A three-drug combination of encorafenib, binimetinib, and cetuximab significantly improve overall survival (OS) in patients with BRAF-mutated metastatic colorectal cancer (mCRC) based on the results of the BEACON CRC Phase III clinical trial led by MD Anderson investigators.

MD Anderson released news that a three-drug combination investigational therapy appears to work, at least in certain circumstances.

The Study

BEACON CRC is the first and only Phase III trial designed to test BRAF/MEK combination targeted therapies in patients with mCRC and the BRAF V600E mutation. BRAF mutations are estimated to occur in up to 15% of patients with mCRC, with V600# being the most common BRAF mutation and representing a poor prognosis for these patients reports MD Anderson.

A multi-center, international collaboration with over 200 sites worldwide, the sponsors designed it as an open-label, three-arm randomized clinical trial. The sponsors recruited 665 patients with BRAF V600-mutant mCRC who had progressed after one or two prior regimens in the metastatic setting were randomized to receive triplet therapy, double therapy (encorafenib and cetuximab) or the investigator’s choice of irinotecan or folinic acid, fluorouracil and irinotecan (FOLFIRI) and cetuximab.

Results

The triplet combination was generally well tolerated with no unexpected toxicities. Grade three or higher adverse events were experienced in 58% of patients of triplet treatment, 50% of those in the doublet group and 61% of those in the standard therapy group.

The treatment combination resulted in a median OS of 9 months for the combination therapy compared to 5.4 months for current standard-of-care treatment. Objective response rate (ORR) for the triple-targeted therapy was 26% compared to just 2% for standard therapy.

The results are being reported at the ESMO World Congress on Gastrointestinal Cancer 2019 by principal investigator Scott Kopetz, MD, associate professor of Gastrointestinal Medical Oncology.

Investigator Comments

Dr. Kopetz reported “This study builds on a decade of research into the tumor biology of BRAF-mutated colorectal cancer, and reflects a rationale combination to address the vulnerabilities unique to this tumor” and noted, “We are encouraged to see a meaningful improvement in outcomes with this new regimen for our patients.”

Moreover based on the results of this study in combination with several other data sources Dr. Kopetz notes “This targeted therapy combination should be a new standard of care for this patient group” but also conveyed that “Further investigation is needed to determine if this combination may also benefit those with less advanced disease as a first-line treatment.”

Colorectal Cancer A Killer

The American Cancer Society reports that colorectal cancer is the third leading cause of cancer-related deaths in men and women and the second most common cause of cancer deaths when men and women are combined. About 51,020 deaths are expected during 2019. About 15% of these colon cancer cases involve BRAF mutations—V600 being the most common BRAF mutation; it represents a poor prognosis for these patients.

FDA Breakthrough Therapy Designation

By August 2019, encorafenib in combination with binimetinib and cetuximab was given Breakthrough Therapy Designation. The agency required that the treatment be applied to patients with BRAF V600E-mutant mCRC, after the failure of one to two prior lines of therapy for metastatic disease.

BEACON CRC Trial Influence

Data derived from the BEACON CRC trial is being used to support regulatory approval of the triplet combination in metastatic BRAF V600E-mutant mCRC, and BRAF inhibitor-based treatment has recently been included as a treatment option in the National Comprehensive Cancer Network (NCCN) guidelines for colon and rectal cancers in the United States.

What is Encorafenib?

Called Braftovi, it is a drug used to treat certain melanomas. A small molecule BRAF inhibitor, it targets key enzymes in the MAPK signaling pathway. This pathway can occur in many different cancers including melanoma and colorectal cancers. First developed by Novartis, then Array Biopharma, in June 2018 it was approved by the FDA in combination with binimetinib for the treatment of patients with unresectable or metastatic BRAF V600E or V600K mutation-positive melanoma.

Sponsors

Array BioPharma

  •         Meck KGaA (aka Merck Germany)
  •         Ono Pharmaceutical
  •         Pierre Fabre

Key Investigators

In addition to Dr. Scott Kopetz of MD Anderson, the list below includes participating investigators.

  •         Axel Grothey, MD, West Cancer Center Research Institute
  •         Eric van Cutsem, MD, Ph.D., University Hospitals Gasthuisberg Leuven, and KU Leuven
  •         Rona Yaeger, MD, Memorial Sloan-Kettering Cancer Center
  •         Harpreet Wasan, MD, BS Hammersmith Hospital, London, UK
  •         Takayuki Yoshino, MD National Cancer Center Hospital East
  •         Jayesh Desai, MD Peter MacCallum Cancer Center
  •         Fortunato Ciardiello, MD, Ph.D. University of Campania
  •         Fotios Loupakis, MD Instituto Oncologico Veneto
  •         Yong Sang Hong, MD, Ph.D. Asan Medical Center, University of Ulsan College of Medicine
  •         Neeltje Steeghs, MD, Ph.D. Netherlands Cancer Institute
  •         Tormod Kyrre Guren, MD, Ph.D. Oslo University Hospital
  •         Hendrik-Tobias Arkenau, MD, Ph.D., Sarah Cannon Research Institute and University College London
  •         Pilar Garcia-Alfonso, MD Hospital Gregorio Maranon
  •         Josep Tabernero, MD, Ph.D., Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology

The source for this press release was EurekAlert! 

Source: EurekAlert!

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