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

• Published in: Nature communications Vol. 12; no. 1; p. 7008
• Main Authors: Gonzalez-Cao, Maria, Mayo de las Casas, Clara, Oramas, Juana, Berciano-Guerrero, Miguel A., de la Cruz, Luis, Cerezuela, Pablo, Arance, Ana, Muñoz-Couselo, Eva, Espinosa, Enrique, Puertolas, Teresa, Diaz Beveridge, Roberto, Ochenduszko, Sebastian, Villanueva, Maria-Jose, Basterretxea, Laura, Bellido, Lorena, Rodriguez, Delvys, Campos, Begoña, Montagut, Clara, Drozdowskyj, Ana, Molina, Miguel A., Lopez-Martin, Jose Antonio, Berrocal, Alfonso
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 45/22; 45/77; 631/67/1813/1634; 692/4028/67/1059; Aged; Anticancer properties; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Antitumor activity; Azetidines - pharmacology; Clinical trials; Deoxyribonucleic acid; DNA; Dosage; Drug delivery; Drug dosages; Drugs; Humanities and Social Sciences; Humans; Imidazoles - pharmacology; MEK inhibitors; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Metastases; multidisciplinary; Mutation; Oximes - pharmacology; Patients; Piperidines - pharmacology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; Pyridones - pharmacology; Pyrimidinones - pharmacology; Schedules; Science; Science (multidisciplinary); Survival; Tumors; Vemurafenib - pharmacology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26572-6

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