biostudies-literatureRose AANConquer Cancer Foundation (Conquer Cancer Foundation of the American Society of Clinical Oncology)Canada Foundation for Innovation (Fondation canadienne pour l'innovation)Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de Recherche en Santé du Canada)1323https://www.ebi.ac.uk/biostudies/studies/S-EPMC12873207biostudies-literatureUnknown17(1)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 mechanisNature communicationsBinimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations: results from the Phase II BEAVER trial.PMC1287320770745742153180379197819Biondini MElia AJCescon DWCianfarano EKamil ZSKing ISoria-Bretones IMaxwell JSpreafico ASiegel PMSiu LLRiaud MButler MHansen ASaibil SDTobin CPugh TJElkholi IELaw RWYRousselle ERose AANMcGuire MBedard PLWang BXZhang TShepherd FAMukonoweshuro CLLeighl NBRazak AAfalseBinimetinib 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 mechanis2026-01-01T00:00:00Z2026 Jan2026-07-15T13:52:28.975Z2026-07-05T03:11:42.462ZS-EPMC128732074148412110.1038/s41467-025-68076-7