American phase I studies have reported that the recommended dose of TAS-102 (trifluridine/tipiracil) was 25 mg/m2 b.i.d., although this schedule did not provide clinically relevant improvements in a phase II study of advanced gastric cancer (AGC). However, a pivotal phase III study revealed that TAS-102 at 35 mg/m2 b.i.d. provided a clinically relevant improvement in overall survival among patients with metastatic colorectal cancer. Thus, we re-evaluated the efficacy, safety, and pharmacokinetic (PK) parameters of TAS-102 at 35 mg/m2 b.i.d. in patients with AGC. In an expanded cohort, we also evaluated the safety and PK parameters of a 40 mg/m2 b.i.d. schedule.
All patients had undergone one or two previous chemotherapy regimens that contained fluoropyrimidine, platinum agents, and taxanes or irinotecan. In this study, we assessed the investigator-determined and the independent central review's disease control rate (DCR), response rate, progression-free survival (PFS), overall survival (OS), safety profiles, and PK profiles.
Twenty-nine patients were assessable after completing the 35 mg/m2 b.i.d. schedule. The investigator-determined DCR was 65.5% (95% confidence interval [CI], 45.7–82.1%) and the independent central review's DCR was 51.9% (n = 27, 95% CI, 31.9–71.3%). The median PFS and OS were 2.9 months (95% CI, 1.1–5.3 months) and 8.7 months (95% CI, 5.7–14.9 months), respectively. The grade 3/4 adverse events included neutropenia (69.0%), leukopenia (41.4%), anemia (20.7%), and anorexia (10.3%). No AGC-specific toxicities were detected. In the expanded cohort, the averages of PK parameters dose-dependently increased for 6 patients treated with the 40 mg/m2 b.i.d. dosage. Although slightly higher grade 3–4 neutropenia (83.3%) and leukopenia (66.7%) were observed, the investigator-determined DCR was 50.0% (SD: 3; PD: 3) and no partial response cases were observed.
The 35 mg/m2 b.i.d. dose of TAS-102 provided positive efficacy and an acceptable toxicity profile in patients with AGC. A randomized, double-blind, placebo-controlled, phase III study is ongoing to validate these findings.
Clinical trial identification
Legal entity responsible for the study
Exploratory Oncology Research & Clinical Trial Center, National Cancer Center
The Renovation Project of Early and Exploratory Clinical Trial Center, National Cancer Center Research and Development Fund (24-A-1)
K. Muro, T. Nishina, A. Ohtsu: Honoraria: Taiho Pharmaceutical Company. S. Takahashi: Research funding: Taiho Pharmaceutical Company. S. Nomura: Japan Breast Cancer Research Group (JBCRG). Grants: Japan Agency for Medical Research and Development (AMED). A. Sato: Corporate-sponsored Research: Taiho, Boehringer-Ingelheim, Novartis, Bayer. All other authors have declared no conflicts of interest.