Impact of postsurgical circulating tumor DNA (ctDNA) dynamics on eligibility of colorectal cancer (CRC) patients for randomized ALTAIR trial: Implications for treat-on-molecular-recurrence (TOMR) trials.

3628 Background: Postsurgical ctDNA positivity is strongly associated with recurrence risk and is driving the development of TOMR trials like the phase III ALTAIR trial (NCT04457297), which evaluated the benefit of trifluridine/tipiracil versus placebo in CRC patients (pts) with ctDNA positivity in the absence of clinical relapse. We evaluated the impact of longitudinal ctDNA dynamics during adjuvant chemotherapy (ACT) and surveillance on eligibility for enrollment into ALTAIR. Methods: CIRCULATE-Japan’s GALAXY (UMIN000039205) study screened clinical stage II-IV CRC pts receiving standard-of-care (SOC) perioperative chemotherapy for eligibility for interventional trials by ctDNA monitoring using the personalized, tumor-informed Signatera assay in plasma collected at 1, 3, 6, 9, 12, 18, and 24 months (mos) post-surgery. Pts with ctDNA positivity without clinical recurrence were eligible for ALTAIR within 3 months of detection. We analyzed ctDNA dynamics and eligibility across all GALAXY sites, extending prior analyses limited to ALTAIR-participating sites. Results: Of 5,355 pts enrolled by April 2023, 693 (12.9%) were ctDNA-positive 2–10 weeks post-surgery (MRD-positive). Of 378 MRD-positive pts who received ACT, 117 (31.0%) remained persistently positive, 76.1% of whom did not relapse within 3 mos. ctDNA cleared after ACT in 237 pts, but 122 (51.5%) reconverted to positive, 67.2% of whom remained relapse-free for ≥3 mos after reconversion. Among 1,341 MRD-negative pts receiving ACT, 183 (13.6%) converted to ctDNA-positive, 123 (67.2%) of whom remained relapse-free for ≥3 mos after molecular relapse. Overall, 17.1% of GALAXY pts met ALTAIR ctDNA-based criteria with stage-specific eligibility rates of 13.2% (II), 14.7 % (III), and 34.6 % (IV). Overall, 243 (4.5%) were enrolled in ALTAIR, including 18.6% of MRD-positive and 2.4% of MRD-negative pts. Conclusions: Approximately one-third (123/334) of ALTAIR-eligible pts were initially MRD-negative and later converted to ctDNA-positive without early clinical relapse, highlighting the importance of longitudinal ctDNA monitoring in TOMR trial design. When compared to the previous analysis limited to ALTAIR-participating sites, we observed higher eligibility yet lower enrollment rates in the full cohort at all GALAXY sites, underscoring the need for broader access and efficient enrollment networks to optimize TOMR trials. Clinical trial information: NCT04457297 . ctDNA dynamics MRD positive(N = 378) MRD negative(N = 1,341) Persistently positive, all 117 (31.0%) NA Persistently positive, eligible for ALTAIR 89 (23.5%) NA Transient clearance, all 122 (32.2%) NA Transient clearance, eligible for ALTAIR 82 (21.7%) NA Turned positive, All NA 183 (13.6%) Turned positive, eligible for ALTAIR NA 123 (9.2%)