Abstract:
Background: Driver mutations at BRAF V600 are frequently identified in papillary thyroid cancer and anaplastic thyroid cancer (ATC), in which BRAF inhibitors have shown clinical effectiveness. This Japanese phase 2 study evaluated the efficacy and safety of a BRAF inhibitor, encorafenib, combined with an MEK inhibitor, binimetinib, in patients with BRAF V600-mutated thyroid cancer. Methods: This phase 2, open-label, uncontrolled study was conducted at 10 institutions targeted patients with BRAF V600-mutated locally advanced or distant metastatic thyroid cancer not amenable to curative treatment who became refractory/intolerant to ≥1 previous vascular endothelial growth factor receptor-targeted regimen(s) or were considered ineligible for those. The primary endpoint was centrally assessed objective response rate (ORR). The secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: We enrolled 22 patients with BRAFV600E-mutated thyroid cancer: 17 had differentiated thyroid cancer (DTC), and 5 had ATC. At data cutoff (October 26, 2022), the median follow-up was 11.5 (range = 3.4-19.0) months. The primary endpoint of centrally assessed ORR was 54.5% (95% confidence interval [CI] 32.2-75.6; partial response in 12 patients and stable disease in 10). The ORRs in patients with DTC and ATC were 47.1% (8 of 17) and 80.0% (4 of 5), respectively. The medians for DOR and PFS by central assessment and for OS were not reached in the overall population, the DTC subgroup, or the ATC subgroup. At 12 months, the rate of ongoing response was 90.9%, and the PFS and OS rates were 78.8% and 81.8%, respectively. All patients developed ≥1 adverse events (AEs): grade 3 AEs in 6 patients (27.3%). No patients developed grade 4-5 AEs. The most common grade 3 AE was lipase increased (4 patients [18.2%]). Those toxicities were mostly manageable with appropriate monitoring and dose adjustment. Conclusions: Treatment with encorafenib plus binimetinib met the primary endpoint criteria and demonstrated clinical benefit in patients with BRAFV600E-mutated thyroid cancer regardless of its histological type, such as DTC or ATC, with no new safety concerns identified. Encorafenib plus binimetinib could thus be a new treatment option for BRAF V600-mutated thyroid cancer. Clinical Trial Registration number: Japan Registry of Clinical Trials: jRCT2011200018.
摘要:
背景:在乳头状甲状腺癌(PTC)和间变性甲状腺癌(ATC)中经常发现BRAFV600的驱动突变,其中BRAF抑制剂已显示出临床有效性。这项日本2期研究评估了BRAF抑制剂的疗效和安全性,恩科拉非尼,结合MEK抑制剂,比米替尼,在BRAFV600突变甲状腺癌患者中。
方法:第二阶段,开放标签,在10个机构进行的非对照研究针对BRAFV600突变的局部晚期或远处转移性甲状腺癌患者,这些患者不适合治愈性治疗,对≥1个先前的血管内皮生长因子受体(VEGFR)靶向方案变得难治性/不耐受或被认为不适合那些。主要终点是集中评估客观缓解率(ORR)。次要终点包括反应持续时间(DOR),无进展生存期(PFS),总生存期(OS),和安全。
结果:我们纳入了22例BRAFV600E突变甲状腺癌患者:17例分化型甲状腺癌(DTC),5例ATC。在数据截止时(2022年10月26日),中位随访时间为11.5(范围,3.4-19.0)个月。集中评估的ORR的主要终点为54.5%(95%置信区间[CI],32.2-75.6;12例患者部分缓解,10例疾病稳定)。DTC和ATC患者的ORR分别为47.1%(17个中的8个)和80.0%(5个中的4个),分别。通过中央评估和OS的DOR和PFS的中位数在总体中未达到,DTC子组,或ATC子组。12个月时,持续反应率为90.9%,PFS和OS率为78.8%,和81.8%,分别。所有患者出现≥1次不良事件(AEs):6例患者出现3级AEs(27.3%)。没有患者出现4-5级AE。最常见的3级AE是脂肪酶升高(4例患者[18.2%])。通过适当的监测和剂量调整,这些毒性大多是可以控制的。
结论:恩科拉非尼联合比尼美替尼治疗符合主要终点标准,并显示出BRAFV600E突变甲状腺癌患者的临床获益,无论其组织学类型如何,如DTC或ATC,没有发现新的安全问题。因此,恩科非尼联合比尼美替尼可能是BRAFV600突变甲状腺癌的新治疗选择。