Adjuvant mFOLFOXFIRI after curative-intent resection of oligometastatic colorectal cancer: Phase II FANTASTIC trial.

Abstract

153 Background: The optimal postoperative systemic therapy in oligometastatic colorectal cancer (CRC) remains undefined. With the increasing evidence to support circulating tumor DNA (ctDNA)-guided monitoring, effective adjuvant strategies incorporating molecular risk stratification are of significant clinical importance. We conducted a multicenter phase II study to assess the feasibility and preliminary efficacy of modified FOLFOXIRI (mFOLFOXIRI) for resected oligometastatic CRC, exploring the utility of serial ctDNA analysis for risk assessment. Methods: Patients with histologically confirmed oligometastatic CRC undergoing complete metastasectomy (Oct 2020–Jan 2024) were registered. Eligible patients who provided informed consent received eight cycles of mFOLFOXIRI (OncoTarget 2021), followed by four cycles of 5-FU/l-LV (mFOLFOXIRI group). Patients who declined or were ineligible for mFOLFOXIRI were observed per standard of care (SOC group). Tumor-informed mPCR-NGS ctDNA assays (Signatera, Natera) were performed 4 weeks and 7 months postoperatively. The primary endpoint was the proportion of patients completing eight cycles of mFOLFOXIRI. Secondary endpoints included recurrence-free survival (RFS) by ctDNA status, ctDNA clearance, and safety. Target sample size was 36 for the mFOLFOXIRI group, designed for 70% power to confirm a completion rate >35% with one-sided α=10%. Results: Among 83 registered patients, 73 were eligible (39 mFOLFOXIRI; 34 SOC). Median age was 61 (34–75) years, and 71 patients had PS 0. Metastatic sites were liver (n=53), lung (n=11), peritoneum (n=8), and ovary (n=1). 25 and 19 patients were ctDNA-positive at 4 weeks and 7 months, respectively. In the mFOLFOXIRI group, completion rate was 74% (80% CI: 63–83; p<0.001). 3-year RFS was 58.2%, and ctDNA positivity vs negativity at 4 weeks post-surgery was strongly associated with worse RFS (median 15.4 months vs. not reached; HR: 7.27 [2.59–20.39]). ctDNA clearance occurred in 33.3% (3/9) of patients who were ctDNA-positive at 4 weeks starting with a median of 0.50 MTM (mean tumor molecules)/mL (0.05-2.96). In the SOC group, 3-year RFS was 27%, and ctDNA positivity also predicted poor outcome (median 4.3 months vs. not reached; HR: 7.17 [2.68–19.17]); clearance was 12.5% (2/16) starting with median of 2.50 MTM/mL (0.11-67.77). Multivariate analysis identified ctDNA negativity at 4 weeks, RAS mutation, metachronous metastases, and mFOLFOXIRI as significant favorable factors with ctDNA as the most significant prognostic marker. Conclusions: Adjuvant mFOLFOXIRI is feasible and may provide clinical benefit following resection of oligometastatic CRC, particularly in ctDNA-positive patients. However, these results should be interpreted with caution, given the small sample size and lack of randomization, warranting further investigation to optimize adjuvant strategies in this setting. Clinical trial information: jRCTs051200026 .