The comparison between UGT1A1 single heterozygous and wild-type regarding the clinical outcomes of fixed-dose irinotecan monotherapy for advanced gastric cancer: a multicenter retrospective study

Irinotecan is a key drug for advanced gastric cancer (AGC). We previously reported that patients with UGT1A1 single heterozygous (SH) had a significantly high frequency of severe hematological adverse events (AEs) compared to patients with UGT1A1 wild type (WT) in irinotecan monotherapy for AGC. However, the difference of initial dose and relative dose intensity (RDI) of irinotecan between UGT1A1 WT and SH might affect those results. Therefore, we compared the clinical outcomes of the fixed-dose irinotecan monotherapy for AGC between patients with UGT1A1 SH and WT.

We retrospectively analyzed the clinical data of patients who received initial fixed-dose irinotecan (150mg/m 2 , bi-weekly) in this multi-institutional study. A total of 106 eligible patients were registered from 8 centers in Japan. This study was analyzed by CTCAE v4.0 for adverse events (AEs), and RECIST v1.1 for response rate (RR)/disease control rate (DCR). To compare UGT1A1 WT and SH, Fisher’s exact test was used to analyze patient characteristics, AE, RR/DCR, and the Log-rank test was used for progression-free survival (PFS) and overall survival (OS).

The number of patients with UGT1A1 WT and SH were 62 and 38, respectively. In WT/SH patients, performance status 0/1/≥2 was 20/40/2 and 11/23/4, treatment line 2nd/3rd or later was 27/35 and 18/20, HER2 positive/negative 17/45 and 8/30, respectively. In WT/SH patients, median PFS was 3.2 and 3.3 months (HR = 1.137, P = 0.543) and median OS was 10.4 and 7.3 months (HR = 0.734, P = 0.184). In WT/SH patients, dose reduction of irinotecan was required in 30.6% and 50.0% (P = .053), delayed treatment due to AE was observed in 44.2% and 39.4% (P = .675), median treatment cycle was 6 and 4 (P = .973), and RDI was 0.85 vs 0.84 (P = .915), respectively. Hematological AEs were observed in 82.2% and 92.1% (P = .138), with severe hematological AEs (≥G3) at 35.4% and 63.1% (P = .006). Non-hematological AEs were 88.7% and 86.8% (P = .507), and severe non-hematological AEs (≥G3) were 6.6% and 15.8% (P = .122), respectively. Severe AEs in more than 5% patients were leukopenia (11.3% and 15.8%), neutropenia (14.5% and 31.6%), anemia (21.0% and 23.7%), and anorexia (1.6% and 10.5%).

UGT1A1 SH patients who received initial fixed-dose irinotecan had increased frequency of severe hematological AE compared with WT patients. However, there was no significant difference in efficacy of Irinotecan monotherapy between the groups.