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Purpose: Trifluridine/tipiracil (FTD/TPI) is approved in Japan, the United States (US), and Europe for metastatic colorectal cancer (mCRC) refractory to standard therapies. This Phase 1b open-label study focused on the pharmacokinetic (PK) and toxicity profiles of FTD/TPI in Chinese patients with solid tumors. Methods: Patients with definitive histologically or cytologically confirmed advanced/metastatic solid tumors refractory to standard treatments were enrolled. FTD/TPI (35 mg/m2) was administered orally twice daily for five consecutive days, followed by a 2-day recovery. Treatment was repeated for five consecutive days, followed by a 16-day recovery. The primary objective was to assess PK characteristics of FTD, 5-trifluoromethyl-2,4 (1H,3H)-pyrimidinedione (FTY; an inactive form of FTD), and TPI, calculated from plasma concentrations. Additionally, these PK values were compared with those from similar Phase 1 studies in patients from Japan and the US, using Tukey–Kramer's honestly significant difference (HSD) multiple comparison tests. Safety and preliminary efficacy of FTD/TPI were assessed. Results: Fifteen patients (12 males, three females) were enrolled, most with CRC (87%). Geometric mean analysis showed that maximum plasma concentration (Cmax) of FTD increased after multiple administration (from day 1 [3019.5 ng/mL] to day 12 [3693.1 ng/mL]), and the exposure (AUC0-t) increased 2.4-fold (day 1:7796.6 ng/mL•h; day 12:18,181.3 ng/mL•h). There was no meaningful change in the exposure to FTY and TPI throughout the study. HSD tests showed comparable PK for FTD, FTY, and TPI between Chinese and Japanese patients, and comparable exposure to FTD between Chinese and US patients. Eight patients (53.3%) experienced Grade 3 treatment-emergent adverse events, most frequently anemia and fatigue (13.3%, two events each). Median progression-free survival was 1.9 months. Conclusion: FTD/TPI had an acceptable safety and efficacy profile and PK characteristics were comparable between Chinese, Japanese, and US patients, suggesting that this treatment may be suitable for Chinese patients with refractory mCRC. Trial Registration: This trial was registered at clinicaltrials.gov as NCT02261532. [ABSTRACT FROM AUTHOR]

The discovery of biomarkers that provide information on drug efficacy is recognized as essential for successful and cost-effective treatment of cancer. However, biomarker discovery is difficult, and requires multiple independent studies to identify a target that serves as a suitable predictor of efficacy and to ensure appropriate biomarker validation. Clinical trials that are performed, sometimes sequentially, in Europe, the USA or Asia, are often similar in their design, in part owing to regulatory, marketing, or safety considerations. We believe some of these trials offer additional unique opportunities for biomarker discovery or validation. There are multiple hurdles to overcome, such as homogenous tissue acquisition and analysis, defining and aligning biomarker hypotheses across trials, and the need to adapt sample sizes and trial designs. Nevertheless, we believe that a collaborative engagement of the academic, regulatory and pharmaceutical community can go a long way in addressing these issues and producing more-rapid results in the field of personalized medicine. In this Perspectives, we describe our views on the current fragmented approach to biomarker discovery and validation in relevant trials run within our own regions-that is, Europe, China, and the USA-and hope this article serves as a base for further reflection.