结直肠癌复方新药Lonsurf（trifluridine/tipiracil，FTD/TPI）提前3个月被FDA批准 2015年9月22日,美国食品和药品监管局(FDA)批准Lonsurf(两药组合药丸，曲氟尿苷和tipiracil)对有晚期结肠直肠癌形式对其他治疗不再反应患者。. FDA的药品评价和研究中心血液学和肿瘤产品室主任 Richard Pazdur，M.D说：“过去十年围绕结肠直肠癌，在如何能检测和治疗这个常常破坏性疾病带来了新的认识，” “但有许多患者仍需要另外选择，而今天的批准证明了FDA与企业合作，开发新的药物仍然存在未满足的需求疾病领域的承诺。” 按照美国国立癌症研究所结肠直肠癌在美国男性和妇女中第三位最常见非-皮肤癌，同时仍是美国癌相关死亡第二大原因，过去十年结肠直肠癌病例数和相关食物已下降，部分归功于筛选，例如结肠镜检查。 Lonsurf是一个口服药物意向治疗有晚期(转移)结肠直肠癌患者以前曾被化疗和生物学治疗治疗过。 在一项国际，随机化，双盲研究涉及800例with 以前治疗过转移结肠直肠癌患者中评价Lonsurf的疗效和安全性。 研究参加者接受Lonsurf加最佳支持疗法，或安慰剂加最佳支持疗法直至他们的疾病恶化或副作用变成不能耐受。研究的主要终点是总体生存和次要终点是无进展生存。用Lonsurf治疗患者平均生存7.1个月与之比较用安慰剂治疗患者为5.3个月。对用Lonsurf患者平均至疾病进展时间为2月，与之比较接受安慰剂患者为1.7个月。 用Lonsurf治疗最常见副作用是贫血，与感染斗争白血细胞减低(中性粒细胞减少)或血小板减少，体质虚弱，极度疲劳和缺乏能量(疲乏)，恶心，食欲减退，腹泻，呕吐，腹痛和发热。 FDA建议卫生保健提供者在Lonsurf每个疗程开始前得到完整血细胞计数和监视患者治疗始终，因为Lonsurf可能致血细胞和血小板生成严重减低(骨髓抑制)。、 还鼓励卫生保健提供者忠告妇女当服用 Lonsurf时对发育胎儿潜在风险。服用Lonsurf妇女不应哺乳喂养。 Lonsurf由在新泽西州普林斯顿Taiho Oncology公司制造。 http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm463650.htm Lonsurf, trifluridine/tipiracil (TAS-102) Lonsurf Approved for Metastatic Colorectal Cancer Taiho Oncology announced that the Food and Drug Administration (FDA) has approved Lonsurf (trifluridine and tipiracil) tablets for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyramidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. The FDA approval was based on data from the global Phase 3 RECOURSE trial (n=800) in patients who were previously treated for mCRC. The study met the primary efficacy endpoint of statistically significant improvement in overall survival (OS) compared to placebo (HR 0.68, CI: 0.58, 0.81; P<0.001). Treatment with Lonsurf reduced the risk of death by 32% vs. placebo. Median OS was 7.1 months for Lonsurf and 5.3 months for placebo, respectively Lonsurf combines trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor. Inclusion of tipiracil increases trifluridine exposure by inhibiting its metabolism by thymidine phosphorylase. Following uptake into cancer cells, trifluridine is incorporated into DNA, interferes with DNA synthesis and inhibits cell proliferation. Lonsurf will be available as 15mg/6.14mg and 20mg/8.19mg strength tablets in 20-, 40-, and 60-count bottles. New Drugs Online Report for trifluridine + tipiracil Information Generic Name: trifluridine + tipiracil   Trade Name: Lonsurf  Synonym: TAS-102  Entry Type: New molecular entity   Development and Regulatory status UK: Pre-registration (Filed)  EU: Pre-registration (Filed)  US: Approved (Licensed)  UK launch Plans: Available only to registered users Actual UK launch date:   Comments Sep 15: Approved in US to treat refractory metastatic colorectal cancer in patients whose tumours have spread despite first-line therapies [12]. 23/09/2015 09:08:01  Mar 15: Filed in the EU. The submission is based on data from the PIII RECOURSE trial [10]. 04/03/2015 11:39:58  Feb 15: The PDUFA goal date is December 19, 2015. [9] 24/02/2015 10:23:15  Dec 14: Taiho announced that it has completed its rolling New Drug Application (NDA) submission to the US FDA for TAS-102 (trifluridine or tipiracil hydrochloride) which is supported by the results from the Phase III RECOURSE trial [8].  23/12/2014 12:08:16  Oct 14: Following positive results from the PIII RECOURSE trial (n=800), the US FDA granted Fast Track designation for TAS-102 (trifluridine and tipiracil hydrochloride) for the treatment of refractory metastatic colorectal cancer in pts whose disease had progressed after or who were intolerant to standard therapies. [7] 21/10/2014 12:44:50  Jun 14: A regulatory submission in Europe is planned in 2015 [6]. 02/07/2014 11:59:10  PIII trial to start June 2012 [2] 01/06/2012 13:09:20  Trial or other data May 15: Results of RECOURSE trial published in NEJM [11]. 17/05/2015 18:35:09 Jun 14: In the PIII RECOURSE trial, TAS-102 improved median overall survival in patients with refractory metastatic colorectal cancer by 1.8 months compared to placebo [6]. 