It’s approved by FDA, EMA to make it into the different guidelines for these patients of cetuximab-encorafinib plus or minus binimetinib, and that’s an important step in the further individualized, personalized treatment of these patients. This is a pivotal practice-changing trial, and that’s why it was published also in The New England Journal of Medicine.
Dr. Kopetz:
I think the other message that’s important to relay is this is something that we should be testing for as a standard in all of our patients. Really understanding the BRAF mutation status of our patients is critical for identifying the right treatments moving forward. And I think that the second point is this discussion’s really related to the BRAF V600E mutation. There are other BRAF mutations that have very different biology, but this more common V600E mutation is really where we see the benefit from data such as BEACON. And I’m encouraged to really see where the BEACON study takes us. I am very excited to see new studies for these patients coming in the near future.
That brings us to the end of our discussion. I want to thank my guest, Dr. Eric Van Cutsem, for joining me and for sharing his insights on the changing landscape of treatment for second-line BRAF V600E-mutated metastatic colorectal cancer. Dr. Van Cutsem, it was great speaking with you today.
Dr. Van Cutsem:
And Dr. Kopetz, Scott, it’s always a pleasure to discuss and to interact with you also. Thank you very much.
Announcer:
You have been listening to CME on ReachMD. This activity is provided by AGILE and is supported by an independent educational grant from Merck KGaA, Darmstadt, Germany.
To receive your free CME credit, or to download this activity, go to ReachMD.com/AGILE. Thank you for listening.
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