Developing a kit-based research use only (RUO) translocation assay for deployment as a lab developed test (LDT) toward changing outcomes for patients with driver-negative tumors

开发一种基于试剂盒的仅用于研究(RUO)的易位试验，用于实验室开发部署 测试(LDT)以改变驾驶员阴性肿瘤患者的预后(RFA小节： 癌症诊断技术平台) 摘要 每年有近100万名患者被诊断为晚期癌症。阿里玛最喜欢的一个病例是一个十几岁的孩子 被诊断出患有晚期脑癌的女孩。她的肿瘤已经用最先进的技术进行了两次测试 基于NGS的实验室开发了测试(LDT)，但没有找到可行的基因驱动因素，从而对她的肿瘤进行了分类 “司机阴性”，无法获得有针对性的治疗，极大地降低了她存活的可能性。 然而，多亏了家长阶段2奖，Arima刚刚开发了一个NGS技术平台- T-Seq试剂盒-用于检测肿瘤活检中的肿瘤驱动易位和基因融合。看哪，什么时候 T-Seq分析了这位患者的肿瘤，发现了与PD-L1有关的易位，引发了一系列事件 导致使用培溴利珠单抗治疗，9个月后没有肿瘤迹象，这都要归功于T-Seq。这 Proposal努力扩大这一临床起源故事，以在50%的患者中产生广泛影响 晚期癌症，没有可检测到的基因驱动因素(美国每年约有48.8万名患者)。然而，要做到这一点， 广泛的影响，T-Seq技术必须以 LDT。该提案的首要目标是执行所有必要步骤来开发和验证T-Seq试剂盒 以便将它们提供给CLIA实验室，他们将验证和部署T-Seq作为LDT，以告知临床护理。 多亏了我们的父母阶段2，朝着这个目标的执行已经开始。从技术的角度来看，T- SEQ试剂盒比现有技术更敏感，因为它们通过空间的透镜描绘易位 3D基因组，而不是线性基因组，从而能够检测到像PD-L1这样的肿瘤驱动易位 否则就错过了。T-Seq技术也已产品化，满足所有关键产品的要求 作为LDT部署，最终推出成套的端到端T-Seq工作流。最后，T-Seq套件 性能与现有技术一致，但它在54%的司机中检测到导致肿瘤的易位。 阴性肿瘤，包括4名由于T-Seq而改变了临床护理过程的患者。 有了手头的产品和基本的临床数据，建议的目标就可以完成其余步骤 朝着我们成为CLIA实验室的技术提供商的目标前进。具体地说，这项提案首先旨在建立 T-Seq的竞争性分析性能指标。然后，本研究旨在证明本研究的临床有效性和实用性。 T-SEQ横跨主流肿瘤类型，以及在严重未满足需求的临床背景下。最后，该提案旨在 在合作的学术和商业CLIA实验室中验证和部署T-Seq试剂盒。每一次的成功 建议的目标是使用与该目标相关的多个量化指标进行衡量的，并由CLIA分析提供信息 由LDT生态系统中的利益相关者定义的验证指南和关键指标。通过得出的结论 2b阶段计划，将实现成为CLIA实验室技术供应商的最终目标， 据此，T-Seq试剂盒将作为LDT部署在最初的学术和商业CLIA实验室中，以及临床数据， 将建立对T-Seq的认识，以加快未来采用T-Seq作为LDT的速度。

Developing a kit-based research use only (RUO) translocation assay for deployment as a lab developed test (LDT) toward changing outcomes for patients with driver-negative tumors (RFA sub-section: Technology platform for Cancer Diagnostics) SUMMARY Nearly 1M patients are diagnosed with advanced stage cancer per year. One case dear to Arima is a teenage girl who was diagnosed with advanced brain cancer. Her tumor had been tested twice using state-of-the-art NGS-based lab developed tests (LDTs), but no actionable genetic driver could be found, classifying her tumor as “driver-negative”, precluding access to targeted therapies and greatly reducing her likelihood of survival. However, thanks to the parental phase-2 award, Arima had just developed an NGS technology platform – the T-Seq kit – to detect tumor driving translocations and gene fusions from tumor biopsies. Lo and behold, when T-Seq analyzed this patient’s tumor, it revealed a translocation implicating PD-L1, triggering a series of events leading to treatment with pembrolizumab and 9 months later no signs of tumor, all thanks to T-Seq. This proposal strives to scale this clinical origin story to make a widespread impact in the 50% of patients with advanced cancers and no detectable genetic drivers (~488,000 patients per year in US). However, to make this widespread impact, T-Seq technology must be made available to oncologist and pathologist in the form of an LDT. The overarching goal of this proposal is to execute all necessary steps to develop and validate T-Seq kits so that they can be supplied to CLIA labs who will validate and deploy T-Seq as an LDT to inform clinical care. Thanks to our parental phase-2, execution towards this goal has already begun. From a tech perspective T- Seq kits are more sensitive than existing tech because they profile translocations through the lens of a spatial 3D genome, rather than a linear genome, enabling detection of tumor driving translocations like PD-L1 that are otherwise missed. T-Seq technology has also been productized, meeting all the key product products for deployment as an LDT, culminating in the launch of a kitted end-to-end T-Seq workflow. Lastly, T-Seq kit performance is concordant with existing tech, yet it detects tumor-driving translocations in 54% of driver- negative tumors, including 4 patients where the course of clinical care has been altered thanks to T-Seq. With a product in hand and foundational clinical data, the proposed aims accomplish the remaining steps towards our goal of becoming a tech provider to CLIA labs. Specifically, this proposal first aims to establish competitive analytical performance metrics for T-Seq. Then it aims to demonstrate clinical validity and utility of T-Seq across mainline tumor types, and in clinical contexts of severe unmet need. Lastly, the proposal aims to validate and deploy T-Seq kits in partnering academic and commercial CLIA laboratories. The success of each proposed aims is measured using multiple quantitative metrics relevant to that aim, informed by CLIA assay validation guidelines and key metrics defined by stakeholders in the LDT ecosystem. By the conclusion of the phase-2b program, the ultimate goal of becoming a technology provider to CLIA labs will be accomplished, whereby T-Seq kits will be deployed as LDTs in initial academic and commercial CLIA labs, and clinical data, publications, and awareness of T-Seq will be established to accelerate future adoption of T-Seq as an LDT.