USC Norris Comprehensive Cancer Center, Los Angeles, CA.
Rutgers Cancer Institute of New Jersey, New Brunswick, NJ.
Am J Health Syst Pharm. 2019 Feb 21;76(6):339-348. doi: 10.1093/ajhp/zxy006.
The pharmacology, pharmacokinetics, clinical efficacy, safety, dosing, and place in therapy of trifluridine-tipiracil are reviewed.
Trifluridine-tipiracil is an oral antineoplastic agent consisting of trifluridine (a trifluorothymidine, a thymidine-based nucleoside analog) and tipiracil (a thymidine phosphorylase inhibitor), at a molar ratio of 1:0.5. Tipiracil blocks the degradation of trifluridine by thymidine phosphorylase, which improves the bioavailability of trifluridine and allows for oral administration. A Phase III study comparing trifluridine-tipiracil versus placebo in metastatic colorectal cancer (mCRC) patients refractory to or intolerant of standard therapy (n = 800) showed a benefit in overall survival (the primary endpoint) and progression-free survival compared with placebo. The most common grade ≥ 3 adverse events in trifluridine-tipiracil groups in Phase II and III trials were neutropenia, anemia, and leukopenia. The recommended dose of trifluridine-tipiracil is 35 mg/m2 twice a day after meals in a 28-day cycle comprising 2 weeks of 5 days of treatment and 2 days of rest (days 1-5 and 8-12 [every] 28 days), followed by 2 weeks of rest. Trifluridine-tipiracil is approved for the treatment of patients with mCRC previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an antivascular endothelial growth factor biological therapy and, if RAS wild-type, an antiepidermal growth factor receptor therapy.
Trifluridine-tipiracil is a new treatment option for patients with mCRC who have received at least 2 prior lines of standard chemotherapy (including fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and an antiepidermal growth factor receptor antibody in patients with KRAS wild-type tumors). Ongoing trials are investigating trifluridine/tipiracil in combination with other anticancer agents for mCRC and its use in other malignancies, such as metastatic gastric cancer.
综述曲氟尿苷替匹嘧啶的药理学、药代动力学、临床疗效、安全性、剂量和治疗地位。
曲氟尿苷替匹嘧啶是一种口服抗肿瘤药物，由曲氟尿苷（三氟胸腺嘧啶核苷，一种基于胸腺嘧啶的核苷类似物）和替匹嘧啶（胸苷磷酸化酶抑制剂）组成，摩尔比为 1:0.5。替匹嘧啶可阻断胸苷磷酸化酶对曲氟尿苷的降解，从而提高曲氟尿苷的生物利用度并实现口服给药。一项比较曲氟尿苷替匹嘧啶与安慰剂在转移性结直肠癌（mCRC）患者中的疗效的 III 期研究（n=800），这些患者对标准治疗（化疗）不耐受或已耐药，结果显示，与安慰剂相比，该药物在总生存期（主要终点）和无进展生存期方面具有获益。在 II 期和 III 期试验中，曲氟尿苷替匹嘧啶组最常见的≥3 级不良事件是中性粒细胞减少症、贫血和白细胞减少症。曲氟尿苷替匹嘧啶的推荐剂量为 35 mg/m2，每日 2 次，于 28 天周期内口服，2 周 5 天治疗，2 天休息（每 28 天的第 1-5 天和第 8-12 天），然后休息 2 周。曲氟尿苷替匹嘧啶已获批用于治疗既往接受氟嘧啶类、奥沙利铂类和伊立替康类化疗、抗血管内皮生长因子生物治疗（如果 RAS 野生型）和表皮生长因子受体治疗的 mCRC 患者。
曲氟尿苷替匹嘧啶是一种新的治疗选择，适用于至少接受过 2 线标准化疗（包括氟嘧啶类、奥沙利铂类、伊立替康类、贝伐珠单抗和表皮生长因子受体抗体治疗 KRAS 野生型肿瘤的患者）的 mCRC 患者。正在进行的临床试验正在研究曲氟尿苷/替匹嘧啶联合其他抗肿瘤药物治疗 mCRC 及其在转移性胃癌等其他恶性肿瘤中的应用。
