Intermittent BRAF inhibition in advanced BRAF mutated melanoma results of a phase II randomized trial

Maria Gonzalez-Cao (), Clara Mayo de las Casas, Juana Oramas, Miguel A. Berciano-Guerrero, Luis Cruz, Pablo Cerezuela, Ana Arance, Eva Muñoz-Couselo, Enrique Espinosa, Teresa Puertolas, Roberto Diaz Beveridge, Sebastian Ochenduszko, Maria-Jose Villanueva, Laura Basterretxea, Lorena Bellido, Delvys Rodriguez, Begoña Campos, Clara Montagut, Ana Drozdowskyj, Miguel A. Molina, Jose Antonio Lopez-Martin and Alfonso Berrocal ()
Additional contact information
Maria Gonzalez-Cao: Dexeus University Hospital
Clara Mayo de las Casas: Dexeus University Hospital
Juana Oramas: Hospital Universitario de Canarias
Miguel A. Berciano-Guerrero: Hospitales Universitarios Regional y Virgen de la Victoria (HURyVV). Instituto de Investigaciones Biomédicas de Málaga (IBIMA)
Luis Cruz: Hospital Universitario Virgen Macarena
Pablo Cerezuela: Hospital Clínico Universitario Virgen de la Arrixaca
Ana Arance: Hospital Clinic
Eva Muñoz-Couselo: Hospital Valle Hebron
Enrique Espinosa: Hospital Universitario la Paz, CIBERONC
Teresa Puertolas: Hospital Miguel Servet
Roberto Diaz Beveridge: Hospital Universitario la Fe
Sebastian Ochenduszko: Hospital Universitario Dr Peset
Maria-Jose Villanueva: Hospital de Vigo
Laura Basterretxea: Hospital Universitario de Donostia
Lorena Bellido: Hospital Universitario de Salamanca
Delvys Rodriguez: Hospital Insular Las Palmas
Begoña Campos: Hospital Lucus Agusti
Clara Montagut: Hospital del Mar, IMIM, CIBERONC
Ana Drozdowskyj: Dexeus University Hospital
Miguel A. Molina: Dexeus University Hospital
Jose Antonio Lopez-Martin: Hospital 12 de Octubre
Alfonso Berrocal: Hospital General de Valencia

Nature Communications, 2021, vol. 12, issue 1, 1-6

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26572-6

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