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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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, 2021. "Intermittent BRAF inhibition in advanced BRAF mutated melanoma results of a phase II randomized trial," Nature Communications, Nature, vol. 12(1), pages 1-6, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26572-6
    DOI: 10.1038/s41467-021-26572-6
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    References listed on IDEAS

    as
    1. Meghna Das Thakur & Fernando Salangsang & Allison S. Landman & William R. Sellers & Nancy K. Pryer & Mitchell P. Levesque & Reinhard Dummer & Martin McMahon & Darrin D. Stuart, 2013. "Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance," Nature, Nature, vol. 494(7436), pages 251-255, February.
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    Cited by:

    1. Masud, M.A. & Kim, Eunjung, 2024. "Theoretical understanding of evolutionary dosing following tumor dynamics," Chaos, Solitons & Fractals, Elsevier, vol. 179(C).

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