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Adjuvant mFOLFOXIRI after curative-intent resection of oligometastatic colorectal cancer: phase II FANTASTIC trial

Year: 2026

Type: article

Abstract: BACKGROUND: Patients with oligometastatic colorectal cancer (mCRC) remain at high risk of recurrence after curative surgery, yet the benefit of adjuvant chemotherapy remains inconclusive. This study evaluated the feasibility and efficacy of adjuvant modified (m)FOLFOXIRI (irinotecan, oxaliplatin, L-leucovorin (L-LV), 5-fluorouracil (5-FU)), as well as the utility of circulating tumour DNA (ctDNA) as a prognostic and predictive biomarker in mCRC. METHODS: Between October 2020 and January 2024, patients with histologically confirmed mCRC undergoing complete metastasectomy were enrolled in this multicentre non-randomized phase II study. Eligible and consenting patients received eight cycles of mFOLFOXIRI followed by four cycles of 5-FU/L-LV; ineligible/non-consenting patients received standard of care (SOC; CAPOX (capecitabine and oxaliplatin), 5-FU, or observation). ctDNA was assessed using the tumour-informed personalized Signatera™ assay (Natera, Austin, TX, USA) at 28 days and 7 months after surgery. The primary endpoint was completion of eight cycles of mFOLFOXIRI in a target sample of 36 patients. RESULTS: Of the 83 registered patients, 73 were enrolled (39 mFOLFOXIRI, 34 SOC). The mFOLFOXIRI completion rate was 74% (80% confidence interval 63% to 83%; P < 0.001). ctDNA positivity predicted significantly inferior recurrence-free survival across both the mFOLFOXIRI and SOC treatment groups at 28 days (hazard ratios (HR) 7.27 and 7.17, respectively) and 7 months (HR 3.96 and 4.38, respectively) after surgery. Multivariate analysis identified ctDNA positivity, RAS mutation, metachronous metastases, and mFOLFOXIRI as significant prognostic factors. mFOLFOXIRI improved recurrence-free survival compared with SOC in the overall population (HR 0.44; P = 0.012), with a trend towards benefit in ctDNA-positive but not ctDNA-negative patients. ctDNA clearance rates were 33% (mFOLFOXIRI) and 20% (SOC). CONCLUSIONS: This study indicates the feasibility of adjuvant mFOLFOXIRI in patients with mCRC, with an acceptable safety profile and potential clinical benefit among those with ctDNA positivity 28 days after surgery.

Source: BJS Open

DOI: 10.1093/bjsopen/zrag144