[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-333050-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-333050-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","combined-raf-and-mek-inhibition-to-treat-activated-non-v600-braf-altered-advanced-cancers","Combined RAF and MEK Inhibition to Treat Activated Non-V600 BRAF-Altered Advanced Cancers","","Cancers with non-V600 BRAF-activating alterations lack matched therapies, and overall clinical responses to MEK/ERK inhibitors remain limited. Preclinical findings indicate dependence on ERK signaling, yet efficacy is constrained by a narrow therapeutic index likely driven by ERK inhibition in healthy tissues. The study tested whether concurrent RAF inhibition with MEK/ERK inhibitors would improve the therapeutic index by opposing ERK inhibition in normal tissues while avoiding ERK activation in the already activated tumors. Cell line, xenograft, and a phase I/II trial combining binimetinib with encorafenib showed inadequate clinical activity and incomplete pathway suppression.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/combined-raf-and-mek-inhibition-to-treat-activated-non-v600-braf-altered-advanced-cancers/333050/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/combined-raf-and-mek-inhibition-to-treat-activated-non-v600-braf-altered-advanced-cancers/333050.png","ImageObject",300,407,{"name":42,"@type":43},"Jiven","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-25","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",6,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"Why are therapies for non-V600 BRAF-activating cancers limited?","Question",{"text":63,"@type":64},"These tumors lack matched therapy, and clinical response to MEK/ERK inhibitors has been overall low despite dependence on ERK signaling. A narrow therapeutic index, driven by ERK inhibition in healthy tissues, is proposed to limit efficacy.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How did the study evaluate RAF inhibition alone and in combination?",{"text":68,"@type":64},"The authors used cell lines and patient-derived xenografts to test RAF inhibition alone and combined with MEK/ERK inhibitors. They then conducted a phase I/II clinical trial combining higher-dose binimetinib with encorafenib in advanced cancers harboring activating non-V600 BRAF alterations.",{"name":70,"@type":61,"acceptedAnswer":71},"What were the clinical and biological findings from the combination treatment?",{"text":72,"@type":64},"The combination was well tolerated without dose-limiting toxicities, but disease control was limited: one confirmed partial response, eight stable disease cases, and six progressions. On-treatment biopsies showed incomplete ERK pathway inhibition, and overall activity was insufficient for activated non-V600 BRAF-mutant tumors.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},333050,1790194150,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,105,110,114,119,122,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":102,"show_sort_weight":103,"slug":104},"Technology",50,"technology",{"id":106,"doc_module":4,"doc_module_name":25,"category_name":107,"show_sort_weight":108,"slug":109},7,"Healthcare",40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":112,"slug":113},8,30,"research-report",{"id":115,"doc_module":4,"doc_module_name":25,"category_name":116,"show_sort_weight":117,"slug":118},9,"Religion & Spirituality",20,"religion-spirituality",{"id":117,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":117,"slug":121},"World Cup","world-cup",{"id":123,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":123,"slug":125},10,"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":111,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":123,"language":139,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":12,"update_tm":143,"read_time":144,"preview_page_count":4},1099513958607,"https://ap-avatar.wpscdn.com/avatar/100002390cf8733938c?