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

The presence of a defective UGT1A1 allele determines the irinotecan dose given, set here at 300 mg/m2 without a defective allele and 250 mg/m2 with one.

In refractory metastatic colorectal cancer, third-line and later options remain limited. This single-arm phase II trial enrolled 32 patients between October 2020 and March 2023 who had received more than two lines of chemotherapy including 5-fluorouracil, oxaliplatin and irinotecan, and who had previously shown a partial response or a durable response beyond 24 weeks on irinotecan. Patients without a defective UGT1A1 allele received irinotecan at 300 mg/m2 every two weeks, those with one defective allele at 250 mg/m2, until progression or unacceptable toxicity. The 12-week disease control rate, the primary endpoint, was 40.6% (13 of 32 patients), the objective response rate 15.6% (5 of 32), median overall survival 9.3 months (95% CI 5.3-13.3) and median progression-free survival 2.9 months (95% CI 2.5-3.3). Grade 3 or higher adverse events occurred in 19 patients (59.4%), with dose reduction in 9 patients (50.0%) of the wild-type group and 4 patients (28.6%) of the heterozygous group.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Selection precludes any reading of efficacy: only patients previously responsive to irinotecan were included, so a 40.6% disease control rate measures that selection first, not the genotype-guided strategy. One detail deserves attention: dose reductions were more frequent in the wild-type group (50.0%) than in heterozygotes (28.6%), suggesting the 300 mg/m2 dose assigned to presumed normal metabolizers was set too high — genotype here guides escalation without securing its ceiling. Overall, 59.4% grade 3 or higher adverse events for 2.9 months of progression-free survival in a palliative setting call for a comparator arm before any generalisation.

Analysis by Dr Thibaut Benquey