Targeted Therapy Wins Big for BRAF-Mutated Metastatic CRC

Medscape

05-06-2025

The latest results from the BREAKWATER trial have confirmed encorafenib plus cetuximab with chemotherapy as the new first-line standard of care for BRAF V600E-mutant metastatic colorectal cancer (CRC), according to research presented at the American Society of Clinical Oncology (ASCO) 2025 annual meeting.
At the interim analysis, encorafenib plus cetuximab with mFOLFOX6 chemotherapy doubled median overall survival compared with the current standard of care — investigators' choice of chemotherapy with or without bevacizumab.
In addition, at a median follow-up of 16.8 months, the new treatment regimen led to a significant improvement in median progression-free survival of almost 6 months.
This survival finding is 'unprecedented' and 'practice changing' for these patients who historically have a poor prognosis, said lead investigator and presenter Elena Élez, MD, PhD, a gastrointestinal medical oncologist at the Vall d'Hebron University Hospital in Barcelona, Italy. The study was published in The New England Journal of Medicine to coincide with Élez's presentation.
BRAF mutations, which occur in up to 12% of patients with metastatic CRC, are associated with poor outcomes. In December 2024, the US Food and Drug Administration (FDA) granted accelerated approval for the BRAF inhibitor encorafenib alongside cetuximab and mFOLFOX6 for patients with metastatic CRC and a BRAF V600E mutation. This approval was based on earlier results from BREAKWATER that showed a 21% higher objective response rate and a longer duration of response with this regimen.
The accelerated approval means that this regimen has already been making its way into the clinic, but 'we were all waiting for this [latest] data,' Pamela Kunz, MD, chief of Gastrointestinal Medical Oncology at Yale University in New Haven, Connecticut, told Medscape Medical News . The doubling of overall survival 'is a big deal,' she said.
In the trial, patients were randomly assigned to receive either first-line encorafenib plus cetuximab with mFOLFOX6 (n = 236) or to a control group — physician's choice of either mFOLFOX6, FOLFOXIRI, or CAPOX chemotherapy (n = 243). Most patients in the control arm also received the tumor angiogenesis inhibitor bevacizumab.
The broad options in the control arm speak to how heterogeneous treatment has been for BRAF V600E-mutant metastatic CRC, said study discussant Andrea Sartore-Bianchi, MD, a medical oncologist at the University of Milan, Milan, Italy.
Patients in the trial had received no prior systemic therapy for metastatic disease. Investigators excluded patients with high levels of microsatellite instability because they are candidates for immunotherapy.
At a median follow-up of 16.8 months, median progression-free survival was 12.8 months for the encorafenib group compared with 7.1 months for the control group (hazard ratio [HR], 0.53; P < .0001).
At a median follow-up of 22 months, overall survival was 30 months in the encorafenib group compared with 15 months in the control group (HR, 0.49; P < .0001).
The benefits of the combination were held up in high-risk subgroups, including in patients with liver metastases and those with metastases in three or more organs.
With the use of more agents and a longer duration of treatment due to improved efficacy, there was an expected increase in toxicity with the new regimen.
The rate of treatment-related grade 3/4 adverse events was 76.3% with encorafenib vs 58.5% with the control regimen. Patients receiving encorafenib also had higher rates of anemia, arthralgia, rash, and pyrexia, but there was no substantial increase in treatment discontinuation.
BREAKWATER also included an encorafenib plus cetuximab arm without chemotherapy, but enrollment was stopped early at 158 patients due to possible futility. Still, these patients had as good or numerically better outcomes than the control group, which means the drug combination alone is a valid option for those unable to tolerate chemotherapy, said Élez.
'The results are striking,' said Sartore-Bianchi in his discussion. 'Now that we have the big picture' from BREAKWATER, the combination should be considered the first-line standard of care.
Mark A. Lewis, MD, a gastrointestinal medical oncologist at Intermountain Healthcare in Murray, Utah, explained that what usually happens in metastatic CRC is that people are treated with chemotherapy for a bit before oncologists notice the tumor is behaving more aggressively than expected and order a BRAF test.
This delay is now 'completely unacceptable,' he told Medscape Medical News . The takeaway from BREAKWATER is that testing must come sooner.
To help with BRAF testing, the FDA approved the Qiagen therascreen BRAF V600E RGQ polymerase chain reaction kit.
'As soon as you know patients are BRAF -mutated, you need to play your entire hand' because it will double survival,' said Lewis. 'This absolutely validates a biomarker-informed approach to colon cancer,' similar to what we have in breast cancer.
BREAKWATER was funded primarily by Pfizer, maker of encorafenib, with support from Eli Lilly and Merck, who jointly market cetuximab. Élez reported numerous ties to the companies, including research grants, travel funding, honoraria, and/or consultant work. Lewis, Kunz, and Sartore-Bianchi had no relationships with the firms.