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| Ref Type | Abstract | ||||||||||||
| PMID | |||||||||||||
| Authors | A. Rose O. Ayodele S. Genta T. Pimentel Muniz D.C. Kelly K. Hodgson I. King T. Stockley T. Pugh Z. Saeed Kamil M.O. Butler F.A. Shepherd P. Bedard N. Leighl A.R. Abdul Razak A.R. Hansen S. Saibil D.W. Cescon L.L. Siu A. Spreafico | ||||||||||||
| Title | Binimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations (mts): Preliminary results of the investigator initiated phase II BEAVER trial | ||||||||||||
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| URL | https://www.annalsofoncology.org/article/S0923-7534(21)03282-8/fulltext | ||||||||||||
| Abstract Text | Background Recurring oncogenic non-V600E BRAF mts can be identified in many cancers. Preclinical data indicate that they 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/MEKi. 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 objective response rate (ORR) per RECIST 1.1. In this Simon 2-stage trial, ≥1 of 7 pts must have a response before commencing stage 2 (26 pts total). Secondary objectives include: safety, DCR, and PFS. Results From Jun 2019 to Apr 2021, 10 pts were enrolled; 10 are evaluable for safety and 9 for efficacy. Tumor types were: melanoma and colon (n=2 each), gallbladder, lung, breast, ampullary, pancreatic and uterine (n=1 each). Median age was 61 yrs (range 40-72). 1 pt had a class 1, 4 pts had class 2, and 5 pts had class 3, non-V600E BRAF mts. Common treatment-related adverse events were mostly Grade ≤ 2, and included: Blurred vision (70%), fatigue (60%) and nausea (50%). Dose reductions were required in 5/10 pts (50%) due to: blurred vision (20%), central serous retinopathy, malaise, increased lipase and nausea (10% each). Eye toxicities were reversible with dose interruption or reduction. Drug-related Grade 3 AEs occurred in 2/10 pts and included: malaise, confusion, fatigue and increased lipase (10% each). ORR was 22% (2/9) with a confirmed PR in a pt with ampullary cancer (BRAF D594G, class 3) who continues on treatment for 5.4+ months, and an unconfirmed PR in a melanoma pt (BRAF G469S, class 2) treated for 6.5 months. One gallbladder cancer pt (BRAF D594N, class 3) had SD, treated for 4.4 months, and 6 pts had PD as best response. Conclusions Preliminary data confirmed the safety of B+E and demonstrated evidence of anti-tumor activity in advanced cancer pts with non-V600E BRAF mts. Enrolment in the BEAVER trial is ongoing. Clinical trial identification NCT03839342. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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| BRAF D594N | gallbladder cancer | predicted - sensitive | Binimetinib + Encorafenib | Case Reports/Case Series | Actionable | In a Phase II trial (BEAVER), combination treatment with Mektovi (binimetinib) and Braftovi (encorafenib) led to stable disease in a gallbladder cancer patient harboring BRAF D594N, with a treatment duration of 4.4 months (Annals of Oncology 32 (2021): S596; NCT03839342). | detail... |
| BRAF G469S | melanoma | predicted - sensitive | Binimetinib + Encorafenib | Case Reports/Case Series | Actionable | In a Phase II trial (BEAVER), Mektovi (binimetinib) and Braftovi (encorafenib) combination therapy resulted in an unconfirmed partial response in a patient with melanoma harboring BRAF G469S (Annals of Oncology 32 (2021): S596; NCT03839342). | detail... |
| BRAF D594G | ampulla of Vater cancer | predicted - sensitive | Binimetinib + Encorafenib | Case Reports/Case Series | Actionable | In a Phase II trial (BEAVER), combination treatment with Mektovi (binimetinib) and Braftovi (encorafenib) led to a confirmed partial response in an ampullary cancer patient harboring BRAF D594G, who remained on treatment for at least 5.4 months (Annals of Oncology 32 (2021): S596; NCT03839342). | detail... |
| BRAF mutant | Advanced Solid Tumor | predicted - sensitive | Binimetinib + Encorafenib | Phase II | Actionable | In a Phase II trial (BEAVER), Mektovi (binimetinib) and Braftovi (encorafenib) combination therapy demonstrated safety and preliminary efficacy in advanced solid tumor patients harboring BRAF non-V600E mutations including class 1 (n=1), class 2 (n=4), and class 3 (n=5), with an objective response rate of 22% (2/9) and a partial response in a patient with ampullary cancer harboring BRAF D594G and an unconfirmed PR in a melanoma patient harboring BRAF G469S (Annals of Oncology 32 (2021): S596; NCT03839342). | detail... |