Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D): a phase 2-3 randomised trial.
Inhibition of EGFR, HER2, and HER3 signalling in patients with colorectal cancer wild-type for BRAF, PIK3CA, KRAS, and NRAS (FOCUS4-D): a phase 2-3 randomised trial.
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DOI：
10.1016/s2468-1253(17)30394-1
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发表时间：
2018-03
期刊：
影响因子：
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通讯作者：
FOCUS4 Trial Investigators
中科院分区：
文献类型：
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作者：
Adams R;Brown E;Brown L;Butler R;Falk S;Fisher D;Kaplan R;Quirke P;Richman S;Samuel L;Seligmann J;Seymour M;Shiu KK;Wasan H;Wilson R;Maughan T;FOCUS4 Trial Investigators
随着对癌症生物学理解的加深，实体瘤试验方法发生了重大变化。FOC 4是一项在分子分层队列中检测晚期结直肠癌患者靶向药物的2-3期试验项目。在这里，我们的目的是测试的假设，EGFR，HER 2和HER 3信号与酪氨酸激酶抑制剂AZD 8931的联合抑制将控制所有野生型肿瘤的生长。在FOSSIL 4-D中，我们纳入了来自英国18家医院的新诊断的晚期或转移性结直肠癌患者，其肿瘤为BRAF，PIK 3CA，KRAS和NRAS野生型。一线治疗16周后，肿瘤稳定或缓解的患者随机接受口服AZD 8931（40 mg，每日两次）或安慰剂治疗。通过最小化（随机元素为20%）、最小化（按医院研究中心、原发性肿瘤部位、WHO体能状态、16周CT扫描结果、转移部位数量和一线化疗方案）进行随机化。主要结局是无进展生存期。CT扫描由当地放射科医生根据实体瘤疗效评价标准（RECIST）第1.1版进行评估。预先计划的中期分析按照方案进行评估，并使用多组多阶段（MAMS）试验设计方法，由安慰剂组中发生的无进展生存期事件触发。最终分析通过意向治疗进行评估。该试验注册于controlled-trials.com，ISRCTN 90061546。在2014年7月7日至2016年3月7日期间，32例患者随机接受研究治疗，16例接受AZD 8931治疗，16例接受安慰剂治疗。在第一次预先计划的中期分析（2016年3月）中，独立数据监测委员会（IDMC）建议关闭FOX 4-D，因为缺乏活动。在最终分析时（2016年8月1日），31例患者发生了无进展生存事件（AZD 8931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），AZD 8931组为2.96个月（1.94 - 5.62）。与安慰剂相比，未观察到AZD 8931的无进展生存期获益（风险比[HR] 1·10，95% CI 0·47-3·57; p=0·95）。AZD 8931组最常见的3级不良事件是皮疹（15例有可用数据的患者中有3例[20%]，安慰剂组16例患者中无1例），安慰剂组最常见的3级不良事件是腹泻（1例[7%] vs 1例[6%]）。未记录4级不良事件，也未报告治疗相关死亡。FOCA 4的MAMS试验设计显示了试验结果交付的效率和有效性，为在分子定义的患者队列中继续或停止靶向治疗的临床评价提供了信息。总体FOC 4试验现在的目标是在所有野生型肿瘤的队列中开放一个替代组。医学研究理事会（MRC）和国家健康研究所（NIHR）疗效和机制评价计划、英国癌症研究、NIHR临床试验研究网络、威尔士健康与护理研究和阿斯利康。
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.