AbstractThe phase III AXEPT study showed the noninferiority of modified capecitabine plus irinotecan (mXELIRI) with or without bevacizumab relative to fluorouracil, leucovorin, and irinotecan (FOLFIRI) with or without bevacizumab as a second‐line treatment for metastatic colorectal cancer. We evaluated the associations between theUGT1A1genotype linked to adverse events—caused by irinotecan—and the efficacy and safety of mXELIRI and FOLFIRI. TheUGT1A1genotype was prospectively determined and patients were categorized into three groups according to WT (*1/*1), single heterozygous (SH; *28/*1 or *6/*1), and double heterozygous or homozygous (DHH; *28/*28, *6/*6, or *28/*6). Overall survival (OS), progression‐free survival, response rate, and safety were assessed. TheUGT1A1genotype was available in all 650 randomized patients (WT, 309 [47.5%]; SH, 291 [44.8%]; DHH, 50 [7.7%]). The median OS was 15.9, 17.7, and 10.6 months in the WT, SH, and DHH groups, respectively, with an adjusted hazard ratio (HR) of 1.53 (95% confidence interval [CI], 1.12‐2.09;P = .008) for DHH vs WT or SH. The median OS in the mXELIRI and FOLFIRI arms was 18.1 vs 14.3 months (HR 0.80; 95% CI, 0.62‐1.03) in the WT group, 16.3 vs 18.3 months (HR 1.04; 95% CI, 0.79‐1.36) in the SH group, and 13.0 vs 9.1 months (HR 0.71; 95% CI, 0.39‐1.31) in the DHH group, respectively. Modified capecitabine plus irinotecan with or without bevacizumab could be a standard second‐line chemotherapy in terms of efficacy and safety regardless of theUGT1A1genotype.