免疫疗法的崛起已经陨石 - 现在依照Clinicaltrials.gov。寻找和注册适当的患者为这些潜在的革命性治疗呈现出深刻的挑战，最近被拟订的New York Times文章：癌症难题：药物试验太多，患者太少。另一个拼图是临床试验设计，当在IO中测试组合治疗时，可以特别详细说明。加剧了这些问题，IO试验是市场上越来越竞争的竞争。分配有很大的价值，减少发展时间，并成为课堂内批准的第一种药物或具体迹象。
本博客文章讨论了目前免疫肿瘤学研究的状态，增强患者招聘的策略，伴随诊断的作用以及处理IO组合研究的复杂性的探讨和解决方案。
在免疫肿瘤学中的新“I / II / III”实现快速进展
The most noticeable shift in oncology drug development has occurred in clinical trial design. Recent trends point toward sponsors no longer designing oncology Phase I trials in isolation, but rather implementing a Phase I/II design. Once a safe dose is identified, biomarker-selected expansion cohorts may be added, providing an accelerated look at both efficacy and safety, and ultimately, supporting the registration of the drug. This rapid cohort expansion approach along with breakthrough therapy designation, and accelerated approval opportunities using Phase II studies for drug registration are becoming the new norm in oncology.
The use of a companion diagnostic in a trial can provide additional efficiency and outcomes benefits. By identifying the right patients for cohort selection and patient stratification, a companion diagnostic can help deliver the highest possible efficacy and further reduce the drug development timeline.
利用伴侣诊断来评估疗效
AstraZeneca’s TAGRISSO® (osimertinib), a specific inhibitor for epidermal growth factor receptor (EGFR), is one example of how a companion diagnostic helped accelerate development and approval process1。在I阶段，在剂量升级阶段随机化患者，用于评估药代动力学，药效学和疗效。在这种阶段，研究疗效增加了NSCLC患者，其肿瘤对于特异性EGFR突变，T790M为阳性。
这些研究在A II期研究中确认，所述患者对先前失败的第一线疗法失败的患者，持续观察到T790M突变的患者表现出最佳反应。
通过掺入伴侣诊断，它们鉴定了T790M的患者，并将OSIMERTINIB与护理标准进行比较，铂 - 培养物。研究人员观察到，Osimertinib从四个月到八个月的无进展生存率翻了一番。因此，待遇加速了FDA的加速批准。值得注意的是，在治疗第一患者后，这只是两年半，通过快速识别主要受益于治疗的患者，部分支持的进展。
Removing Pain Points in Patient Recruitment
Given that patient recruitment consumes nearly 40% of a trial’s costs, and anywhere from 20-60% of the total clinical development timeline, sponsors are eager to find more efficient solutions to find and enroll patients. This is especially true in oncology studies, where only 3% of cancer patients are enrolled in trials and half of all sites under-enroll (including 11% that fail to enroll a single patient).
Recognizing this issue as an opportunity to leverage data analytics and bio informatics capabilities with both public and proprietary trial data, Covance has been supporting IO clinical trials with theXcellate.® Informatics Suite。例如，如果赞助商想要运行非小细胞肺癌（NSCLC）研究，例如，Xcellerate预测和站点选择工具可以评估NSCLC发病率的全球数据。
按地区甚至特定国家或城市过滤，该团队可以确定有多少潜在患者在任何特定的区域和调查员绩效和招聘百分比的交叉引用。通过建模多种方案来比较招聘速度，网站激活，成本和复杂性，赞助商可以选择最佳网站，以支持他们的学习，优化患者招聘和提高操作表现。
这些工具，耦合诊断数据Labcorp.，赞助商可以根据生物标志物的结果查看临床试验机会和潜在患者人口，例如PD-1 / PD-L1状态。这些数据允许赞助商不仅可以看到正在测试高表达患者的位置，而且还查看分子表达水平，可以引导议定书的包含/排除标准的有价值的信息，并促进更智能，更有效的试验设计。
Tackling the Complexity of Combination Trials
最近的研究已经研究了IO治疗的添加剂效应，例如金生物与黑色素瘤患者的IPILIMIMAB相结合。虽然这些研究揭示了有希望的结果，但它们通常需要新颖和复杂的试验设计来挑选最佳组合。
Decision points appear at many junctions, such as at initial tumor evaluation to identify specific markers, ongoing tumor assessment under the iRECIST guidelines, and then options to randomize, continue treatment based on changes in the tumor size or even introduce a combination treatment and repeat with the next iteration. Very quickly, the complexity of these studies can explode.
伴随诊断可以帮助处理这些试验中面临的一些挑战。自适应的两级人口丰富的设计是一个例子，由Bhatt和Mehta发表新英格兰医学杂志2。这里，患者分层分层，然后放入治疗或控制臂中。在临时分析时，如果在任一组中没有响应，则停止研究，如果两个组中存在响应，或者可以将非响应子组重新分配给响应组并增加其事件数量。该分组和重新组合过程可以帮助赞助商更快地达到最终分析，这是达到拥挤市场的重要因素。
As the next wave of combination trials in immuno-oncology emerges, sponsors face a variety of choices and decision points. With the help of companion diagnostic assays, historical investigator/clinical trial data and appropriate trial strategies, we hope to enable faster clinical development and regulatory approval to ultimately help patients get access to more effective, targeted oncology treatments.
参考资料：
1Pasi A. Jänne, M.D., Ph.D., et.al. “AZD9291 in EGFR Inhibitor-Resistant Non-Small-Cell Lung Cancer”.新英格兰医学杂志。2015;376:629-640.
2Deepak L. Bhatt，M.D.，M.P.H.和Cyrus Mehta，Ph.D.“临床试验的自适应设计”。新英格兰医学杂志。2016; 375：65-74。
