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Authors April A. N. Rose, Olubukola Ayodele, Sofia Genta, Thiago Pimentel Muniz, Deirdre Kelly, Kelsey Hodgson, Ian King, Tracy Stockley, Trevor J. Pugh, Zaid Saeed Kamil, Marcus O. Butler, Frances A. Shepherd, Philippe L. Bedard, Natasha B. Leighl, Albiruni Ryan Abdul Razak, Aaron Richard Hansen, Samuel Saibil, David W. Cescon, Lillian L. Siu, Anna Spreafico
Title Preliminary results of BEAVER: An investigator-initiated phase II study of binimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations (mts).
Abstract Text Background: Recurring oncogenic non-V600E BRAF mts have been identified in many cancer types. Preclinical data indicate that some BRAF non-V600E mts can be targeted with BRAF + MEK inhibitors. BEAVER is an investigator-initiated study designed to test the safety and efficacy of binimetinib and encorafenib (B+E) in patients (pts) with non-V600E BRAF mts. Methods: Key eligibility criteria are: pts with advanced solid tumors with BRAF non-V600E activating (class 1 and 2) or inhibitory (class 3) mts, and no prior BRAF/MEK inhibitors. Pts receive binimetinib (45mg PO BID) and encorafenib (450mg PO daily) on a 28-day cycle until intolerable toxicity or progression. The primary objective is OR rate (ORR) as per RECIST 1.1. In this Simon 2-stage trial, ≥1 of 7 pts need to have an objective response (OR) before commencing second stage of study (26 pts total). Secondary objectives include: safety, DCR, PFS, and OS. Exploratory objectives include: genomic profiling of tumors, evaluating circulating tumor DNA dynamics and development of patient derived xenograft (PDX) models. Results: From June 2019 to Feb 2021, 12 pts were screened and 9 pts enrolled; 9 are evaluable for safety and 8 for efficacy. Tumor types were melanoma and colon (n=2 each), as well as gallbladder, lung, breast and uterine cancers (n=1 each). Median age was 62 yrs (range 40-72). Median number of prior treatments was 2 (range 0-6). 1 pt had a class 1, 3 pts had class 2, and 5 pts had class 3, non-V600E BRAF mts. The median number of cycles was 2 (range: 1-7). Common treatment-related adverse events were mostly grade ≤ 2, and included: Blurred vision (78%), fatigue (67%), nausea (44%), vomiting (33%), and rash (33%). Dose reductions were required in 4/9 pts (44%) due to: blurred vision (22%), central serous retinopathy (11%), malaise (11%) and increased lipase (11%). Drug-related grade 3 AEs occurred in 2/9 pts and included: malaise (11%), confusion (11%), fatigue (11%) and increased lipase (11%). All eye toxicities were reversible with dose interruption. ORR was 12.5% (1/8) with one unconfirmed PR in a melanoma pt (BRAF G469S), treated for 6.5 months. One gallbladder cancer pt (BRAF D594N) had SD, and 6 pts had PD as best response. Genomic profiling was performed on archival tumors for 8 pts. Two PDX models were established. Responses to B+E in PDX models mirrored responses in 2 corresponding pts who had PD. Genomic and molecular profiling of pt tumors and corresponding PDXs identified multiple potential mechanisms of B+E resistance including: activation of EGFR and Akt pathways and inactivation of NF1 and Rb1. Conclusions: Preliminary data confirmed the safety of B+E and showed preliminary evidence of anti-tumor activity in advanced cancer pts with non-V600E BRAF mts. This study met the criterion for advancing to stage 2. Enrolment in the BEAVER trial and correlative biomarker analyses are ongoing. Clinical trial information: NCT03839342.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References