Impact of postoperative ctDNA dynamics on eligibility for the ALTAIR randomized trial in patients with colorectal cancer: Implications for clinical trial enrollment.

12 Background: Postoperative circulating tumor DNA (ctDNA) positivity is strongly associated with increased recurrence risk, prompting a growing number of treatment escalation trials targeting patients (pts) with ctDNA-positive colorectal cancer (CRC). The phase III ALTAIR trial (NCT04457297) randomizes pts with post-surgical ctDNA-positivity to trifluridine/tipiracil versus placebo. We evaluated if fluctuating ctDNA status influences both eligibility and enrollment. Methods: GALAXY (UMIN000039205) study evaluates ctDNA monitoring post curative-intent surgery in pts with clinical stage II-IV CRC receiving standard-of-care (SOC) perioperative chemotherapy. ctDNA was assessed using a personalized, tumor-informed assay (Signatera, Natera, Inc.) in plasma collected at 1, 3, 6, 9, 12, 18, and 24 months after surgery. Pts from GALAXY with post-surgical ctDNA-positivity in the absence of clinical evidence of recurrence were eligible for enrollment into the ALTAIR study within 3 months of a ctDNA-positive result. We analyzed each pt’s postoperative ctDNA trajectory and calculated the proportion meeting ctDNA-based inclusion criteria. Results: Of 2,016 pts enrolled in GALAXY at ALTAIR-participating sites as of April 2023, 290 (14.4%) were ctDNA-positive 2-10 weeks post-surgery (i.e., molecular residual disease, MRD, positive). Among 148 MRD-positive pts receiving adjuvant chemotherapy (ACT), 50 (33.8%) remained persistently ctDNA-positive, 39 (78%) of whom had no clinical relapse within 3 months of MRD detection. Eighty-five pts (57.4%) cleared ctDNA after ACT; 39 (45.9%) later reconverted to positive, 29 (74.3%) of whom remained relapse-free for ≥3 months after reconversion. Among 572 MRD-negative pts in GALAXY receiving ACT, 71 (12.4%) converted to ctDNA-positive, 55 (77.5%) of whom remained relapse-free for ≥3 months after molecular relapse. Overall, 14.8% of all pts from GALAXY study were ctDNA-positive without early clinical relapse post-SOC therapy and thus met ALTAIR ctDNA-based criteria. Stage-specific rates of meeting the ALTAIR ctDNA-based criteria were 13.0 % (stage II), 13.2 % (stage III), and 30.0 % (stage IV). Overall, 121 (6.0%) were enrolled in ALTAIR, including 24.1% (70/290) of MRD-positive and 3.0% (51/1,726) of MRD-negative pts. Among pts who were ctDNA-positive, median ctDNA levels were significantly higher in those who relapsed within 3 months (31.8% of ctDNA-positive pts) compared with those who did not (68.2%) (2.1 versus 0.4 MTM/mL, P<0.001). Conclusions: Serial postoperative ctDNA monitoring in the GALAXY study reveals that 14.8% of pts were eligible for ALTAIR based on ctDNA positivity without early relapse post-SOC therapy. These data underscore the importance of longitudinal ctDNA assessment in trial design and may inform the planning of future ctDNA-guided adjuvant studies. Clinical trial information: NCT04457297 .