Pts with a favourable UGT1A1 genotype (homozygous wild type *1/*1 and heterozygous *1/*28) can be treated with HD of irinotecan without significant adverse events. This randomized phase II trial aimed to evaluate the efficacy and safety of FOLFIRI regimen with HD of irinotecan (HD-FOLFIRI) in mCRC pts. Pts genetically at risk for toxicity (*28/*28) were excluded. Potential prognostic factors and specific population subgroups are presented.
Chemotherapy-naïve patients with the UGT1A1 *1/*1 or *1/*28 genotypes were randomized to receive HD-FOLFIRI vs FOLFIRI every two weeks. Irinotecan doses for UGT1A1 *1/*1 and *1/*28 pts in the experimental group were 300mg/m2 and 260mg/m2 respectively. The standard irinotecan dose of 180mg/m2 was administered in the control group. Main clinical-pathological characteristics and clinical outcomes of pts included were analysed.
Between Jun-12 and Oct-16 82 pts were included. The ORR was significantly higher in the experimental group (67.5% vs 43.6%; p = 0.001). There were not interactions between ORR and clinical characteristics (sex, age, ECOG, tumour location, synchronous disease) and RAS/BRAF status. However, when BRAF mutation was considered, no objective response was observed in the control group compared with 41.7% of pts treated with HD-FOLFIRI (p = 0.003). Metastatic surgical resection was performed in 15 pts (22.5% in HD-FOLFIRI and 15.4% in FOLFIRI) and was associated with ORR (29.5% vs 5.7%; p = 0.007). Median PFS and OS were 8.6 and 26 months (m) (HD-FOLFIRI) and 8.2 and 29 m (FOLFIRI). ECOG 0/1(9.9 vs 7.2 m) and metastatic resection (15.5 vs 7.8 m) were significantly associated with PFS. In terms of OS pts with metastatic surgery (not reach vs 18.4 m) achieved better outcome. Multivariate analysis showed significant association between metastatic resection with both, PFS and OS.
These data confirm the safety of chemotherapy with HD of irinotecan and demonstrate that such strategy improves ORR, which may, in turn, impact favourably on pts survival, especially in those with poor prognosis.
Clinical trial identification
Legal entity responsible for the study
Institut de Recerca de l’Hospital de la Santa Creu i Sant Pau
Spanish Ministry of Health and Social Policy - EC11/336
All authors have declared no conflicts of interest.