PD-032Pharmacogenetic clinical randomized phase II trial to evaluate the efficacy and safety of FOLFIRI with high dose of irinotecan (FOLFIRI-HD) in metastatic colorectal cancer patients according to UGT1A 1 genotype

Introduction: UGT1A1 is a critical enzyme for elimination of SN-38, the active metabolite of irinotecan. It is known that patients harboring the UGT1A1 *28/*28 genotype (Gilbert’s Syndrome) are at risk of severe toxicities with the standard irinotecan dose. However, the recommended dose of irinotecan within the FOLFIRI regimen (fluorouracil, leucovorin, and irinotecan) is considerably inferior to the dose that can be tolerated by UGT1A1 *1/*1 and *1/*28 patients. This randomized phase II trial aimed to evaluate the efficacy and safety of FOLFIRI regimen with high-dose of irinotecan (HD-FOLFIRI) in metastatic colorectal cancer (mCRC) patients with a favorable UGT1A1 genotype (homozygous wild type *1/*1 and heterozygous *1/*28). Patients genetically at risk for toxicity (*28/*28) were excluded from the trial. Methods: Eighty-two patients with the UGT1A1 *1/*1 or *1/*28 genotypes were randomized to receive HD-FOLFIRI (experimental group) vs. FOLFIRI (control group) every two weeks. Irinotecan dose for UGT1A1 *1/*1 or *1/*28 patients in the experimental group was 300mg/m2 and 260mg/m2 respectively. The standard irinotecan dose of 180mg/m2 was administered in the control group regardless UGT1A1 genotype. The overall response rate, toxicity, and survival were analyzed. Results: The overall response rate of mCRC patients treated with HD-FOLFIRI was significantly higher than in patients treated with FOLFIRI (67.5% vs 43.6%, respectively; p = 0.001 OR: 1.73 [95% CI: 1.03-2.93]). Neutropenia (17.7%), diarrhoea (5.1%) and asthenia (5.1%) were the most common grade 3 or 4 toxicities. No differences in severe toxicities (22.5 vs. 20.5%), dose reduction (22.5 vs. 28.2%) or prophylactic use of G-CSF (17.5 vs. 12.8%) were observed irrespective of irinotecan dose. The median PFS was 8.6 months (HD-FOLFIRI) and 8.2 months (FOLFIRI). Conclusion: Our study shows that mCRC patients with UGT1A1 *1/*1 and *1/*28 genotypes could receive high doses of irinotecan to obtain a more favorable clinical outcome without significant adverse events. This trial supports further investigation of intensive treatment with irinotecan in patients with the UGT1A1 *1/*1 or *1/*28 genotypes.