02/07/2014 11:58:56 Mar 13: Estimated RECOURSE completion date December 2014 [4].  11/03/2013 14:56:42 Aug 12: Japanese PII trial published early online in Lancet Oncology. Eligible pts were 20 years or older; had confirmed colorectal adenocarcinoma; have an ECOG performance status of between 0 and 2; had a treatment history of two or more regimens of standard chemotherapy; and were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin. Pts were randomised to TAS-102 (n=112; 35 mg/m2 given orally twice a day in a 28-day cycle [2-week cycle of 5 days of treatment followed by a 2-day rest period, and then a 14-day rest period]) or placebo (n=57); all pts received best supportive care. After a median follow up period of 11.3 months, median overall survival, the primary endpoint, was 9.0 months in the TAS-102 arm & 6.6 months in the placebo group (hazard ratio for death 0.56, 80% CI 0.44-0.71, 95% CI 0.39-0.81; p=0.0011). 57 (50%) of 113 pts given TAS-102 in the safety population had neutropenia of grade 3 or 4, 32 (28%) leucopenia, & 19 (17%) anaemia. No pt given placebo had grade 3 or worse neutropenia or leucopenia; three (5%) of 57 had grade 3 or worse anaemia. Serious adverse events occurred in 19% pts in the TAS-102 group & in 9% in the placebo group. No treatment-related deaths occurred [3]. 30/08/2012 10:12:50 May 12: The global PIII trial (RECOURSE) will start in June 2012. The double-blind, placebo-controlled RCT will compare TAS-102 with best supportive care in 800 patients with advanced recurrent colorectal cancer that is both unresectable and relapsed/refractory to standard chemotherapies (including fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and, in the case of patients with tumours with wild-type KRAS gene, an anti-EGFR monoclonal antibody). The primary endpoint is overall survival [2].  01/06/2012 13:09:33 July 11: Phase II trial in 172 patients refractory to standard chemotherapy for metastatic colorectal cancer who have received at least two or more regimens containing a fluoropyrimidine, irinotecan, and oxaliplatin. Patients were randomly assigned to the TAS-102 (n=114) or a placebo (n=58). The primary endpoint was overall survival. TAS-102 and placebo were administered at dose of 70mg/m2/day twice daily for five days followed by two days rest and repeated twice. This was followed by a 14-day rest period to make a 28-day schedule for one course. In both cohorts, the 28-day cycle was repeated until the established criteria for termination were met. [1]  25/07/2011 08:47:39 TAS-102 is a novel oral nucleoside antitumor agent with a novel mechanism of action, composed of a mixture of Trifluorothymidine (FTD), which demonstrates antitumor effects through incorporation into DNA, and 5-chloro-6-(2-iminopyrrolidin-1-yl)-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride (TPI), which inhibits the degradation of FTD. [1] 25/07/2011 08:44:53  References   Available only to registered users  Category BNF Category: Other antineoplastic drugs (08.01.05) Pharmacology: a mix of FTD, which has antitumour effects through incorporation into DNA, and TPI which inhibits FTD degradation   Epidemiology: The age-standardised incidence rate per 100,000 population in the UK in 2008 was 47.2 (29.4 colon, 17.8 rectum). The figures were higher for men than women for both colon and rectal cancers [5].   Indication: Colorectal cancer  Additional Details: metastatic in adults previously treated with, or are not considered suitable for fluoropyrimidine-based chemotherapy, anti-VEGF therapy, and/or anti-EGFR therapy  Method(s) of Administration   Oral  Company Information Name: Taiho  US Name: Taiho  Further Information Anticipated commissioning route (England) NHSE  High cost drug list? Awaiting Update Implications Available only to registered users