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BRAF-mutant metastatic colorectal cancer: triple combination of BRAF, MEK and EGFR inhibitors extends overall survival


The triplet combination of the BRAF inhibitor, Encorafenib ( Braftovi ), MEK inhibitor, Binimetinib ( Mektovi ), and EGFR inhibitor, Cetuximab ( Erbitux ), not only has significantly improved overall survival ( OS ) but has also increased objective response rates ( ORR ) compared with standard of care in patients with BRAF V600E-mutant metastatic colorectal cancer.

Results were published in The New England Journal of Medicine ( NEJM ).

Inhibition of BRAF, a gene that produces the B-RAF protein implicated in sending signals in cells and cell growth, has shown promise in improving survival of patients across certain tumor types including melanoma.
BRAF blockade as monotherapy has not proven effective in the treatment of colorectal cancer.
BRAF inhibition alone in colorectal cancer has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.

Preclinical models of BRAF V600E-mutant colorectal cancer have shown that BRAF inhibition leads to the rapid activation of EGFR.
Treatment with BRAF inhibitors as monotherapy does not sufficiently block pathway signaling, which explains the resistance of most colon cancers despite the presence of the BRAF V600E mutation.

BEACON CRC randomized, open-label, 3-arm phase III study has evaluated the combination of Encorafenib plus Cetuximab with or without Binimetinib towards improving outcomes for this particular patient population.
The study included patients with BRAF V600E-mutant metastatic colorectal cancer who had had disease progression after one or two previous regimens.

The BRAF mutation occurs in around 8-12% of colorectal cancer patients with a poor prognosis.

The aim of the researchers was to identify the sub-population baring this mutation, and seek to improve outcomes for these patients.

655 patients were enrolled and randomly assigned to receive triplet therapy with Encorafenib, Binimetinib and Cetuximab, doublet therapy with Encorafenib and Cetuximab, or the investigators' choice of either Cetuximab and Irinotecan or Cetuximab and FOLFIRI ( Folinic acid, Fluorouracil, and Irinotecan ).

Results have shown significant clinical benefits with median overall survival of 9.0 months in the triplet group, 8.4 months in the doublet, and 5.4 months in the control arm.
Regarding response rates, the researchers confirmed 26% in the triplet and 2% in the control.

Tolerability of this novel combination was favorable. ( Xagena )

Source: ESMO ( European Society of Medicine Oncology ) Meeting, 2019

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