Triple-Drug Regimen Improves Survival in Metastatic Colorectal Cancer with BRAF V600E Mutation

Updated results from the safety lead-in of the phase 3 BEACON CRC clinical trial show a mature median overall survival (OS) of 15.3 months with the triple-drug regimen of encorafenib (Braftovi), a BRAF inhibitor; binimetinib (Mektovi), a MEK inhibitor; and cetuximab (Erbitux), an epidermal growth factor receptor (EGFR) inhibitor, for the treatment of patients with metastatic colo­rectal cancer (CRC) and BRAF V600E mutation.

These findings represent an improvement over the historical benchmark of 4 to 6 months for median OS with the current standard of care, said Scott Kopetz, MD, PhD, FACP, Deputy Chair for Translational Research, Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston, at the 2019 Gastrointestinal Cancers Symposium.

The updated median progression-free survival (PFS) and updated confirmed overall response rate (ORR) for patients who received the triple-drug therapy in the lead-in study phase remain as previously reported—8 months for median PFS (95% confidence interval [CI], 5.6-9.3 months) and 48% for ORR (95% CI, 29.4%-67.5%).

A BRAF mutation is present in up to 15% of patients with metastatic CRC, with V600 being the most common BRAF mutation. Patients with BRAF V600E mutations have poor survival rates, with a median survival of approximately 12 months, said Dr Kopetz.

BRAF inhibitors alone are minimally effective in this population “due in part to feedback through growth factor receptors such as epidermal growth factor receptor,” he said. By adding an EGFR inhibitor and a MEK inhibitor to the BRAF inhibitor, feedback reactivation of the MAP kinase pathway is blunted.

The ORR of 48% in the lead-in of the BEACON CRC study “is substantially better than historic controls, and it’s encouraging that our OS is a median of 15 months with reasonably mature data,” Dr Kopetz said. “This is encouraging, because these were patients who were either second- or third-line of treatment, and we’re seeing survivals that would exceed even what a first-line popu­lation would expect. This sets the stage for the phase 3 BEACON CRC results,” he added.

BEACON CRC is a randomized, open-label, global study evaluating the efficacy and safety of triple-drug therapy in patients with metastatic CRC and BRAF V600E mutation whose disease progressed after 1 or 2 regimens. The safety lead-in phase enrolled 30 patients, 29 of whom had a BRAF V600 mutation.

The patients received encorafenib 300 mg daily, binimetinib 45 mg twice daily, and cetuximab at the standard weekly dose of 400 mg/m2, then 250 mg/m2 once weekly. Overall, 60% of patients had received 1 previous therapy and 40% had received 2 therapies. At the data cutoff point (September 2, 2018), 6 patients were still receiving treatment.

The 6-month OS was 86.2% and the 12-month OS was 62.1%.

Among the responders, 3 (10%) patients had complete responses and 11 (38%) had partial responses. Another 13 (45%) patients had stable disease. The ORR was 41%. The median duration of response was 5.5 months by local assessment and 8.2 months by central assessment. The duration of response was ≥6 months in 43% of patients by local assessment and 73% by central assessment.

“We’re encouraged by the durability of the regimen, acknowledging that durability with doublets is on the shorter side,” said Dr Kopetz.

The triple-drug therapy was generally well-tolerated with no unexpected side effects. The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased aspartate aminotransferase (10%), and urinary tract infections (10%).

Breakthrough Therapy Designation

In August 2018, the FDA granted this triple-drug regimen a breakthrough therapy designation for the treatment of patients with metastatic CRC and BRAF V600E mutation, as detected by an FDA-approved test, after treatment failure with 1 or 2 previous lines of therapy for metastatic disease.

Just before that, in June 2018, the FDA approved the combination of the 2 novel drugs—encorafenib and binimetinib—for the treatment of patients with metastatic melanoma.

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