Benefit of adjuvant chemotherapy in resected stage I-IV CRC patients based on ctDNA dynamics across two timepoints: Results from GALAXY study.

102 Background: In current clinical practice, ACT for stages IIB-III CRC is administered as soon as the patient is medically able, and within 8 weeks post-surgery. However, initiation >8 weeks may be appropriate in some patients. The interim analysis of the CIRCULATE-Japan GALAXY showed that patients with ctDNA-negativity during 2-10 weeks post-surgery do not derive benefit from ACT, although a small subset of these ctDNA-negative patients recurred. In this study, we analyzed early ctDNA dynamics to assess if turning ctDNA-positive at 12 weeks identifies the subgroup of initially (4-weeks post-surgery) ctDNA-negative patients who will benefit from ACT. Methods: This analysis included 1,034 patients with stage I-IV CRC undergoing curative-intent surgery from the GALAXY study who were ctDNA-negative at the first timepoint (TP#1; 4 ± 2 weeks post-surgery) and had subsequent ctDNA results available at the second TP (TP#2; 12 ± 2 weeks post-surgery). ctDNA was assessed using a personalized, tumor-informed assay (Signatera, Natera). DFS was assessed between TP#1-negative patients receiving ACT versus observation, stratified by ctDNA dynamics (turned positive at TP#2 or remained negative at both TPs). Analysis was landmarked at the TP#2 (12 weeks ± 2 weeks post-surgery) and Hazard ratios (HRs) were estimated using Cox proportional hazards models. Results: Of the 1,034 patients with ctDNA-negativity at TP#1 included in this analysis, 47.8% were females, and 73.8% had colon cancer, whereas 26.2% had rectal cancer. The pathologic stage distribution included: 11% Stage I / Low Risk Stage II, 72% High Risk Stage II / Stage III, and 17% Stage IV. The median patient age was 69 years (range 25-93) and the median follow-up was 33 months. Median time to ACT initiation was 6.7 weeks (range 3-12) post-surgery. Among patients who became positive at TP#2 (N=36), ACT was associated with significantly improved DFS compared with observation (HR 0.3; p=0.0165). Two-year DFS rates were 45.5% in the ACT group and 9.8% in the observation group, with a median DFS of 22 months and 2.5 months, respectively. In contrast, among patients who remained ctDNA-negative at both TPs (N=998), DFS outcomes were favorable regardless of ACT administration (HR 0.8, p=0.1744), with 2-year DFS rates of 87.1% and 84.1%, respectively, and median DFS was not reached in either group. Conclusions: A statistically significant and clinically meaningful benefit of ACT in resected stage I-IV CRC patients who were ctDNA-negative at 4 weeks but converted to positive at 12 weeks post-surgery was observed. These results underscore the critical role of both the 4- and 12-week post-surgery time points for risk stratification and indicate that early ctDNA dynamics can identify a subgroup of initially ctDNA-negative patients who may benefit from delayed ACT. Clinical trial information: UMIN000039205.