S-1 (combination of tegafur, gimeracil, and oteracil) and irinotecan (CPT) have different mechanisms of action. Combined therapy of S-1 and CPT is an attractive option for anthracycline and taxane-refractory breast cancer.
Patients with advanced HER2-negative breast cancer previously treated with anthracycline and taxane and with measurable lesions were eligible for the trial. Those with brain metastases and homozygous for UGT1A1*6 or *28 or compound heterozygous (*6/*28) were excluded. A 3 + 3 dose escalation design was used in phase I (Level 1: CPT 80 mg/m2 on days 1 and 8, and S-1 80 mg/m2 on days 1-14, every 3 weeks; Level 2: CPT 100 mg/m2 and S-1 80 mg/m2). The objectives were to determine the recommended dose (RD) for the phase II (primary for phase I) study, response rate (RR, primary for phase II), progression-free survival (PFS), and safety in relation to UGT1A1. Pharmacokinetics (PK) of CPT and circulating endothelial cells (CEC) as pharmacodynamics (PD) of S-1 were analysed.
Thirty-seven patients (13 for phase I, 24 for phase II) were enrolled. One patient at level 1 developed grade (G) 3 non-haematological toxicity and another at level 2 developed G4 neutropenia; therefore, level 2 was used as the RD. Common adverse events and their rates in the UGT1A1 wt/wt and wt/*6 or *28 heterozygous groups were diarrhoea, 25% and 46%; vomiting, 17% and 9%; anorexia, 25% and 9%; and fatigue, 25% and 9% respectively. As shown in Table 1 and supported by PK data, PFS seemed better for the UGT1A1 wt/*6 or *28 group compared to that for the wt/wt group. There also seemed to be an association between clinical benefit and suppression of CD34+ CEC by S-1 (Wilcoxon p = 0.047).
Efficacy results of Level 2 patients (n = 29, 6 for phase I and 23 for phase II)
|Wild/Wild (n = 15)||Wild/*6 or *28 (n = 14)|
|Response Rate||1 (7%)||3 (21%)||-|
|Clinical Benefit Rate||4 (27%)||5 (36%)||-|
|Median PFS (month)||8.3||12.3||HR = 0.47 (p = 0.0600)|
|Median OS (month)||17.4||23.1||HR = 0.74 (p = 0.5607)|
A combination of CPT and S-1 is effective in patients having recurrent/metastatic breast cancer, and further study of the underlying pharmacogenomics/PK/PD is warranted.
Clinical trial identification
Legal entity responsible for the study
S. Saji: Lecture fee from Taiho Pharmaceutical Co. Ltd. S. Nomura: Receiving personal fees from Japan Breast Cancer Research Group.Y. Sasaki: Financial interest with Taiho Pharmaceutical Co. Ltd.
All other authors have declared no conflicts of interest.