Department of Medical Oncology, UZ Brussel, Brussels, Belgium.
Department of Medical Oncology, UZ Gent, Ghent, Belgium.
Lancet Oncol. 2017 Apr;18(4):464-472. doi: 10.1016/S1470-2045(17)30171-7. Epub 2017 Mar 4.
Patients with BRAF-mutant melanoma benefit from treatment with the combination of BRAF and MEK inhibitors, but resistance and disease progression develops in most patients. Preclinical studies and case studies have indicated that acquired resistance to BRAF inhibition can be reversible. We aimed to assess the anti-tumour activity of rechallenge with BRAF plus MEK inhibition in a prospective clinical trial.
In this open-label, single arm, dual-centre, phase 2 academic study in Belgium, patients aged 18 years or older with BRAF-mutant melanoma who had previously progressed on BRAF inhibitors (with or without MEK inhibitors) and were off-treatment for at least 12 weeks, were treated with dabrafenib 150 mg orally twice per day plus trametinib 2 mg orally once per day. The primary endpoint was the proportion of patients with investigator-assessed overall response at any time (defined as complete response or partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed on two occasions, at least 28 days after the first response was recorded). Analyses were done in the intention-to-treat population. The study is ongoing but no longer recruiting patients. This trial is registered with ClinicalTrials.gov, number NCT02296996.
Between April 5, 2014, and Feb 2, 2016, 25 patients were enrolled and initiated treatment in our study. A partial response was documented in eight (32%) of 25 patients (95% CI 15-54; six patients had progressed on previous treatment with dabrafenib plus trametinib and two patients had progressed on previous BRAF inhibitor monotherapy). Stable disease was noted in ten patients (40%; 95% CI 21-61). Rechallenge with dabrafenib plus trametinib was well tolerated. There were no unexpected or grade 4 or 5 treatment-related adverse events. Grade 3 adverse events occurred in two patients (8%; panniculitis [n=1] and pyrexia [n=1]). Serious adverse events which occurred on study were one patient with an Addison crisis triggered by grade 2 pyrexia symptoms that resolved after discontinuation of dabrafenib and trametinib. No patients died as a result of study treatment.
Rechallenge with dabrafenib plus trametinib showed anti-tumour activity in patients who had previously progressed on BRAF inhibitors and as such, rechallenge represents a potential new treatment option for these patients.
Vlaamse Liga Tegen Kanker, Novartis.
BRAF 突变型黑色素瘤患者接受 BRAF 和 MEK 抑制剂联合治疗可获益，但大多数患者会出现耐药和疾病进展。临床前研究和病例研究表明，对 BRAF 抑制的获得性耐药可能是可逆的。我们旨在评估 BRAF 加 MEK 抑制再挑战在一项前瞻性临床试验中的抗肿瘤活性。
在比利时的这项开放标签、单臂、双中心、2 期学术研究中，年龄在 18 岁及以上、先前接受过 BRAF 抑制剂（有或无 MEK 抑制剂）治疗且停药至少 12 周的 BRAF 突变型黑色素瘤患者，接受每日两次口服 150mg 达布拉非尼和每日一次口服 2mg 曲美替尼治疗。主要终点是任何时间（根据实体瘤反应评价标准 1.1 定义，在首次记录应答后至少 28 天，两次确认完全缓解或部分缓解）评估的患者总体应答比例（完全缓解或部分缓解；有 6 例患者在先前接受达布拉非尼联合曲美替尼治疗时进展，有 2 例患者在先前接受 BRAF 抑制剂单药治疗时进展）。分析采用意向治疗人群。该研究正在进行中，但不再招募患者。该试验在 ClinicalTrials.gov 注册，编号为 NCT02296996。
2014 年 4 月 5 日至 2016 年 2 月 2 日，共有 25 例患者入组并开始接受我们的研究治疗。25 例患者中有 8 例（32%；95%CI15-54；6 例患者先前接受达布拉非尼联合曲美替尼治疗时进展，2 例患者先前接受 BRAF 抑制剂单药治疗时进展）记录到部分缓解。10 例患者（40%；95%CI21-61）病情稳定。达布拉非尼联合曲美替尼再挑战耐受良好。无意外或 4 级或 5 级与治疗相关的不良事件。2 例患者发生 3 级不良事件（脂肪炎[1 例]和发热[1 例]）。研究期间发生的严重不良事件为 1 例因 2 级发热症状导致的艾迪生病危象，停用达布拉非尼和曲美替尼后缓解。无患者因研究治疗而死亡。
先前接受 BRAF 抑制剂治疗的患者再次接受达布拉非尼联合曲美替尼治疗显示出抗肿瘤活性，因此，再挑战可能成为这些患者的一种新的潜在治疗选择。
Vlaamse Liga Tegen Kanker，诺华。
