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

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.