Circulating tumor DNA for detection of molecular residual disease (MRD) in patients (pts) with stage II/III colorectal cancer (CRC): Final analysis of the BESPOKE CRC sub-cohort.

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15 Background: BESPOKE CRC, a multicenter, prospective, observational study investigated the clinical utility of ctDNA for detecting MRD-based early recurrence in pts with surgically resected CRC. The primary endpoint was to assess the impact of ctDNA testing on treatment decisions and asymptomatic recurrence rates. The secondary endpoint was to assess the MRD clearance rate, survival of MRD-negative pts, overall survival, and patient-reported outcomes. Methods: Complete clinical and laboratory data were available for 1001 pts with stages II–III CRC. Longitudinal ctDNA testing was performed prospectively using a clinically validated, personalized, tumor-informed 16-plex mPCR-NGS assay (Signatera, Natera, Inc.). Plasma time points (n=8,536) were collected during the MRD (2-12 weeks postoperatively) and surveillance (post-adjuvant chemotherapy [ACT] completion/12 weeks postoperatively for pts observed) windows. We evaluated the correlation between ctDNA status and disease-free survival (DFS) as part of exploratory analysis. Results: Following curative resection, 62.4% (625/1001) pts received ACT: 25.9% (115/443) stage II, and 91.3% (510/558) stage III.Among pts with ctDNA results available during the MRD window with a median follow-up of 23.15 (range: 2.89-33.45) months, ctDNA-positivity was observed in 8.1% (34/420) of stage II and 24.9% (126/505) of stage III pts. A significant association between ctDNA positivity and inferior DFS was observed in stage II (HR=10.4; p<0.0001), and stage III (HR=10.1, p<0.0001) pts. 18/24 month DFS estimates for stages II-III combined were: (MRD-negative: 93.0%/91.7%; MRD-positive: 44.4%/41.4%). Analysis of surveillance was performed separately for pts observed (N=368) vs. ACT-treated (N=597). During surveillance, in the observation cohort, 6.8% (22/323) of stage II, and 33.3% of stage III (15/45) pts tested ctDNA-positive correlating with significantly worse DFS (stage II: HR=34.9; p<0.0001, stage III: HR=34.1; p=0.0008). Likewise, in the ACT cohort, 10.9% (12/110) of stage II and 21.1% of stage III (103/487) pts turned ctDNA-positive and had significantly worse DFS (stage II: HR=131.4; p<0.0001, stage III: HR=54.6; p<0.0001). Analysis of primary and secondary endpoints will be presented. Conclusions: ctDNA positivity was highly prognostic of DFS within MRD and surveillance windows in a subset of stages II-III pts enrolled in the BESPOKE CRC study. Our results highlight the potential value of ctDNA-based MRD detection for treatment-decision making, and findings relevant to clinical utility will be reported in the conference presentation. Clinical trial information: NCT04264702 .

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