Intermittent BRAF inhibition in advanced BRAF mutated melanoma results of a phase II randomized trial
| Autor: | Clara Mayo de las Casas, Maria Gonzalez-Cao, Sebastian Ochenduszko, Juana Oramas, Miguel Angel Molina, Eva Muñoz-Couselo, Ana Arance, Roberto Diaz Beveridge, Miguel A Berciano-Guerrero, Enrique Espinosa, Luis de la Cruz, Delvys Rodriguez, Pablo Cerezuela, Ana Drozdowskyj, L. Bellido, Clara Montagut, Teresa Puertolas, Laura Basterretxea, Jose A. Lopez-Martin, Alfonso Berrocal, Maria-Jose Villanueva, Begoña Campos |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proto-Oncogene Proteins B-raf
Oncology medicine.medical_specialty Cancer therapy Pyridones Science General Physics and Astronomy Antineoplastic Agents Pyrimidinones VEMURAFENIB Article General Biochemistry Genetics and Molecular Biology DOUBLE-BLIND chemistry.chemical_compound Piperidines Internal medicine Oximes medicine Clinical endpoint Humans Progression-free survival MEK INHIBITION Càncer Vemurafenib Melanoma Protein Kinase Inhibitors Aged Cobimetinib Trametinib Multidisciplinary business.industry Imidazoles Dabrafenib General Chemistry EFFICACY medicine.disease Clinical trial chemistry Mutation Azetidines Melanoma -- Tractament business medicine.drug |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-6 (2021) Nature Communications r-FIHGUV. Repositorio Institucional de Producción Científica de la Fundación de Investigación del Hospital General de Valencia instname NATURE COMMUNICATIONS r-FISABIO. Repositorio Institucional de Producción Científica r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe |
| ISSN: | 2041-1723 |
| Popis: | Combination treatment with BRAF (BRAFi) plus MEK inhibitors (MEKi) has demonstrated survival benefit in patients with advanced melanoma harboring activating BRAF mutations. Previous preclinical studies suggested that an intermittent dosing of these drugs could delay the emergence of resistance. Contrary to expectations, the first published phase 2 randomized study comparing continuous versus intermittent schedule of dabrafenib (BRAFi) plus trametinib (MEKi) demonstrated a detrimental effect of the “on−off” schedule. Here we report confirmatory data from the Phase II randomized open-label clinical trial comparing the antitumoral activity of the standard schedule versus an intermittent combination of vemurafenib (BRAFi) plus cobimetinib (MEKi) in advanced BRAF mutant melanoma patients (NCT02583516). The trial did not meet its primary endpoint of progression free survival (PFS) improvement. Our results show that the antitumor activity of the experimental intermittent schedule of vemurafenib plus cobimetinib is not superior to the standard continuous schedule. Detection of BRAF mutation in cell free tumor DNA has prognostic value for survival and its dynamics has an excellent correlation with clinical response, but not with progression. NGS analysis demonstrated de novo mutations in resistant cases. Whether intermittent strategies of delivering drugs can improve cancer patients survival is still unclear. Here, the authors reports the results of a randomized phase II clinical trial aimed to compare the efficacy and safety of two dosing regimens (continuous and intermittent) of vemurafenib and cobimetinib combination as first-line treatment of patients with unresectable or metastatic advanced melanoma with BRAFV600 mutation |
| Databáze: | OpenAIRE |
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