Patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC) – a type of colorectal cancer with poor outcomes – have benefitted from first-line treatment with the targeted therapies in a Phase 3 clinical trial.
The findings demonstrated a 60.9 per cent overall response rate (ORR) with a three-drug combination compared to 40 per cent with the standard-of-care (SOC) treatment – chemotherapy with or without bevacizumab.
The three-drug combination included encorafenib, cetuximab and a mFOLFOX6 chemotherapy regimen.
In the experimental arm, 68.7 per cent of patients had a duration of response of at least six months, compared to 34.1 per cent of patients in the SOC arm.
Data from this multi-institutional collaboration across 28 countries has now supported the accelerated approval of this combination by the Food and Drug Administration (FDA), providing an effective new first-line treatment option for patients with BRAF V600E-mutant mCRC.
“Chemotherapy has had limited efficacy as a first-line treatment in controlling the aggressive tumour growth we see in patients with this mutation,” said co-principal investigator Scott Kopetz, professor of Gastrointestinal Medical Oncology at the University of Texas.
“This new regimen highlights the importance of combining dual-targeted therapy with chemotherapy to improve patient outcomes in the first-line setting, and the durable responses are a significant development as we work to improve quality of life for these patients.”
The BREAKWATER trial was one of the first studies to utilise the FDA’s Project FrontRunner, an initiative to encourage the evaluation of therapies in earlier clinical settings for advanced cancers rather than after patients received numerous previous treatments.
The trial enrolled patients who were at least 16 years of age with previously untreated BRAF V600E-mutant mCRC. Patients were randomised equally to one of three treatment arms: SOC chemotherapy with or without bevacizumab; a dual combination of encorafenib plus cetuximab; or a triple combination of encorafenib, cetuximab and mFOLFOX6.
When researchers analysed patient subgroups on the trial, the triple combination showed benefits across important groups, including patients with cancer spread to three or more organs and those with liver metastases.
“These results support this combination as a new first-line standard of care for patients with BRAF V600E-mutant metastatic colorectal cancer,” Kopetz said.
“It also highlights the importance of swiftly identifying molecular subtypes of colorectal cancer at diagnosis to optimise treatment strategies for our patients.”
The safety profile of this combination was consistent with the known safety profile of each respective drug. No new safety signals were identified.
The most common adverse reactions included nausea, rash, fatigue, vomiting, abdominal pain, diarrhoea and decreased appetite, all of which were reported in at least 25 per cent of patients and were similar between arms.
Final calculations of progression-free survival and overall survival will be formally assessed in the next phase of the trial. Future analyses of this trial may shed light on predictive biomarkers for this combination therapy.