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.

BRAF (BRAFi) 加 MEK 抑制剂 (MEKi) 的联合治疗已证明对具有活化BRAF 的晚期黑色素瘤患者的生存有益突变。先前的临床前研究表明，这些药物的间歇给药可以延缓耐药性的出现。与预期相反，第一个发表的 2 期随机研究比较了达拉非尼 (BRAFi) 加曲美替尼 (MEKi) 的连续和间歇方案，证明了“开-关”方案的不利影响。在这里，我们报告了来自 II 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的抗肿瘤活性与 vemurafenib (BRAFi) 加 cobimetinib (MEKi) 的间歇组合在晚期 BRAF 突变黑色素瘤患者 (NCT02583516) 中的疗效。该试验未达到其无进展生存期 (PFS) 改善的主要终点。我们的结果表明，vemurafenib 加 cobimetinib 的实验性间歇方案的抗肿瘤活性并不优于标准的连续方案。检测无细胞肿瘤 DNA 中的BRAF突变对生存具有预后价值，其动力学与临床反应具有极好的相关性，但与进展无关。NGS 分析证明了耐药病例中的从头突变。