| ——Lenvima（lenvatinib）将成为不可切除甲状腺癌临床治疗新标准 2015年3月26日讯，卫材（Eisai）新型口服抗癌药Lenvima（lenvatinib）近日获日本批准用于不可切除性甲状腺癌的治疗。这也是该药继今年2月获美国批准之后，攻下的又一重要市场。此前，lenvatinib在美国、日本、欧盟均被授予孤儿药地位及优先审查资格。该药作为一种具有重大公共卫生利益的创新药物，将帮助解决甲状腺癌领域存在的严重未满足的医疗需求。 卫材表示，Lenvima将成为不可切除性甲状腺癌临床治疗的新标准 根据卫材官方信息，在一项大型III期SELECT研究中，与安慰剂相比，lenvatinib显著延长了放射性碘难治性分化型甲状腺癌的无进展生存期（PFS：18.3个月 vs 3.6个月）；同时，lenvatinib治疗组有显著更高比例的患者实现肿瘤体积缩小（65% vs 2%）。此外，在日本开展的另一项II期研究中，lenvatinib针对甲状腺髓样癌和未分化型甲状腺癌也表现出了很好的疗效和耐受性。 Lenvima, lenvatinib (E7080) Important Safety Information Warnings and Precautions Hypertension was reported in 73% of LENVIMA-treated patients (of which 44% were ≥ Grade 3) and 16% of patients in the placebo group. Control blood pressure prior to treatment and monitor blood pressure after 1 week, then every 2 weeks for the first 2 months, and then at least monthly during treatment. Withhold LENVIMA for Grade 3 hypertension; resume at a reduced dose when hypertension is controlled at ≤ Grade 2. Discontinue LENVIMA for life-threatening hypertension. Cardiac dysfunction was reported in 7% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor patients for clinical symptoms or signs of cardiac decompensation. Withhold LENVIMA for development of Grade 3 cardiac dysfunction until improved to Grade 0 or 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of cardiac dysfunction. Discontinue LENVIMA for Grade 4 cardiac dysfunction. Arterial thromboembolic events were reported in 5% of LENVIMA-treated patients; events of Grade 3 or greater were 3%. Discontinue LENVIMA following an arterial thrombotic event. LENVIMA has not been studied in patients who have had an arterial thromboembolic event within the previous 6 months. 4% of LENVIMA-treated patients experienced an increase in ALT and 5% experienced an increase in AST that was Grade 3 or greater. Monitor liver function before initiation and during treatment with LENVIMA. Withhold LENVIMA for the development of ≥ Grade 3 liver impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hepatotoxicity. Discontinue LENVIMA for hepatic failure. Proteinuria was reported in 34% of LENVIMA-treated patients (of which 11% were Grade 3). Monitor for proteinuria before initiation of, and periodically during treatment. Obtain a 24 hour urine protein if urine dipstick proteinuria ≥2+ is detected. Withhold LENVIMA for ≥ 2 grams of proteinuria/24 hours and resume at a reduced dose when proteinuria is <2 gm/24 hours. Discontinue LENVIMA™ (lenvatinib) for nephrotic syndrome. Events of renal impairment were reported in 14% of LENVIMA-treated patients. Renal failure or impairment ≥ Grade 3 was 3% in LENVIMA-treated patients. Withhold LENVIMA for development of Grade 3 or 4 renal failure/impairment until resolved to Grade 0 to 1 or baseline. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of renal impairment. Events of gastrointestinal perforation or fistula were reported in 2% of LENVIMA-treated patients. Discontinue LENVIMA in patients who develop gastrointestinal perforation or life-threatening fistula. QT/QTc interval prolongation was reported in 9% of LENVIMA-treated patients (2% Grade 3 or greater). Monitor ECG in patients with congenital long QT syndrome, CHF, bradyarrhythmias, or patients taking drugs known to prolong the QT interval. Monitor and correct electrolyte abnormalities in all patients. Withhold LENVIMA for the development of ≥ Grade 3 QT interval prolongation. Resume LENVIMA at a reduced dose when QT prolongation resolves to Grade 0 or 1 or baseline. Hypocalcemia ≥ Grade 3 was reported in 9% of LENVIMA-treated patients. Monitor blood calcium levels at least monthly and replace calcium as necessary during LENVIMA treatment. Interrupt and adjust LENVIMA dosing as necessary depending on severity, presence of ECG changes, and persistence of hypocalcemia. Reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 3 patients across clinical studies in which 1108 patients received LENVIMA. Confirm the diagnosis of RPLS with MRI. Withhold LENVIMA for RPLS until fully resolved. