Minimal residual disease (MRD) trials in colorectal cancer (CRC): An overview of a heterogeneous field.

140 Background: MRD is a state where circulating tumor DNA (ctDNA) is detected without visible radiologic disease after curative intent procedures. As this is associated with a high risk of recurrence, several clinical trials are ongoing for CRC in this setting with the goal of eradicating the disease before overt metastases establish. We aim to provide an overview of this field of research. Methods: Clinicaltrials.gov was screened for colorectal, colon, and rectal cancer trials containing the keywords minimal residual disease or MRD. Information on geographical region, phase, tumor stage and site, requirements on ctDNA, radiological no evidence of disease (NED) and prior adjuvant therapy, duration and type of therapy, and endpoints was collected. Results: A total of 41 MRD trials (USA 46%, Asia 24%, Europe 24%, multinational 5%) were identified, of which 23 are recruiting, 8 active not recruiting, 8 not yet recruiting, and 2 have an unknown status. Among interventional trials (n = 39), 37% are phase 3, 39% phase 2, and 20% phase 1, with 54% having a randomized design. Localized-only disease is included in 49%, localized or stage IV in 34%, stage IV-only in 10%, and not defined in 7%. CRC is enrolled in 23 trials, colon only in 13, and multiple disease types in 5. All except one trial have specific requirements for ctDNA positivity, with timing criteria being mentioned in 31 trials, of which 16 define a specific amount of time from resection or adjuvant therapy (range 1-12 weeks). ctDNA negative arms are present in 10 trials and all but 5 specifically require radiological NED. Post-adjuvant therapies for MRD are studied in 25 trials, ctDNA-informed adjuvant therapy in 13, and either of these in 2. Chemotherapies are studied in 23 trials, with some evaluating multiple regimens (FOLFOXIRI in 7, FOLFOX / CAPOX in 9, FOLFIRI in 5, TAS-102 ± other in 4, TEMIRI in 2, and capecitabine / 5-FU in 2), with durations from 3 to 6 months and number of patients varying from 25 to 4812. The primary endpoint is disease-free survival (DFS), recurrence-free survival (RFS), or time to recurrence in 12 trials (52%), ctDNA clearance in 5 (22%), and other in 6 (26%). Novel approaches are studied in 20 trials (checkpoint inhibitors ± other in 9, vaccines in 3, immune-modulation in 2, NK cells in 2, CAR-T cells in 1, ADCs in 1, and targeted therapy based on dMMR, HER2 , and BRAF -V600E in 4). Compared with chemotherapy trials, treatment duration is more variable (single infusion to 12 months) and sample size smaller (range 10-327), with ctDNA clearance (n = 8, 40%) and safety (n = 3, 15%) more often being the primary endpoint and DFS/RFS (n = 7, 35%) and other (n = 2, 10%) being used less frequently. Conclusions: The landscape of MRD trials in CRC reflects longstanding questions on optimal adjuvant therapy delivery. Heterogeneous eligibility criteria, increasing use of innovative therapeutics, and novel endpoints such as ctDNA clearance, warrant a consensus on MRD trial design.