Binimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations (mts): Final results of the investigator-initiated phase II BEAVER trial.

• DOI: 10.1200/jco.2024.42.16_suppl.3104
• Publication Date: 2024-06-14T17:04:07Z
• Authors: April A. N. Rose; Jennifer Maxwell; Emmanuelle Rousselle; Melody Riaud; Chantal Tobin; Meghan Mcguire; Ian King; Tong Zhang; Zaid Saeed Kamil; Trevor J. Pugh; Marcus O. Butler; Frances A. Shepherd; Philippe L. Bedard; Natasha B. Leighl; Albiruni Ryan Abd...; Aaron Richard Hansen; Samuel Saibil; Lillian L. Siu; David W. Cescon; Anna Spreafico
• Keywords: Solid tumor

3104 Background: Oncogenic non-V600E BRAF mts are present in many cancer types. Pre-clinical data indicate that some can be targeted with + MEK inhibitors. The BEAVER trial was designed to test the safety and efficacy of binimetinib encorafenib (B+E) patients (pts) mts. Safety were previously presented [ https://doi.org/10.1016/j.annonc.2021.08.1053 ]. Here, we final analysis exploratory objectives. Methods: Key eligibility criteria were: pts advanced solid tumors activating (Class 1 2) or inhibitory 3) mts, no prior BRAF/MEK Pts received (45mg PO BID) (450mg daily) on a 28-day cycle until intolerable toxicity progression. primary objective is OR rate (ORR) as per RECIST 1.1. Secondary objectives included PFS. Log-rank used assess Exploratory included: development patient derived xenograft (PDX) models, genomic/transcriptomic profiling tumors. Mice bearing PDXs treated inhibitors measured by caliper measurement. Whole exome RNAseq performed PDXs. Results: From June 2019 Nov 2023, 27 screened 23 enrolled; 21 evaluable for ORR. Tumor types melanoma, colorectal pancreaticobiliary (n=6 each), lung (n=2), breast, uterine, small bowel cancers (n=1 each).Median age 59 yrs (range 40-73). had Class (n=1), 2 (n=9), 3 (n=13) Best ORR 13% (3/23) one confirmed PR pt ampullary (BRAF D594G) unconfirmed PRs melanoma G469S K601E), 4 SD best response. median PFS 2.4 months (mo) entire cohort. mt not associated differences TP53 most frequently co-mutated gene (9/23; 39%) experienced shorter (1.8 vs. 4.0 mo, P=0.008). (4.0 mo) longer than (2.6 other tumor (1.6 mo); P=0.006. PDX models established from 9 pts, 8/9 expressed same corresponding tumor. Responses B+E correlated measurements (R=-0.63; P=0.046). identified PTPN11 (Shp2) CDK4/6 potential therapeutic targets B+E-resistant Combination therapies Shp2 inhibitor significantly enhanced B+E-induced growth inhibition multiple models. Conclusions: has only modest clinical activity resistance develops quickly. Alternative approaches incorporating warrant further investigation this population. Clinical information: NCT03839342 .