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of neurologic symptoms. Hemorrhagic events occurred in 35% of LENVIMA-treated patients and in 18% of the placebo group. The incidence of Grade 3-5 hemorrhage was similar between arms at 2% and 3%, respectively. The most frequently reported hemorrhagic event was epistaxis (11% Grade 1 and 1% Grade 2). Discontinuation due to hemorrhagic events occurred in 1% of LENVIMA-treated patients. There was one case of fatal intracranial hemorrhage among 16 patients who received LENVIMA and had CNS metastases at baseline. Withhold LENVIMA for the development of Grade 3 hemorrhage until resolved to Grade 0 to 1. Resume at a reduced dose or discontinue LENVIMA depending on the severity and persistence of hemorrhage. Discontinue LENVIMA in patients who experience Grade 4 hemorrhage. LENVIMA impairs exogenous thyroid suppression. Elevation of TSH level above 0.5 mU/L was observed post baseline in 57% of LENVIMA-treated patients. Monitor TSH levels monthly and adjust thyroid replacement medication as needed. LENVIMA can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with LENVIMA and for at least 2 weeks following completion of therapy. Advise women not to breastfeed during treatment with LENVIMA. Adverse Reactions The most common adverse reactions observed in LENVIMA-treated patients vs. placebo-treated patients respectively were hypertension (73% vs 16%), fatigue (67% vs 35%), diarrhea (67% vs 17%), arthralgia/myalgia (62% vs 28%), decreased appetite (54% vs 18%), weight decreased (51% vs 15%), nausea (47% vs 25%), stomatitis (41% vs 8%), headache (38% vs 11%), vomiting (36% vs 15%), proteinuria (34% vs 3%), palmar-plantar erythrodysesthesia syndrome (32% vs 1%), abdominal pain (31% vs 11%), and dysphonia (31% vs 5%). New Drugs Online Report for lenvatinib Information Generic Name: lenvatinib Trade Name: Lenvima Synonym: E7080 Entry Type: New molecular entity Development and Regulatory status UK: Recommended for approval (Positive opinion) EU: Recommended for approval (Positive opinion) US: Approved (Licensed) UK launch Plans: Available only to registered users Actual UK launch date: Comments Mar 15: EU positive opinion for treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine [17]. 27/03/2015 16:24:19 Feb 15: Approved in US [16] 16/02/2015 12:52:00 Oct 14: FDA grants NDA Priority Review status lenvatinib as a treatment for progressive radioactive iodine-refractory differentiated thyroid cancer. A decision is expected by 14 Apr 2015 [14]. 16/10/2014 12:14:35 Aug 14: Filed for marketing approval in EU and US for progressive radioiodine-refractory differentiated thyroid cancer [13]. 26/08/2014 12:51:08 Jul 14: EMA agrees to undertake an accelerated assessment of lenvatinib as a treatment for progressive radioiodine-refractory, differentiated thyroid cancer. Eisai plan to file imminently [12]. 01/08/2014 12:14:12 Feb 14: Filing anticipated 2014 [10]. 06/03/2014 10:57:38 May 13: Granted orphan drug status in the EU for treatment of follicular (EU/3/13/1121) & papillary thyroid cancer (EU/3/13/1119) [7]. 15/05/2013 11:28:27 Feb 13: Granted orphan drug status in the US [6]. 21/02/2013 10:02:16 Aug 11: In PIII global development programme [5]. 07/09/2011 13:15:49 Filing anticipated 2013 [4]. 13/06/2011 11:29:37 Mar 11: PIII study (NCT01321554 ) started [3]. 04/04/2011 16:15:08 PII in the EU & US [1]. 