PD-014 Final survival results and onset of neutropenia as an indicator of therapeutic effect in phase 2 of TAS-102 vs placebo with metastatic colorectal cancer (J003-10040030)

Abstract

Introduction: TAS‐102 is comprised of a trifluridine and a tipiracil hydrochloride. The J003‐10040030 randomized phase 2 trial demonstrated a significant improvement in overall survival (OS) and progression‐free survival (PFS) favoring TAS‐102 versus placebo in patients with metastatic colorectal cancer (mCRC) refractory/intolerant to standard therapies (Yoshino T, et al. Lancet Oncology 2012), of which results were confirmed by the Phase 3 RECOURSE trial. Neutropenia is the most common TAS‐102 related adverse event and is associated with the concentration of phosphorylated trifluridine in tumors. Therefore, positive correlation between neutropenia and OS in mCRC could be hypothesized. Here we report results of a prespecified updated survival analysis and a post hoc analysis for correlations between onset of neutropenia and OS. Methods: Patients were randomized 2:1 to receive TAS‐102 or placebo. Study treatment continued until disease progression, death or unacceptable toxicity. The primary endpoint was OS; Final survival data were collected on January 19 2015. Investigation of neutrophil count at time points of day 15, 22, and 29 in cycle 1 was prespecified. The correlations between onset of neutropenia and OS were evaluated for patients receiving TAS‐102 with onset of neutropenia at different time points of day 15, 22, and 29 in cycle 1, compared to patients receiving TAS‐102 without neutropenia in cycle 1 and to patients receiving placebo. To minimize lead‐time bias, both multivariate analysis with or without time‐dependent covariates (TDC) and landmark multivariate analysis were conducted. No adjustment was taken for multiple comparisons. Results: Median follow‐up was 57.5 months. The number of OS events was 167(98.8%) while it was 123 (72.8%) in the original analysis. The median OS was 9.0 months in TAS‐102 arm and 6.6 months in placebo arm [hazard ratio (HR) 0.63; 95% confidence interval (CI) 0.45‐0.87; p= 0.0066]. Of 112 patients given TAS‐102, eight (7%) developed any grade neutropenia at day 15, 61 (54%) at day 22, and 46 (41%) at day29 in cycle 1. The patients with neutropenia in cycle 1 showed a longer OS when compared to patients without neutropenia in cycle 1 and patients with placebo (Table), which was consistent in both TDC and landmark analysis. Similar tendency was observed in PFS. The best time point showing the greatest OS benefit in patients with neutropenia over patients without neutropenia and over patients with placebo was day 22 in cycle 1, followed by day 29. Conclusion: The OS results in the updated survival analysis were consistent with those in the original survival analysis. Patients who experienced TAS‐102 related neutropenia in cycle 1 showed the greater OS benefit than those who did not. In addition, patients who experienced neutropenia at day 22 in cycle 1 showed the greatest OS benefit. However, considering the feasible time point of investigating neutrophil count in real‐world clinical practice setting, day 29 in cycle 1 might become an acceptable alternative option. The occurrence of neutropenia may be an on‐treatment predictive biomarker of TAS‐102.