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778829742770036399","Combined RAF and MEK Inhibition to Treat Activated NonV600 BRAF-Altered Advanced Cancers  \nNaryan Rustgi1, Ann Maria2, Nicolas Toumbacaris3, HuiYong Zhao4, Katherine Kargus5, Morgan Bryant2, Alexandra Waksmundzki2, Ilinca Aricescu6, RobertA. Lefkowitz7, Bob T. Li2, Joanne Chou3, Marinela Capanu3, Elisa de Stanchina4, Sandra Misale8, Jinru Shia9,, Rona Yaeger*,2,  \n1 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA 2Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA  \n3Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5Department of Nursing, Memorial Sloan Kettering Cancer Center, New York, NY, USA  \n6Gerstner Sloan Kettering Graduate School of Biomedical Sciences, New York, NY, USA 7Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 8Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA 9Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA  \n* Corresponding author: Rona Yaeger, MD, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Tel: +1 646 888 5109; [Email:](Email: yaegerr@mskcc.org)[ yaegerr@mskcc.org](Email: yaegerr@mskcc.org)  \nAbstract  \nBackground: Cancers with non-V600 BRAF-activating alterations have no matched therapy. Preclinical data suggest that these tumors depend on ERK signaling; however, clinical response to MEK/ERK inhibitors has overall been low. We hypothesized that a narrow therapeutic index, driven by ERK inhibition in healthy (wild-type) tissues, limits the efficacy of these inhibitors. As these mutants signal as activated dimers, we further hypothesized that RAF inhibitors given concurrently would improve the therapeutic index by opposing ERK inhibition in normal tissues and not activate ERK in the already activated tumor.  \nMaterials and Methods: Using cell lines and patient-derived xenografts, we evaluated the effect of RAF inhibition, alone and in combination with MEK/ERK inhibitors. We then undertook a phase I/II clinical trial of a higher dose of the MEK inhibitor binimetinib combined with the RAF inhibitor encorafenib in patients with advanced cancer with activating non-V600 BRAF alterations.  \nResults: RAF inhibition led to modest inhibition of signaling and growth in activated non-V600 BRAF preclinical models and allowed higher dose of MEK/ERK inhibitors in vivo for more profound tumor regression. Fifteen patients received binimetinib 60 mg twice daily plus encorafenib 450 mg daily (6 gastrointestinal primaries, 6 genitourinary primaries, 3 melanoma, and 2 lung cancer; 7 BRAF mutations and 8 BRAF fusions) . Treatment was well tolerated without dose-limiting toxicities. One patient had a confirmed partial response, 8 had stable disease, and 6 had radiographic or clinical progression as best response. On-treatment biopsies revealed incomplete ERK pathway inhibition.  \nConclusion: Combined RAF and MEK inhibition does not sufficiently inhibit activated non-V600 BRAF-mutant tumors in patients.  \nKey words: BRAF; MEK; translational research; precision medicine.  \nImplications for Practice  \nLeveraging the distinct effect of RAF inhibitors in tumors with activating non-V600 BRAF alterations, the authors administered the RAF inhibitor encorafenib to offset MEK inhibitor toxicity and up-titrate the dose of the MEK inhibitor binimetinib in a phase I/II clinical trial. Despite this dose increase, combined RAF and MEK inhibition did not lead to sufficient activity in patients and should not be administered for non-V600 BRAF-altered cancers in clinical practice. Non-V600 BRAF alterations are recurrent in prostate cancer, but these tumors are likely less responsive to ERK pathway inhibition, as no patients with prostate cancer had regression to treatme","cbCaijqb0htKbuL8","https://ap.wps.com/l/cbCaijqb0htKbuL8","pdf",14113977,"English","# Abstract\n## Background\n## Materials and Methods\n## Results\n## Conclusion\n## Implications for Practice\n# Introduction","[{\"question\":\"Why are therapies for non-V600 BRAF-activating cancers limited?\",\"answer\":\"These tumors lack matched therapy, and clinical response to MEK/ERK inhibitors has been overall low despite dependence on ERK signaling. A narrow therapeutic index, driven by ERK inhibition in healthy tissues, is proposed to limit efficacy.\"},{\"question\":\"How did the study evaluate RAF inhibition alone and in combination?\",\"answer\":\"The authors used cell lines and patient-derived xenografts to test RAF inhibition alone and combined with MEK/ERK inhibitors. They then conducted a phase I/II clinical trial combining higher-dose binimetinib with encorafenib in advanced cancers harboring activating non-V600 BRAF alterations.\"},{\"question\":\"What were the clinical and biological findings from the combination treatment?\",\"answer\":\"The combination was well tolerated without dose-limiting toxicities, but disease control was limited: one confirmed partial response, eight stable disease cases, and six progressions. On-treatment biopsies showed incomplete ERK pathway inhibition, and overall activity was insufficient for activated non-V600 BRAF-mutant tumors.\"}]","Combined RAF and MEK Inhibition to Treat Activated Non-V600 BRAF-Altered Advanced Cancers | PDF",1790000579,25]