BREAKWATER Study Shows Promise for Encorafenib/Cetuximab Plus FOLFIRI in BRAF V600E-Mutant Colorectal Cancer
Key Insights
The BREAKWATER safety lead-in study demonstrated that combining encorafenib/cetuximab with FOLFIRI (search) chemotherapy was tolerable with only one dose-limiting toxicity in patients with BRAF V600E-mutant metastatic colorectal cancer (search).
First-line treatment with the combination achieved an impressive 83.3% objective response rate, including 2 complete responses and 8 partial responses among 12 treatment-naive patients.
Previously treated patients receiving the combination as second-line therapy showed a 44.4% response rate with median progression-free survival of 12.6 months and overall survival of 19.7 months.
The combination of encorafenib and cetuximab with FOLFIRI (search) chemotherapy demonstrated promising antitumor activity and manageable safety in patients with BRAF V600E-mutant metastatic colorectal cancer (search), according to updated results from the safety lead-in portion of the phase 3 BREAKWATER study presented at the 2024 ESMO Congress.
Josep Tabernero, MD, PhD, head of the Department of Medical Oncology at Vall d'Hebron University Hospital and director of the Vall d'Hebron Institute of Oncology (search) in Barcelona, Spain, reported that only one dose-limiting toxicity occurred with the encorafenib/cetuximab plus FOLFIRI (search) combination - grade 4 neutropenia lasting more than 7 days.
Efficacy Results Show Strong Response Rates
Among the 30 patients enrolled in cohort 1 of the safety lead-in, efficacy outcomes varied by treatment line. In the first-line metastatic setting, the objective response rate per blinded independent central review reached 83.3% (95% CI, 55.2%-95.3%), with 2 complete responses, 8 partial responses, and 1 patient achieving stable disease. The median duration of response was not estimable (95% CI, 12.4-NE), and both median progression-free survival and overall survival were not estimable.
For previously treated patients receiving the combination as second-line therapy, the objective response rate was 44.4% (95% CI, 24.6%-66.3%), including 1 complete response, 7 partial responses, and 7 patients with stable disease. The median duration of response was 12.5 months (95% CI, 5.5-NE), with median progression-free survival of 12.6 months (95% CI, 6.9-18.0) and median overall survival of 19.7 months (95% CI, 13.9-25.1).
Safety Profile Remains Manageable
The safety analysis revealed that treatment-related adverse events of any grade occurred in 93.3% of patients, with 50% experiencing grade 3/4 treatment-related adverse events and 16.7% experiencing serious adverse events related to study treatment. No treatment-related deaths were reported.
All patients experienced treatment-emergent adverse events, with 63.3% and 46.7% experiencing grade 3/4 and serious treatment-emergent adverse events, respectively. The most common adverse events across all grades included nausea (50%), diarrhea (46.7%), constipation (43.3%), fatigue (43.3%), dermatitis acneiform (40%), rash (33.3%), and skin hyperpigmentation (30%).
Treatment modifications were necessary in a substantial portion of patients, with dose reductions, dose interruptions, or permanent discontinuation occurring in 53.3%, 73.3%, and 30% of patients, respectively. Two patient deaths were associated with treatment-emergent adverse events.
Study Design and Patient Characteristics
The BREAKWATER study is an open-label, multicenter trial assessing encorafenib and cetuximab with or without chemotherapy in patients with metastatic colorectal cancer (search) harboring BRAF V600E (search) mutations. Patients with microsatellite instability-high or mismatch repair-deficient tumors were excluded from the study.
In cohort 1 of the safety lead-in, patients received encorafenib at 300 mg orally once daily plus cetuximab at 500 mg/m² intravenously every 2 weeks combined with FOLFIRI (search) every 2 weeks in 28-day cycles. The median age was 56.5 years (range 37-77), with 66.7% male patients. Seventy percent had right-sided tumors, and 66.7% had liver metastases. Twelve patients were treatment-naive, while 18 had received one prior line of therapy.
Clinical Implications and Future Directions
"Currently, there are no specifically targeted first-line treatments for BRAF V600E (search)-mutant mCRC which highlights the unmet need for novel treatment options for this patient population," Tabernero noted. The encorafenib/cetuximab combination is currently FDA-approved only for previously treated patients with BRAF V600E-mutated metastatic colorectal cancer (search).
"The combination of EC plus FOLFIRI (search) was tolerable without new safety signals in patients with BRAF V600E (search)-mutant mCRC and showed promising improvement in key efficacy measures," Tabernero concluded, adding that these results support continued evaluation of the combination in cohort 3 of the BREAKWATER study.
The study's findings are particularly significant given that BRAF V600E (search) mutations occur in approximately 10-15% of colorectal cancers and are associated with poor prognosis and limited treatment options. The promising first-line results could potentially establish a new standard of care for this challenging patient population if confirmed in the phase 3 portion of the trial.