1 University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium.
2 Netherlands Cancer Institute, Amsterdam, the Netherlands.
J Clin Oncol. 2019 Jun 10;37(17):1460-1469. doi: 10.1200/JCO.18.02459. Epub 2019 Mar 20.
To determine the safety and preliminary efficacy of selective combination targeted therapy for V600E-mutant metastatic colorectal cancer (mCRC) in the safety lead-in phase of the open-label, randomized, three-arm, phase III BEACON Colorectal Cancer trial ( ClinicalTrials.gov identifier: NCT02928224; European Union Clinical Trials Register identifier: EudraCT2015-005805-35).
Before initiation of the randomized portion of the BEACON Colorectal Cancer trial, 30 patients with V600E-mutant mCRC who had experienced treatment failure with one or two prior regimens were to be recruited to a safety lead-in of encorafenib 300 mg daily, binimetinib 45 mg twice daily, plus standard weekly cetuximab. The primary end point was safety, including the incidence of dose-limiting toxicities. Efficacy end points included overall response rate, progression-free survival, and overall survival.
Among the 30 treated patients, dose-limiting toxicities occurred in five patients and included serous retinopathy (n = 2), reversible decreased left ventricular ejection fraction (n = 1), and cetuximab-related infusion reactions (n = 2). The most common grade 3 or 4 adverse events were fatigue (13%), anemia (10%), increased creatine phosphokinase (10%), increased AST (10%), and urinary tract infections (10%). In 29 patients with V600E-mutant tumors (one patient had a non- V600E-mutant tumor and was not included in the efficacy analysis), the confirmed overall response rate was 48% (95% CI, 29.4% to 67.5%), median progression-free survival was 8.0 months (95% CI, 5.6 to 9.3 months), and median overall survival was 15.3 months (95% CI, 9.6 months to not reached), with median duration of follow-up of 18.2 months (range, 16.6 to 19.8 months).
In the safety lead-in, the safety and tolerability of the encorafenib, binimetinib, and cetuximab regimen is manageable and acceptable for initiation of the randomized portion of the study. The observed efficacy is promising compared with available therapies and, if confirmed in the randomized portion of the trial, could establish this regimen as a new standard of care for previously treated V600E-mutant mCRC.
在 BEACON 结直肠癌试验（ClinicalTrials.gov 标识符：NCT02928224；欧盟临床试验注册标识符：EudraCT2015-005805-35）的开放标签、随机、三臂 III 期研究的安全导入阶段，确定 V600E 突变转移性结直肠癌（mCRC）的选择性联合靶向治疗的安全性和初步疗效。
在开始 BEACON 结直肠癌试验的随机部分之前，招募了 30 名 V600E 突变 mCRC 患者，这些患者在接受一种或两种前期方案治疗后失败，他们将接受恩考芬尼 300mg 每日、比尼替尼 45mg 每日两次联合标准每周西妥昔单抗的安全导入治疗。主要终点是安全性，包括剂量限制毒性的发生率。疗效终点包括总缓解率、无进展生存期和总生存期。
在 30 名接受治疗的患者中，有 5 名患者发生了剂量限制毒性，包括浆液性视网膜病变（n=2）、可逆性左心室射血分数降低（n=1）和西妥昔单抗相关输注反应（n=2）。最常见的 3 级或 4 级不良事件是疲劳（13%）、贫血（10%）、肌酸磷酸激酶升高（10%）、AST 升高（10%）和尿路感染（10%）。在 29 名 V600E 突变肿瘤患者中（1 名患者有非 V600E 突变肿瘤，未纳入疗效分析），确认的总缓解率为 48%（95%CI，29.4%至 67.5%），中位无进展生存期为 8.0 个月（95%CI，5.6 至 9.3 个月），中位总生存期为 15.3 个月（95%CI，9.6 个月至未达到），中位随访时间为 18.2 个月（范围为 16.6 至 19.8 个月）。
在安全导入期，恩考芬尼、比尼替尼和西妥昔单抗方案的安全性和耐受性可控，可接受用于研究的随机部分。与现有疗法相比，观察到的疗效很有希望，如果在试验的随机部分得到证实，该方案可能成为治疗先前治疗过的 V600E 突变 mCRC 的新的护理标准。
