Transparency Submission

FDA Clearance: N/A

Rationale for Requested Change: Published data across numerous manuscripts and presentations have demonstrated the prognostic performance of Foresight’s MRD test using PhasED-Seq-technology in LBCLs [2-12]. The published data has consistently demonstrated that Foresight’s MRD test is more prognostic than the current standard of care (PET-CT) at EOT for patients with LBCLs [7-9, 11], and, importantly, provides additional prognostic information even when considering PET-CT scans [reference 11, slide 10]. In a multi-center study led by Roschewski et al, ctDNA-MRD positive status by PhasED-Seq at the end of 1L therapy for DLBCL had a higher Hazard Ratio for PFS than a non-CR response by PET-CT (PR/SD/PD) [reference 7, slide 16]. In this same study, ctDNA-MRD status was significantly prognostic for PFS when considering only patients in a PET CR [reference 7, slide 16]. In a single center study led by Sworder et al, both interim ctDNA-MRD and ctDNA-MRD at the end of 1L therapy for DLBCL were more prognostic than interim or EOT PET-CT scan, including in both univariable and multivariable analyses [reference 11, slides 9-10]. In a single center study comparing response assessment using a singular EOT PET-CT scan versus a singular ctDNA-MRD assessment, ctDNA-MRD assessment better predicted PFS [reference 9, slide 16]. Importantly, when PET-CT is negative, ctDNA-MRD status is predictive of clinical outcomes [reference 7, slide 16; reference 10, slide 12; reference 11, slide 12]. As such, additional short-term surveillance is warranted in PET-CT negative, ctDNA-MRD positive patients to identify those for whom additional therapy may be appropriate. In addition, such patients may be eligible for emerging ctDNA-driven clinical trials. The analytical performance of Foresight’s MRD test has also been demonstrated to be robust and reproducible with an analytical limit of detection below 1 in 1,000,000 and a false positive rate of less than 1% [1]. Though there are many emerging MRD tests in lymphoma, only Foresight’s ctDNA-MRD test has demonstrated the robust analytical [1] and clinical validity [2-12] necessary to support clinical use. Collectively, we believe this data demonstrates that the Foresight CLARITY test provides robust and reliable results for clinical use. The consistent, superior performance of Foresight’s MRD test compared to standard of care PET-CT overall and in the subset of patients who are PET-negative supports the use of ctDNA-MRD assessment in the CR pathway at end-of-therapy.