Onset of neutropenia as an indicator of treatment response in the randomized phase II of TAS-102 vs placebo in Japanese patients with metastatic colorectal cancer (Study J003-10040030).
3557 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil hydrochloride. Primary results of the J003-10040030 randomized phase 2 trial demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) favoring TAS-102 vs placebo (pbo) in patients (pts) with metastatic colorectal cancer refractory/intolerant to standard therapies (Yoshino T, et al. Lancet Oncology 2012). Neutropenia is the most common TAS-102-associated adverse event and it has been hypothesized to reflect a relatively high FTD concentration in pts. Methods: Study J003 data were analyzed post hoc for correlations between initial onset of Grade 3/4 neutropenia and OS benefit. Results: Of 112 pts given TAS-102, 31 (28%) developed Grade 3/4 neutropenia in treatment cycle 1, 19 (17%) in cycle 2, and 8 (7%) in ≥ cycle 3. Onset of Grade 3/4 neutropenia at cycle 1 and 2 was associated with longer median OS compared to pts without neutropenia as summarized by the hazard ratio (against cycle-matched placebo control groups) and the corresponding median OS differences (see Table). Conclusions: Pts experienced Grade 3/4 neutropenia in cycle 1 and 2 showed a greater OS benefit over pbo. In contrast, pts who did not experience Grade 3/4 neutropenia appear to show no OS benefit. The occurrence of Grade 3/4 neutropenia might become an on-treatment predictive biomarker of TAS-102 and TAS-102 treatment should not be discontinued permanently due to the onset of Grade 3/4 neutropenia. The correlation between efficacy of TAS-102 and onset of neutropenia warrants further analyses. Clinical trial information: 090880.