Translational Cancer Research Unit, Instituto Oncologico Dr Rosell, Dexeus University Hospital, Barcelona, Spain.
Hospital Universitario de Canarias, Tenerife, Spain.
Nat Commun. 2021 Dec 1;12(1):7008. 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.
联合治疗 BRAF（BRAFi）加 MEK 抑制剂（MEKi）已证明对携带激活 BRAF 突变的晚期黑色素瘤患者具有生存获益。先前的临床前研究表明，这些药物的间歇性给药可能会延迟耐药性的出现。与预期相反，第一项比较达布拉非尼（BRAFi）加曲美替尼（MEKi）连续与间歇性给药方案的发表的 2 期随机研究表明“开-关”方案具有不利影响。在这里，我们报告了一项 2 期随机、开放标签临床试验的确认数据，该试验比较了标准方案与晚期 BRAF 突变黑色素瘤患者中维莫非尼（BRAFi）加考比替尼（MEKi）间歇性联合治疗的抗肿瘤活性（NCT02583516）。该试验未达到无进展生存期（PFS）改善的主要终点。我们的结果表明，实验性间歇性维莫非尼联合考比替尼方案的抗肿瘤活性并不优于标准连续方案。游离肿瘤 DNA 中 BRAF 突变的检测对生存具有预后价值，其动态与临床反应具有极好的相关性，但与进展无关。NGS 分析显示耐药病例中存在新出现的突变。
