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

Abstract Background There is an unmet need for optimal third- or later-line treatment options for patients with refractory or metastatic colorectal cancer (mCRC). This phase II study evaluated whether high-dose irinotecan rechallenge guided by UGT1A1 genotype could improve the 12-week disease control rate (12-week DCR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety among patients with refractory mCRC. Methods Patients who had previously received at least two lines of chemotherapy, including 5-fluorouracil, oxaliplatin, and irinotecan, and who had shown a partial or durable response to irinotecan lasting more than 24 weeks were included. Patients without a 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/m 2 and 250 mg/m 2 , respectively, every 2 weeks until disease progression or unacceptable toxicity. Results A total of 32 patients were enrolled between October 2020 and March 2023. The primary endpoint, 12-week 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 occurred in 9 (50.0%) of the UGT1A1 wild-type group and 4 (28.6%) of the heterozygous group. Conclusion High-dose irinotecan rechallenge guided by UGT1A1 genotype appeared feasible and achieved disease control as a third- or later-line therapy in patients with mCRC who had previously responded to irinotecan. Trial registration: KCT0005303 (UHD clinical trial, approval date: September 22, 2022)