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
How targeted therapies and immunotherapies shape tumours and thereby influence subsequent therapeutic responses is poorly understood.,Here, we show in melanoma patients and mouse models that when tumours relapse following targeted therapy with MAPK pathway inhibitors, they are cross-resistant to immunotherapies, despite the different modes of action of these therapies.,We find that cross-resistance is mediated by a cancer cell-instructed, immunosuppressive tumour microenvironment that lacks functional CD103+ dendritic cells, precluding an effective T cell response.,Restoring the numbers and functionality of CD103+ dendritic cells can re-sensitize cross-resistant tumours to immunotherapy.,Cross-resistance does not arise from selective pressure of an immune response during evolution of resistance, but from the MAPK pathway, which is not only reactivated, but also exhibits an increased transcriptional output that drives immune evasion.,Our work provides mechanistic evidence for cross-resistance between two unrelated therapies, and a scientific rationale for treating patients with immunotherapy before they acquire resistance to targeted therapy.