Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT
Molecular selection of therapy in metastatic colorectal cancer: the FOCUS4 molecularly stratified RCT
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DOI：
10.3310/htnb6908
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发表时间：
2022-12
影响因子：
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通讯作者：
L. Brown;D. Fisher;R. Adams;J. Seligmann;M. Seymour;R. Kaplan;S. Richman;P. Quirke;R. Butler;H. Roberts;J. Graham;R. Wilson;T. Maughan
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作者：
L. Brown;D. Fisher;R. Adams;J. Seligmann;M. Seymour;R. Kaplan;S. Richman;P. Quirke;R. Butler;H. Roberts;J. Graham;R. Wilson;T. Maughan
具有创新设计的复杂试验变得越来越普遍，并有可能在更短的时间内改善患者结局。有证据表明，结直肠癌患者分为不同的亚组，对治疗的反应不同，这种变化与遗传生物标志物有关。据我们所知，FOC 4是转移性结直肠癌的第一个分子分层试验，并且仍然是全球启动的第一个伞形试验设计之一。在转移性结直肠癌的分子亚组中确定改善疾病控制的新型疗法，其中新型疗法预期是最有效的。这是一项II/III期分子分层伞式试验，使用适应性统计方法来决定哪一项子试验应提前关闭;新的子试验作为方案修订案添加。一线联合化疗16周后的维持治疗。登记新诊断的转移性结直肠癌患者，并使用中心实验室检测将其肿瘤分层为分子亚型。一线治疗16周后，病情稳定或缓解的患者有资格随机分配至分子分层子试验或非分层FOX 4-N试验。在探索纳入平台试验的20种药物组合中，启动了3项分子靶向子试验：FOX 4-B（PIK 3CA突变或PTEN过表达）-阿司匹林vs安慰剂; FOX 4-C（TP 53和RAS突变）-阿达沃塞B（AstraZeneca Ltd，剑桥，英国）vs主动监测; FOX 4-D（BRAF-PIK 3CA-RAS野生型）-AZD 8931 vs安慰剂。还进行了一项未分层的子试验：FOC 14-N -卡培他滨与主动监测。主要结局指标是从随机化到进展的无进展生存期，将干预与主动监测/安慰剂进行比较。收集所有随机化患者的毒性和总生存期数据，仅收集FOQOL 4-N患者的生活质量（使用EuroQol-5维度）数据。2014年1月至2020年10月，英国88家医院共登记了1434名患者。1382份样本中有1291份（93%）成功完成了生物标志物检测，1315例完成16周一线治疗的患者中有908例（69%）有资格接受随机化，其中361例随机分配至子试验。FOX 4-B在PIK 3CA突变/ PTEN缺失亚组中评估了阿司匹林与安慰剂的对比，但仅招募了6名患者，因此因无效而关闭。FOSSIL 4-C在RAS + TP 53双突变亚组的67例患者中评价了adavosertib与主动监测，并达到了其主要终点，显示无进展生存期改善（中位3.61 vs. 1.87个月;风险比0.35，95%置信区间0.18 - 0.68; p = 0022）。FOX 4-D在BRAF-PIK 3CA-RAS野生型亚组的32例患者中评估了AZD 8931，未显示获益，因此在首次中期分析后中止。FOSSIL 4-N在254例患者中评估了卡培他滨单药治疗与积极监测的对比，并达到了其主要终点，显示无进展生存期的改善（风险比0.40，95%置信区间0.21至0.75; p < 0.0001）。由于COVID-19，FOC 4-C和FOC 4-N提前关闭，因此没有增加其计划的招聘人数。适应性分层医学研究在常见癌症中是可行的，但存在挑战。卡培他滨单药治疗是一种有效的维持治疗。使用adavosertib的Wee 1抑制显示出显著的临床活性，特别是在左侧结直肠癌中。本试验注册为ISRCTN 90061546。该项目由疗效和机制评估（EME）计划，MRC和国家健康与护理研究所（NIHR）合作伙伴关系以及英国癌症研究所共同资助。这将全文发表在《疗效和机制评价》;第9卷，第9期。请参阅NIHR期刊图书馆网站了解更多项目信息。
Complex trials with innovative designs are becoming increasingly common and offer the potential to improve patient outcomes in a shorter time frame. There is evidence that patients with colorectal cancer fall into different subgroups with varying responsiveness to therapy, and that this variation is linked to genetic biomarkers. To the best of our knowledge, FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and remains one of the first umbrella trial designs to be launched globally. To identify novel therapies that improve disease control within the molecular subgroup of metastatic colorectal cancer in which the novel therapies were expected to be most effective. This was a Phase II/III molecularly stratified umbrella trial that used adaptive statistical methodology to decide which subtrial should close early; new subtrials were added as protocol amendments. The maintenance setting following 16 weeks of first-line combination chemotherapy. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified subtrial or the non-stratified FOCUS4-N trial. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted subtrials were activated: FOCUS4-B (PIK3CA mutation or PTEN overexpression) – aspirin versus placebo; FOCUS4-C (TP53 and RAS mutation) – adavosertib (AstraZeneca Ltd, Cambridge, UK) versus active monitoring; and FOCUS4-D (BRAF-PIK3CA-RAS wild type) – AZD8931 versus placebo. A non-stratified subtrial was also carried out: FOCUS4-N – capecitabine versus active monitoring. The main outcome measure was progression-free survival from the time of randomisation to progression, comparing the intervention with active monitoring/placebo. Toxicity and overall survival data were collected in all randomised patients, and quality of life (using EuroQol-5 Dimensions) data were collected in FOCUS4-N only. Between January 2014 and October 2020, 1434 patients were registered from 88 hospitals in the UK. Successful biomarker testing was completed in 1291 out of 1382 samples (93%), and 908 out of 1315 patients (69%) completing 16 weeks of first-line therapy were eligible for randomisation, with 361 randomly allocated to a subtrial. FOCUS4-B evaluated aspirin versus placebo in the PIK3CA-mutant/ PTEN -loss subgroup, but recruited only six patients, so was closed for futility. FOCUS4-C evaluated adavosertib versus active monitoring in 67 patients in the RAS + TP53 double-mutant subgroup and met its primary end point, showing an improvement in progression-free survival (median 3.61 vs. 1.87 months; hazard ratio 0.35, 95% confidence interval 0.18 to 0.68; p = 0022). FOCUS4-D evaluated AZD8931 in 32 patients in the BRAF-PIK3CA-RAS wild-type subgroup and showed no benefit, so was discontinued after the first interim analysis. FOCUS4-N evaluated capecitabine monotherapy versus active monitoring in 254 patients and met its primary end point, showing improvement in progression-free survival (hazard ratio 0.40, 95% confidence interval 0.21 to 0.75; p < 0.0001). FOCUS4-C and FOCUS4-N were closed early owing to COVID-19, so did not accrue their planned recruitment numbers. Adaptive stratified medicine studies are feasible in common cancers but present challenges. Capecitabine monotherapy is an effective maintenance therapy. Wee1 inhibition using adavosertib shows significant clinical activity, notably in left-sided colorectal cancer. This trial was registered as ISRCTN90061546. This project was jointly funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership, and Cancer Research UK. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 9. See the NIHR Journals Library website for further project information.