02/12/2010 09:34:30 Trial or other data Feb 15: Eisai present positive data from the PIII SELECT trial, published in the New England Journal of Medicine, which show that lenvatinib improves response rate in 64.8% of people with RR-DTC compared with 1.5% given placebo. Adverse effects were managed with dose reductions and standard interventions, but were greater with lenvatinib, and include six treatment-related deaths [15]. 13/02/2015 14:23:38 June 14: Results from the SELECT study presented at 50th ASCO. Primary endpoint, progression-free survival with lenvatinib was extended significantly compared to placebo (HR=0.21, [99% CI: 0.14-0.31]; p<0.0001). The median PFS with lenvatinib and placebo were 18.3 months and 3.6 months, respectively. Secondary endpoints included overall response rate (ORR), overall survival (OS) and safety. The ORR for lenvatinib was significantly increased to 64.8% (95% CI: 59.0-70.5) compared to 1.5% (95% CI: 0.0-3.6; p<0.0001) in the placebo arm. Median OS has not been reached yet. Most common treatment-related AEs were hypertension (67.8%), diarrhoea (59.4%), decreased appetite (50.2%), weight loss (46.4%) and nausea (41%). [11] 03/06/2014 09:24:23 Feb 14: The SELECT (Study of E7080 LEnvatinib in Differentiated Cancer of the Thyroid) study was a multicenter, randomised, double-blind, placebo-controlled Phase 3 study to compare the progression-free survival (PFS) of patients with radioiodine-refractory differentiated thyroid cancer and radiographic evidence of disease progression within the prior 12 months, treated with once-daily, oral lenvatinib (24mg) versus placebo. Compared to placebo, lenvatinib showed a highly statistically significant improvement in progression free survival (PFS) in patients with radioiodine-refractory differentiated thyroid cancer (RR-DTC). [9] 04/02/2014 10:27:04 Mar 11: NCT01321554 is a US multicentre, randomized, double-blind, placebo-controlled, PIII trial of E7080 in 360 patients with 131I-refractory differentiated thyroid cancer. The objective is to compare progression-free survival (PFS) with radiographic evidence of disease progression over 12 months. Subjects with confirmed disease progression while receiving blinded study drug may request to receive open label E7080 [3]. 04/04/2011 16:13:49 Aug 09: an open-label PII (NCT00784303) study to determine the safety & efficacy of E7080 in pts with medullary & iodine-131 refractory, unresectable differentiated thyroid cancer began recruitment of 104 pts in the US, France, Germany, Italy, Poland & the UK. Enrolment is complete and the study is estimated to complete data collection in Oct 11 [2]. 02/12/2010 09:39:23 References Available only to registered users Category BNF Category: Other antineoplastic drugs (08.01.05) Pharmacology: multi-targeted kinase inhibitor, which inhibits VEGFR1-3, FGFR1-4 & RET tyrosine kinases Epidemiology: In 2008, 2,154 people were diagnosed with thyroid cancer in the UK (age-standardised incidence rate 3.2 per 100,000 population). Thyroid cancer caused 354 deaths in the UK in 2008. There is a male:female ratio of 1:3. The estimated lifetime risk of developing thyroid cancer in 2008 was 1 in 650 for men and 1 in 243 for women in the UK. Indication: Thyroid cancer Additional Details: radioiodine-refractory differentiated cancer Method(s) of Administration Oral Company Information Name: Eisai US Name: Eisai Further Information Anticipated commissioning route (England) NHSE High cost drug list? No Tariff Chemotherapy is locally negotiated. Implications Available only to registered users |
新型甲状腺癌口服药Lenvima获日本批准即将上市简介：
——Lenvima（lenvatinib）将成为不可切除甲状腺癌临床治疗新标准2015年3月26日讯，卫材（Eisai）新型口服抗癌药Lenvima（lenvatinib）近日获日本批准用于不可切除性甲状腺癌的治疗。这也是该药继今年2月 ... 责任编辑：admin |
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