A single-arm phase II trial of UGT1A1 genotype-guided high-dose irinotecan rechallenge in refractory metastatic colorectal cancer

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• Picked for Genetics (clinical) (top studies of the week, 9 August 2026).

Abstract

BACKGROUND: There is an unmet need for optimal third- or later-line treatment options for refractory or metastatic colorectal cancer (mCRC) patients. This phase II study investigated whether high-dose irinotecan rechallenge based on UGT1A1 genotype improves the 12-week disease control rate (12w DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety in refractory mCRC patients. METHODS: Patients who had previously received more than two lines of chemotherapy, including 5-fluorouracil, oxaliplatin, irinotecan and had shown either a partial response or durable response for more than 24 weeks to irinotecan were included. Patients without the defective allele of UGT1A1 (UGT1A1 *1/*1) and one defective allele (UGT1A1 *1/*6, *1/*28) were treated with intravenous irinotecan at doses of 300 mg/m2 and 250 mg/m2, respectively, every 2 weeks until disease progression or unacceptable toxicity. RESULTS: A total of 32 patients was enrolled between October 2020 and March 2023. The primary endpoint, 12w DCR was 40.6% (13 of 32 patients). The ORR was 15.6% (5 of 32). The median OS was 9.3 months (95% CI, 5.3 to 13.3) and the median PFS was 2.9 months (95% CI, 2.5 to 3.3). Grade 3 or higher adverse events were observed in 19 patients (59.4%). Dose reduction due to adverse events occurred in 9 patients (50.0%) in UGT1A1 wild-type group and 4 patients (28.6%) in the heterozygous group. CONCLUSION: High-dose irinotecan rechallenge guided by UGT1A1 genotype was feasible and showed meaningful disease control in third-line or later settings for mCRC patients previously responsive to irinotecan.

Abstract as published, via PubMed.