Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials
Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials
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DOI：
10.1016/j.annonc.2019.10.005
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发表时间：
2020-01-01
影响因子：
50.5
通讯作者：
Lenz, H-J
中科院分区：
文献类型：
--
作者：
Yoshino, T.;Cleary, J. M.;Lenz, H-J
背景资料：II期J 003（N = 169）和III期RECOURSE（N = 800）试验证明，与安慰剂相比，曲氟尿苷（FTD）/替吡嘧啶（TPI）治疗难治性转移性结直肠癌患者的生存期显著改善。该事后分析研究了FTD/TPI暴露的药代动力学数据和药效学标志物，如化疗诱导的中性粒细胞减少症（CIN）和临床结局。患者和方法：共有210例来自RECOURSE的患者入组该子研究。采用有限采样方法，在周期1第12天采集3份药代动力学样本。患者被分类为高于或低于FTD和TPI的中位血药浓度-时间曲线下面积（AUC）。我们对整个RECOURSE人群进行了事后分析，以确定CIN与临床结局之间的相关性。然后，我们对J 003试验进行了类似的分析，以验证结果。结果：在RECOURSE亚组中，高FTD AUC组患者的CIN风险显著增加。对整个人群的分析表明，在第1和第2周期中接受FTD/TPI治疗的任何级别的CIN患者的中位总生存期（OS）和无进展生存期（PFS）明显长于未发生CIN的患者和安慰剂组患者。与安慰剂组和未发生CIN的患者相比，需要FTD/TPI治疗延迟的患者的OS和PFS增加。结论：在RECOURSE研究中，FTD药物暴露量较高的患者CIN风险增加。发生CIN的FTD/TPI治疗患者与安慰剂组和未发生CIN的患者相比，OS和PFS改善。在J 003队列中报告了类似的结果，因此验证了RECOURSE结果。CIN的发生可能是FTD/TPI治疗患者治疗结局的有用预测因素。
Background: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes.Patients and methods: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results.Results: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort.Conclusions: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients.