Cardiff University and Velindre Cancer Centre, Cardiff, UK.
Edinburgh Cancer Centre NHS Lothian, Edinburgh, UK.
Lancet Gastroenterol Hepatol. 2018 Mar;3(3):162-171. doi: 10.1016/S2468-1253(17)30394-1. Epub 2017 Dec 16.
A substantial change in trial methodology for solid tumours has taken place, in response to increased understanding of cancer biology. FOCUS4 is a phase 2-3 trial programme testing targeted agents in patients with advanced colorectal cancer in molecularly stratified cohorts. Here, we aimed to test the hypothesis that combined inhibition of EGFR, HER2, and HER3 signalling with the tyrosine kinase inhibitor AZD8931 will control growth of all wild-type tumours.
In FOCUS4-D, we included patients from 18 hospitals in the UK with newly diagnosed advanced or metastatic colorectal cancer whose tumour was wild-type for BRAF, PIK3CA, KRAS, and NRAS. After 16 weeks of first-line therapy, patients with stable or responding tumours were randomised to oral AZD8931 (40 mg twice a day) or placebo. Randomisation was done by minimisation with a random element of 20%, minimisation by hospital site, site of primary tumour, WHO performance status, 16-week CT scan result, number of metastatic sites, and first-line chemotherapy regimen. The primary outcome was progression-free-survival. CT scans were assessed by local radiologists according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Preplanned interim analyses were assessed per protocol and were agreed using multiarm multistage (MAMS) trial design methodology triggered by occurrence of progression-free survival events in the placebo group. The final analysis was assessed by intention to treat. This trial is registered at controlled-trials.com, ISRCTN 90061546.
Between July 7, 2014, and March 7, 2016, 32 patients were randomised to study treatment, 16 to AZD8931 and 16 to placebo. At the first preplanned interim analysis (March, 2016), the independent data monitoring committee (IDMC) recommended closure of FOCUS4-D because of a lack of activity. At the final analysis (Aug 1, 2016), 31 patients had had a progression-free survival event (15 with AZD8931 and 16 with placebo). Median progression-free survival was 3·48 months (95% CI 1·51-5·09) in the placebo group and 2·96 months (1·94-5·62) in the AZD8931 group. No progression-free survival benefit of AZD8931 compared with placebo was noted (hazard ratio [HR] 1·10, 95% CI 0·47-3·57; p=0·95). The most common grade 3 adverse event in the AZD8931 group was skin rash (three [20%] of 15 patients with available data vs none of 16 patients in the placebo group), and in the placebo group it was diarrhoea (one [7%] vs one [6%]). No grade 4 adverse events were recorded and no treatment-related deaths were reported.
The MAMS trial design for FOCUS4 has shown efficiency and effectiveness in trial outcome delivery, informing the decision to proceed or stop clinical evaluation of a targeted treatment within a molecularly defined cohort of patients. The overarching FOCUS4 trial is now aiming to open a replacement arm in the cohort with all wild-type tumours.
Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation programme, Cancer Research UK, NIHR Clinical Trials Research Network, Health and Care Research Wales, and AstraZeneca.
针对癌症生物学的深入理解，实体瘤临床试验方法发生了重大变化。FOCUS4 是一项 2-3 期临床试验计划，旨在对分子分层队列中晚期结直肠癌患者进行靶向药物治疗。在这里，我们旨在检验联合抑制 EGFR、HER2 和 HER3 信号通路与酪氨酸激酶抑制剂 AZD8931 将控制所有野生型肿瘤生长的假设。
在 FOCUS4-D 中，我们纳入了来自英国 18 家医院的新诊断为晚期或转移性结直肠癌的患者，其肿瘤为 BRAF、PIK3CA、KRAS 和 NRAS 野生型。在一线治疗 16 周后，稳定或有反应的肿瘤患者随机接受口服 AZD8931（每天两次，每次 40mg）或安慰剂。随机化采用最小化方法，随机元素为 20%，最小化因素包括医院地点、原发肿瘤部位、世界卫生组织表现状态、16 周 CT 扫描结果、转移部位数量和一线化疗方案。主要终点是无进展生存期。CT 扫描由当地放射科医生根据实体瘤反应评估标准（RECIST），版本 1.1 进行评估。根据安慰剂组无进展生存事件的发生情况，按方案进行了预计划的中期分析，并使用多臂多阶段（MAMS）试验设计方法达成一致。最终分析按意向治疗进行评估。该试验在 controlled-trials.com 上注册，ISRCTN 90061546。
2014 年 7 月 7 日至 2016 年 3 月 7 日期间，32 名患者被随机分配至研究治疗组，16 名患者接受 AZD8931 治疗，16 名患者接受安慰剂治疗。在第一次预计划的中期分析（2016 年 3 月）时，独立数据监测委员会（IDMC）建议由于缺乏活性而关闭 FOCUS4-D。在最终分析（2016 年 8 月 1 日）时，31 名患者出现无进展生存期事件（AZD8931 组 15 例，安慰剂组 16 例）。安慰剂组的中位无进展生存期为 3.48 个月（95%CI 1.51-5.09），AZD8931 组为 2.96 个月（1.94-5.62）。AZD8931 与安慰剂相比，无无进展生存期获益（HR 1.10，95%CI 0.47-3.57；p=0.95）。AZD8931 组最常见的 3 级不良事件是皮疹（15 名可获得数据的患者中有 3 名[20%]，安慰剂组无 16 名患者），安慰剂组是腹泻（1 名[7%] vs 1 名[6%]）。没有记录到 4 级不良事件，也没有与治疗相关的死亡。
FOCUS4 的 MAMS 试验设计在试验结果交付方面显示出了效率和有效性，为在分子定义的患者队列中对靶向治疗的临床评估进行继续或停止的决策提供了信息。总体 FOCUS4 试验现在旨在该所有野生型肿瘤队列中开放一个替代臂。
英国医学研究理事会（MRC）和国家健康研究所（NIHR）疗效和机制评估计划、英国癌症研究中心、英国国家健康研究所临床试验研究网络、威尔士健康与护理研究中心和阿斯利康公司。
