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ASCO 2025 | BREAKWATER: PFS & OS results of encorafenib, cetuximab & mFOLFOX6 in mCRC
Scott Kopetz, MD, PhD, FASCO, The University of Texas MD Anderson Cancer Center, Houston, TX, comments on progression-free survival (PFS) and updated overall survival (OS) findings from the BREAKWATER trial (NCT04607421) of encorafenib plus cetuximab with or without mFOLFOX6 in previously untreated BRAF V600E-mutant metastatic colorectal cancer (mCRC). The triplet regimen significantly improved progression-free and overall survival, with a manageable safety profile. These findings support encorafenib plus cetuximab and mFOLFOX6 as a potential new standard of care in this population. This interview took place during the 2025 American Society of Clinical Oncology (ASCO) Meeting in Chicago, IL.
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Transcript
So the BREAKWATER study is looking at a patient with metastatic BRAF V600E mutated colorectal cancer. This is a population that historically has had a very poor outcome and standard cytotoxic chemotherapy is considered the standard of care in this setting. The BREAKWATER study is a Phase III study investigating first-line encorafenib and cetuximab in combination with chemotherapy in this population...
So the BREAKWATER study is looking at a patient with metastatic BRAF V600E mutated colorectal cancer. This is a population that historically has had a very poor outcome and standard cytotoxic chemotherapy is considered the standard of care in this setting. The BREAKWATER study is a Phase III study investigating first-line encorafenib and cetuximab in combination with chemotherapy in this population. It was a three-arm study looking at a control cytotoxic chemotherapy control arm of FOLFOX, FOLFIRI, or FOLFOX with bevacizumab with a comparator arm of encorafenib, cetuximab, and FOLFOX. There was also a second arm, or our second experimental arm, the encorafenib and cetuximab alone without the cytotoxic therapy. We previously reported out at ASCO GI, a higher response rate with the encorafenib, cetuximab, and FOLFOX compared to control arm. That was updated with 66% response rate versus a 37% with the standard of care. The EC alone actually had a very respectable 46% response rate, in a chemotherapy-free regimen. Importantly, the co-primary endpoint of progression-free survival was reported with an improvement from 7.1 months to 12.8 months between standard of care and the EC FOLFOX. And in a very compelling finding, the overall survival was doubled, median of 15.1 to 30.3 month median overall survival. So hazard ratio of survival of 0.49 for this regimen. The EC arm was active and did have an intermediate survival between the standard of care and the EC FOLFOX. But for patients who may not be able to tolerate a cytotoxic chemotherapy. This was a regimen that was well tolerated. The side effects were consistent with the individual components and now represents a new standard of care for this population. So the finding of improved overall survival, progression-free survival, and response rate in patients with EC and FOLFOX is very compelling. And this is especially compelling because patients had access to EC after progression of the control arm. And so, you know, 72% of patients that were treated in second line and beyond the control arm received targeted therapy, most typically you see. And so in that setting, this really shows that how and when you administer therapy really does matter.
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