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Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer

Scott Kopetz¹, Axel Grothey¹, Rona Yaeger¹

¹From the University of Texas M.D. Anderson Cancer Center, Houston (S.K., V.M.); West Cancer Center and Research Institute, OneOncology, Germantown, TN (A. Grothey); Memorial Sloan Kettering Cancer Center, New York (R.Y., A.K.); University Hospital Gasthuisberg and University of Leuven, Leuven, Belgium (E.V.C., J. Dekervel); the Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (J. Desai, C.G.); National Cancer Center Hospital East, Kashiwa, Japan (T.Y.); Hammersmith Hospital, Division of Cancer, Imperial College London (H.W.), and the Sarah Cannon Research Institute and University College London Cancer Institute (H.-T.A.), London, and the Christie NHS Foundation Trust/National Institute for Health Research Manchester Biomedical Research Centre, Manchester (M.B.) - all in the United Kingdom; the University of Campania Luigi Vanvitelli, Naples (F.C.), and Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico, Padua (F.L., S.L.) - both in Italy; Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea (Y.S.H., T.-W.K.); the Netherlands Cancer Institute, Amsterdam (N.S., J.H.M.S.); Oslo University Hospital, Oslo (T.K.G.); Hospital Gregorio Marañón, Madrid (P.G.-A., A.C.F.), and Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology, UVic, IOB-Quiron, Barcelona (E.E., J.T.) - both in Spain; Odense University Hospital, Odense, Denmark (P.P., L.S.T.); Pavlov First St. Petersburg State Medical University, St. Petersburg, Russia (S.O.); and Array BioPharma, Boulder, CO (A. Gollerkeri, C.K., K.M., M.P., J.C.-B., L.A., V.S.).

The New England Journal of Medicine

|October 1, 2019

Abstract

Background:

Patients with metastatic colorectal cancer with the BRAF V600E mutation have a poor prognosis, with a median overall survival of 4 to 6 months after failure of initial therapy. Inhibition of BRAF alone has limited activity because of pathway reactivation through epidermal growth factor receptor signaling.

Methods:

In this open-label, phase 3 trial, we enrolled 665 patients with BRAF V600E-mutated metastatic colorectal cancer who had had disease progression after one or two previous regimens. Patients were randomly assigned in a 1:1:1 ratio to receive encorafenib, binimetinib, and cetuximab (triplet-therapy group); encorafenib and cetuximab (doublet-therapy group); or the investigators' choice of either cetuximab and irinotecan or cetuximab and FOLFIRI (folinic acid, fluorouracil, and irinotecan) (control group). The primary end points were overall survival and objective response rate in the triplet-therapy group as compared with the control group. A secondary end point was overall survival in the doublet-therapy group as compared with the control group. We report here the results of a prespecified interim analysis.

Results:

The median overall survival was 9.0 months in the triplet-therapy group and 5.4 months in the control group (hazard ratio for death, 0.52; 95% confidence interval [CI], 0.39 to 0.70; P<0.001). The confirmed response rate was 26% (95% CI, 18 to 35) in the triplet-therapy group and 2% (95% CI, 0 to 7) in the control group (P<0.001). The median overall survival in the doublet-therapy group was 8.4 months (hazard ratio for death vs. control, 0.60; 95% CI, 0.45 to 0.79; P<0.001). Adverse events of grade 3 or higher occurred in 58% of patients in the triplet-therapy group, in 50% in the doublet-therapy group, and in 61% in the control group.

Conclusions:

A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer overall survival and a higher response rate than standard therapy in patients with metastatic colorectal cancer with the BRAF V600E mutation. (Funded by Array BioPharma and others; BEACON CRC ClinicalTrials.gov number, NCT02928224; EudraCT number, 2015-005805-35.).

Insights

A triplet therapy of encorafenib, binimetinib, and cetuximab significantly improved overall survival and response rates for patients with BRAF V600E-mutated metastatic colorectal cancer compared to standard care.

Area of Science:

Oncology
Molecular Biology
Clinical Trials

Background:

Metastatic colorectal cancer (mCRC) with BRAF V600E mutation confers a poor prognosis.
Standard treatments show limited efficacy due to pathway reactivation.
Identifying effective targeted therapies is crucial for improving patient outcomes.

Purpose of the Study:

To evaluate the efficacy of encorafenib, binimetinib, and cetuximab combination therapy in patients with BRAF V600E-mutated mCRC.
To compare overall survival (OS) and objective response rate (ORR) of triplet therapy versus doublet therapy and standard care.

Main Methods:

An open-label, phase 3 trial enrolled 665 patients with previously treated BRAF V600E-mutated mCRC.
Patients were randomized to triplet therapy (encorafenib, binimetinib, cetuximab), doublet therapy (encorafenib, cetuximab), or control (investigator's choice of cetuximab plus irinotecan or FOLFIRI).
Primary endpoints were OS and ORR for triplet vs. control; secondary endpoint was OS for doublet vs. control.

Main Results:

Triplet therapy demonstrated significantly longer median OS (9.0 months) versus control (5.4 months) (HR 0.52, P<0.001).
Confirmed ORR was 26% for triplet therapy compared to 2% for control (P<0.001).
Doublet therapy also showed improved median OS (8.4 months) versus control (HR 0.60, P<0.001).

Conclusions:

The combination of encorafenib, cetuximab, and binimetinib offers a significant survival benefit and higher response rates in BRAF V600E-mutated mCRC.
This triplet regimen represents a promising new standard of care for this patient population.
The study met its primary and secondary endpoints, supporting the efficacy of targeted combination therapy.

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