Background
Randomized, double-blind phase 3 trial embedded in the CIRCULATE-Japan platform (N=243). Adults with resected stage 0–IV colorectal cancer who became tumor-informed ctDNA-positive (molecular residual disease) after completing standard-of-care therapy and had no radiologic evidence of disease, testing whether early intervention on molecular recurrence improves outcomes.
Results
Interventions and follow up: Arm A: trifluridine/tipiracil (FTD/TPI) 35 mg/m² PO BID, days 1–5 and 8–12 every 28 days, for 6 months.
Arm B: Placebo for 6 months.
Primary endpoint: investigator-assessed disease-free survival (DFS).
mFollow up: NR (enrollment Jul 2020–Jun 2023).
Results: DFS: median 9.30 vs 5.55 months, HR 0.79 (95% CI 0.60–1.05), P=.107 — primary endpoint not met.
OS: NR.
Arm B: Placebo for 6 months.
Primary endpoint: investigator-assessed disease-free survival (DFS).
mFollow up: NR (enrollment Jul 2020–Jun 2023).
Results: DFS: median 9.30 vs 5.55 months, HR 0.79 (95% CI 0.60–1.05), P=.107 — primary endpoint not met.
OS: NR.
Adverse events
Grade ≥3 hematologic: 73.0% vs 3.3%
Safety signals: no new signals reported.
Safety signals: no new signals reported.
Conclusions
In ctDNA-positive, radiologically occult resected CRC, 6 months of post-adjuvant FTD/TPI did not significantly improve DFS versus placebo. ctDNA reliably identified a high-risk molecular-relapse population, but single-agent FTD/TPI was insufficient to convert detectable MRD into durable disease control.
Key Limitations
Modest sample size (N=243) limited power, with a wide DFS confidence interval crossing 1; FTD/TPI is a cytotoxic with limited single-agent activity, so the negative result may reflect drug choice rather than the MRD-guided strategy itself; short 6-month treatment; OS immature; predominantly Japanese (CIRCULATE-Japan) population; DFS investigator-assessed.
Clinical Context
First randomized phase 3 test of ctDNA/MRD-guided treatment escalation in CRC. FTD/TPI (Lonsurf) is approved for refractory metastatic CRC but not for the MRD-positive post-resection setting. ASCO and ESMO do not currently endorse ctDNA-directed treatment escalation outside trials; this negative result tempers enthusiasm for acting on ctDNA positivity with FTD/TPI and supports awaiting more active regimens within the CIRCULATE/GALAXY program.