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<p>Class 2 and 3 non-V600E <i>BRAF</i> mutations are oncogenic drivers in many cancer types. Currently, there are no established targeted therapies with proven efficacy for cancers with non-V600E <i>BRAF</i> 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 <i>BRAF</i> 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 &amp; 3 <i>BRAF</i> mutant cell lines, we discovered MAPK-dependent and independent mechanisms of resistance to BRAF/MEK inhibition. These mechanisms include the acquisition of new mutations in <i>NRAS, MAP2K1, RAF1</i>, and <i>RB</i> in ctDNA at the time of disease progression. CDK4/6 and SHP2 emerge as mediators of intrinsic resistance to BRAF/MEK inhibition in Class 2 &amp; 3 BRAF mutant tumors. Therapeutic strategies combining CDK4/6 or SHP2 inhibitors with BRAF/MEK inhibitors in preclinical models show greater efficacy than BRAF/MEK inhibitors alone in these cancers.</p>

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Binimetinib and encorafenib for the treatment of advanced solid tumors with non-V600E BRAF mutations: results from the Phase II BEAVER trial

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月3日

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  • April A. N. Rose,
  • Jennifer Maxwell,
  • Emmanuelle Rousselle,
  • Chantel L. Mukonoweshuro,
  • Islam E. Elkholi,
  • Melody Riaud,
  • Marco Biondini,
  • Erica Cianfarano,
  • Isabel Soria-Bretones,
  • Chantal Tobin,
  • Meghan McGuire,
  • Rhoda W. Y. Law,
  • Andrew J. Elia,
  • Ben X. Wang,
  • Ian King,
  • Tong Zhang,
  • Trevor J. Pugh,
  • Zaid Saeed Kamil,
  • Marcus Butler,
  • Frances A. Shepherd,
  • Natasha B. Leighl,
  • Albiruni Abdul Razak,
  • Aaron Hansen,
  • Samuel D. Saibil,
  • Philippe L. Bedard,
  • Peter M. Siegel,
  • Lillian L. Siu,
  • David W. Cescon,
  • Anna Spreafico

摘要

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 mechanisms include the acquisition of new mutations in NRAS, MAP2K1, RAF1, and RB in ctDNA at the time of disease progression. CDK4/6 and SHP2 emerge as mediators of intrinsic resistance to BRAF/MEK inhibition in Class 2 & 3 BRAF mutant tumors. Therapeutic strategies combining CDK4/6 or SHP2 inhibitors with BRAF/MEK inhibitors in preclinical models show greater efficacy than BRAF/MEK inhibitors alone in these cancers.