背景：三氟尿苷/替吡拉西（FTD/P）聯合貝伐單抗（BEV）作為晚期轉移性結直腸癌（MCRC）的治療方法，其療效已在臨床試驗中得到證實。因此，我們進行了一項 2/3 期隨機研究，以確定 FTD/PI 加 BEV 作為 MCRC 患者二線治療的總生存率（OS）是否不低於 FOLFIRI 或 S-1 和胰島素能加 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：經組織學證實的 MCRC 患者在一線化療失敗，包括氟嘧啶聯合奧沙利鉑聯合 ei-ther-BEV 或抗 EGFR 抗體（RAS 野生型患者）均符合條件。受試者隨機接受 FTD/PI+BEV（實驗組 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，每天兩次）或 FOLFIRI 或 S-1 和伊立替康+BEV（對照組）。主要終點是操作係統。危險比（HR）為 1.33 的非劣效性界限。基於對照組中位生存時間為 19 個月的假設（冪 0.80，單側 α0.025）。次要終點是無進展生存率（PFS）、有效率（RR）、疾病控製率（DCR）、治療失敗時間、研究後治療失敗時間、接受研究後治療的患者比例、生活質量和安全性。

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.

結果：由於中期分析無效，本研究於 2020 年 7 月終止，從 2017 年 10 月起，共有 397 名患者在 65 家醫療機構登記。兩組間基線特征相似。FTD/TPI 加 BEV 組中位 OS 為 14.8 個月，18 個月,對照組 1 個月。38:95%可信區間（C）：0.99-1.93:p=0.5920 為非劣效性 FD/PI 加 BEV 的非劣效性未被證實。FTD/PI 加 BEV 組 PFS 中位數為 4.5 個月，對照組為 6.0 個月（HR::1.38;95%可信區間(CI): 0.99-1.93;非劣效性 P = 0.5920) . FTD/TPI+BEV 組 RR 和 DCR 分別為 3.8%和61.2%，DCR 為 7.0%。對照組分別為 1%和 71.7%。FTDTPI+BEV 組和對照組接受研究後治療的患者比例分別為 59.9%和 52%。分別為 3%。FTD/TPI+BEV 組和對照組的主要 3 級或 4 級不良事件為中性粒細胞減少（65.8%和 41.8%）。腹瀉（1.5%和 7.1%），以及 1 級或 2 級脫發（3.6%和 24%,分別為 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).

結論：FTD/TPI+BEV 在 mCRC 患者的二線治療中並不低於 FOLFIRI 或 S-1 和伊立替康加 BEV。正在進行事後亞組分析，以調查可能受益於 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.