Binimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations: results from the Phase II BEAVER trial
Class 2 and 3 non-V600E BRAF mutations are oncogenic drivers in many cancer types. Currently, there are no established targeted therapies with proven efficacy for cancers with non-V600E BRAF mutations. We developed the investigator-initiated, Phase II BEAVER clinical trial (NCT03839342) to evaluate the efficacy of BRAF and MEK inhibitors in patients with non-V600E BRAF mutations. The primary outcome was objective response rate (ORR). The best ORR was 14% (3/21), the primary endpoint was not met. By analyzing genomic data from patient tumors, circulating tumor DNA (ctDNA), patient-derived xenograft (PDX) models generated from enrolled patients, and Class 2 & 3 BRAF mutant cell lines, we discovered MAPK-dependent and independent mechanisms of resistance to BRAF/MEK inhibition. These mechanisms include the acquisition of new mutations in NRAS, MAP2K1, RAF1, and RB in ctDNA at the time of disease progression. CDK4/6 and SHP2 emerge as mediators of intrinsic resistance to BRAF/MEK inhibition in Class 2 & 3 BRAF mutant tumors. Therapeutic strategies combining CDK4/6 or SHP2 inhibitors with BRAF/MEK inhibitors in preclinical models show greater efficacy than BRAF/MEK inhibitors alone in these cancers.
Authors
- Lillian L. Siu (ORCID: https://orcid.org/0000-0002-3500-0540)
- I. King
- B. Wang
- F SHEPHERD
- Philippe Lucien Bedard (ORCID: https://orcid.org/0000-0002-6771-2999)
- Jennifer Maxwell
- T. Zhang
- Marco Biondini (ORCID: https://orcid.org/0000-0002-1389-6622)
- Zaid Saeed Kamil (ORCID: https://orcid.org/0000-0003-1067-9881)
- Melody Riaud
- Islam E. Elkholi (ORCID: https://orcid.org/0000-0002-8019-2481)
- D Cescon
- Trevor J. Pugh (ORCID: https://orcid.org/0000-0002-8073-5888)
- Andrew Elia (ORCID: https://orcid.org/0000-0001-8619-1415)
- A. Rose
- Chantal Tobin
- Emmanuelle Rousselle (ORCID: https://orcid.org/0009-0006-8831-7871)
- Peter M. Siegel (ORCID: https://orcid.org/0000-0002-5568-6586)
- I. Soria-Bretones
- A. Abdul Razak
- Anna Spreafico (ORCID: https://orcid.org/0000-0002-3034-3042)
- Erica Cianfarano (ORCID: https://orcid.org/0000-0002-3458-9373)
- Chantel L. Mukonoweshuro
- A. Hansen
- Samuel D. Saibil
- Marcus Butler
- Natasha B. Leighl
- Meghan McGuire
- Rhoda W. Y. Law
Institutions
- Ontario Institute for Cancer Research (CA)
- Montreal Neurological Institute and Hospital (CA)
- University Health Network (CA)
- University of Toronto (CA)
- Jewish General Hospital (CA)
- Princess Margaret Cancer Centre (CA)
- McGill Genome Centre (CA)
- McGill University (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-01-03
- DOI
- https://doi.org/10.1038/s41467-025-68076-7
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Conquer Cancer Foundation
- Pfizer
- McGill University
- Cancer Research Society
- Jewish General Hospital
- Fondation de l'Hôpital général juif
- Canadian Institutes of Health Research
- Fonds de Recherche du Québec - Santé
- Faculty of Medicine and Health, University of Sydney