Efficacy and safety of regorafenib plus FOLFIRI with UGT1A1 genotyping-guided irinotecan dose escalation against metastatic colorectal cancer: a multicenter, phase II, open-label, two-arm randomized controlled tria.

Background: Regorafenib targets tumor angiogenesis and oncogenic signaling by inhibiting multiple kinases involved in angiogenesis, oncogenesis, and the tumor microenvironment. Chemotherapy of FOLFIRI causes direct cytotoxic damage to tumor cells. Objectives: We evaluated the efficacy and safety of regorafenib plus FOLFIRI with uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotyping-guided irinotecan dose escalation in patients with metastatic colorectal cancer (mCRC) who had received second- or third-line systemic therapy. Design: A total of 153 patients were randomized (at a ratio of 2:1) to receive either regorafenib plus FOLFIRI (experimental group, 102 patients) or regorafenib alone (control group, 51 patients). Methods: Both groups received regorafenib (120 mg daily) for 21 consecutive days in 28-day cycles. In addition, the experimental group received FOLFIRI with UGT1A1 genotyping-guided irinotecan dose escalation. The primary outcome was progression-free survival (PFS). The secondary outcomes were overall survival (OS), disease control rate (DCR), and adverse events. Results: The final cohort included 116 patients. The experimental group exhibited significant improvement in PFS (p = 0.016) but marginally significant improvements in DCR (p = 0.055). Specifically, PFS improved significantly for experimental group patients carrying wild-type rat sarcoma virus (RAS; p = 0.003) and those carrying left-sided colon tumors (p = 0.015). A trend toward improved OS was noted in experimental group patients carrying wild-type RAS (p = 0.096). No significant between-group difference was observed in the incidence of severe adverse events (all p > 0.05). Conclusion: Our findings suggest that regorafenib plus FOLFIRI significantly improved PFS in patients with mCRC and offers a safety profile similar to that of regorafenib alone. This regimen may be particularly beneficial for patients with mCRC carrying wild-type RAS and those carrying left-sided tumors. However, larger phase III randomized controlled trials are necessary to confirm the efficacy and safety of this combination therapy before adoption into standard practice. Trial registration: ClinicalTrials.gov registry: NCT03880877 (https://clinicaltrials.gov/search?cond=NCT03880877).