背景：三氟尿苷/替吡拉西（FTD/P）联合贝伐单抗（BEV）作为晚期转移性结直肠癌（MCRC）的治疗方法，其疗效已在临床试验中得到证实。因此，我们进行了一项 2/3 期随机研究，以确定 FTD/PI 加 BEV 作为 MCRC 患者二线治疗的总生存率（OS）是否不低于 FOLFIRI 或 S-1 和胰岛素能加 BEV。

Background: The efficacy of trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) as a later-line treatment for metastatic colorectal cancer (mCRC) has been demonstrated in clinical trials. Therefore, we conducted a randomized phase 2/3 study to determine whether FTD/TPI plus BEV is non-inferior to either FOLFIRI or S-1 and irinotecan plus BEV in terms of overall survival (OS) as second-line treatment in patients with mCRC.

方法：经组织学证实的 MCRC 患者在一线化疗失败，包括氟嘧啶联合奥沙利铂联合 ei-ther-BEV 或抗 EGFR 抗体（RAS 野生型患者）均符合条件。受试者随机接受 FTD/PI+BEV（实验组 BEV 5.0 mg/kg，第 1 天和第 15 天，FTD/PI 35 mg/m，每 28 天周期第 1-5 天和第 8-12 天，每天两次）或 FOLFIRI 或 S-1 和伊立替康+BEV（对照组）。主要终点是操作系统。危险比（HR）为 1.33 的非劣效性界限。基于对照组中位生存时间为 19 个月的假设（幂 0.80，单侧 α0.025）。次要终点是无进展生存率（PFS）、有效率（RR）、疾病控制率（DCR）、治疗失败时间、研究后治疗失败时间、接受研究后治疗的患者比例、生活质量和安全性。

Methods: Patients with histologically confirmed mCRC who failed first-line doublet chemotherapy including fluoropyrimidine plus oxaliplatin with either BEV or an anti-EGFR antibody (in cases of RAS wild-type) were eligible. Patients were randomized to receive either FTD/TPI plus BEV (experimental group, BEV 5.0 mg/kg on days 1 and 15, FTD/TPI 35 mg/m2 twice daily on days 1–5 and 8–12 of each 28-day cycle) or either FOLFIRI or S-1 and irinotecan plus BEV (control group). The primary endpoint was the OS. The non-inferiority margin of a hazard ratio (HR) of 1.33 was based on the assumption of a median survival time of 19 months for the control (power 0.80, 1-sided alpha 0.025). The secondary endpoints were the progression-free survival (PFS), response rate (RR), disease control rate (DCR), time to treatment failure, time to post-study treatment failure, proportion of patients receiving post-study treatment, quality of life, and safety.

结果：由于中期分析无效，本研究于 2020 年 7 月终止，从 2017 年 10 月起，共有 397 名患者在 65 家医疗机构登记。两组间基线特征相似。FTD/TPI 加 BEV 组中位 OS 为 14.8 个月，18 个月,对照组 1 个月。38:95%可信区间（C）：0.99-1.93:p=0.5920 为非劣效性 FD/PI 加 BEV 的非劣效性未被证实。FTD/PI 加 BEV 组 PFS 中位数为 4.5 个月，对照组为 6.0 个月（HR::1.38;95%可信区间(CI): 0.99-1.93;非劣效性 P = 0.5920) . FTD/TPI+BEV 组 RR 和 DCR 分别为 3.8%和61.2%，DCR 为 7.0%。对照组分别为 1%和 71.7%。FTDTPI+BEV 组和对照组接受研究后治疗的患者比例分别为 59.9%和 52%。分别为 3%。FTD/TPI+BEV 组和对照组的主要 3 级或 4 级不良事件为中性粒细胞减少（65.8%和 41.8%）。腹泻（1.5%和 7.1%），以及 1 级或 2 级脱发（3.6%和 24%,分别为 9%）。

Results: As a result of the interim analysis for futility, the study was terminated in July 2020, and 397 patients were finally enrolled at 65 institutions from October 2017. The baseline characteristics were similar between the groups. The median OS were 14.8 months in the FTD/TPI plus BEV group and 18.1 months in the control group [HR: 1.38; 95% confidence interval (CI): 0.99–1.93; p = 0.5920 for non-inferiority]; non-inferiority of FTD/TPI plus BEV was not demonstrated. The median PFS were 4.5 months in the FTD/TPI plus BEV group and 6.0 months in the control group (HR: 1.45; 95% CI: 1.14–1.84). The RR and DCR were 3.8% and 61.2% in the FTD/TPI plus BEV group, respectively, and 7.1% and 71.7% in the control group, respectively. The proportions of patients receiving post-study treatment in the FTD/TPI plus BEV and control groups were 59.9% and 52.3%, respectively. The main grade 3 or 4 adverse events in the FTD/TPI plus BEV and control groups were neutropenia (65.8% and 41.6%, respectively), diarrhea (1.5% and 7.1%, respectively), and grade 1 or 2 alopecia (3.6% and 24.9%, respectively).

结论：FTD/TPI+BEV 在 mCRC 患者的二线治疗中并不低于 FOLFIRI 或 S-1 和伊立替康加 BEV。正在进行事后亚组分析，以调查可能受益于 FTD/TPI 加 BEV 的患者。

Conclusions: FTD/TPI plus BEV did not show non-inferiority to FOLFIRI or S-1 and irinotecan plus BEV as second-line treatment in patients with mCRC. Post hoc subgroup analyses are ongoing to investigate patients who likely benefit from FTD/TPI plus BEV.