Longitudinal clinical performance of a novel tumor-naive minimal residual disease assay in patients with resected stage II and III colorectal cancer: A subset analysis from the GALAXY study in CIRCULATE-Japan

Authors Yoshiaki Nakamura, Kristiyana Kaneva, Christine Lo, Farahnaz Islam, Seung Won Hyun, Daniel Neems, Jason Yamada-Hanff, Terri Driessen, Hala Boulos, Chithra Sangli, Richard Blidner, Hideaki Bando, Robert Tell, Daisuke Kotani, Kate Sasser, Halla Nimeiri, Eiji Oki, Takayuki Yoshino

Background: The presence of circulating tumor DNA (ctDNA) can identify patients (pts) at higher risk of recurrence. Longitudinal surveillance of ctDNA may enable early identification of pts who are likely to relapse and presents a window of opportunity for early interventions to improve outcomes. A tumor-naïve plasma-only approach for minimal residual disease (MRD) assessment accelerates turnaround time, enabling rapid adjuvant chemotherapy (ACT) treatment decisions and ongoing molecular surveillance.

Methods: Samples were collected from GALAXY in CIRCULATE-Japan and analyzed for postsurgical ctDNA detection at a landmark time point (LMT), 4 weeks after surgery in pathological stage II or III colorectal cancer (CRC). Initially, 80 pts meeting pre-specified eligibility criteria were randomly selected, with enrichment for recurrence to 50% while maintaining the stage II:III recurrent (R)/nonrecurrent (NR) ratio observed in GALAXY. Of those, 23 pts also had longitudinal plasma samples analyzed to date (including 17 false negative (FN) at LMT). Residual plasma samples were analyzed with the Tempus xM MRD assay (xM), a tumor-naïve MRD ctDNA assay that integrates methylation and genomic variant data to deliver a binary MRD call blinded to clinical outcomes. The methylation workflow detects fragments with CRC methylation signatures in differentially methylated regions. The variant classifier detects highly prevalent CRC variants. Longitudinal MRD+ status was defined as any MRD+ call after surgery or ACT; lead time as the time from first MRD+ call after definitive therapy to clinical recurrence.

Results: Of the 80 pts, 70 [Stage II n= 29 (41%), Stage III n= 41 (59%)] were evaluable (36 R and 34 NR). At the LMT and with at least 1-year follow-up, 18/36 R pts had detectable ctDNA (MRD+) and 30/34 NR pts had undetectable ctDNA (MRD-), providing clinical sensitivity (CS) of 50% and specificity of 88%. Additional sensitivity analysis included 2 false positive pts who cleared ctDNA with ACT and provided CS 53% and specificity 94% at LMT. Longitudinal analysis of all FNs and ACT treated true positive (TP) pts improved CS from 50% at LMT to 90.9% (stage II 91.7%, stage III 90.5%) on surveillance. The mean lead time was 4.72 mos overall, 5.29 mos for pts treated with surgery alone. Additionally, xM MRD status at LMT strongly correlated with disease-free survival (DFS) with a hazard ratio (HR) of 5.09, superior to 12 week carcinoembryonic antigen (CEA) correlation with DFS, HR 2.63.

Conclusions: xM is a novel tumor-naïve MRD assay that demonstrated remarkable clinical longitudinal performance, and can accurately predict clinical recurrence on surveillance. xM ctDNA status was a strong prognostic biomarker to DFS and superior to standard of care CEA.