Lenvatinib (E7080)

之前在论坛看到过一点讨论http://www.yuaigongwu.com/forum. ... page%3D2&page=2。
在此，我再发下更全面一些的信息。

Lenvatinib (E7080)
Lenvatinib (E7080)是一种多靶点抑制剂，作用于VEGFR2(KDR)/VEGFR3(Flt-4)最有效，IC50为4 nM/5.2，对VEGFR1/Flt-1作用效果稍弱，作用于VEGFR2/3比作用于FGFR1， PDGFRα/β选择性高10倍左右。

中国有40多家医院加入了三期试验。

靶点        VEGFR2/KDR        VEGFR3/FLT4        VEGFR1/FLT1        PDGFRβ        FGFR1       
IC50         4.0 nM [1]         5.2 nM [1]         22 nM [1]         39 nM [1]         46 nM [1]

体外研究        E7080有效抑制血管生成，也显著抑制VEGF/KDR和SCF/KIT信号通路。根据体外受体酪氨酸和丝/苏氨酸激酶实验, E7080抑制Flt-1, KDR, 和Flt-4 时，IC50分别为22, 4.0 和5.2 nM。 除了这些激酶, E7080也抑制FGFR1和PDGFR 酪氨酸激酶，作用于FGFR1, PDGFRα 和PDGFRβ时，IC50分别为46, 51和 100 nM。[1] E7080 分别作用于由VEGF和VEGF-C刺激的HUVECs，有效抑制VEGFR2和VEGFR3磷酸化，IC50分别为0.83 nM和0.36 nM。[2] 最新研究显示用 1 μM 和10 μM E7080 处理，通过抑制FGFR和PDGFR信号通路，而明显抑制细胞迁移和入侵。[3]

体内研究        E7080按30和100 mg/kg剂量口服给药处理 H146 移植瘤模型，抑制H146肿瘤生长，这种作用存在剂量依赖性，按100 mg/kg剂量时导致肿瘤衰退。而且, E7080按 100 mg/kg剂量处理，比VEGF抗体和Imatinib处理，更加降低微脉管密度。

临床试验
1期，日本，2012年，肝细胞癌。建议用药：体重<60 Kg: 8 mg每天；≥60kg，12 mg
PHASE I/II TRIAL OF LENVATINIB (E7080), A MULTI-TARGETED TYROSINE KINASE INHIBITOR, IN PATIENTS (PTS) WITH ADVANCED HEPATOCELLULAR CARCINOMA (HCC)
K. Ikeda1, H. Kumada2, M. Kudo3, S. Kawazoe4, Y. Osaki5, M. Ikeda6, T. Okusaka7, T. Suzuki8, J.P. O'Brien9 and K. Okita10
+ Author Affiliations
1Department of Hepatology, Toranomon Hospital, Tokyo, JAPAN
2Department of Hepatology, Toranomon Hospital Kajigaya, Kanagawa, JAPAN
3Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, JAPAN
4Department of Internal Medicine, Saga prefectural Hospital Koseikan, Saga, JAPAN
5Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Osaka, JAPAN
6Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Chiba, JAPAN
7Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, JAPAN
8Oncology Clinical Development, Eisai, Tokyo, JAPAN
9Oncology, Eisai Inc., Woodcliff Lake, NJ, UNITED STATES OF AMERICA
10Department of Gastroenterology and Hepatology, Shimonoseki Kohsei Hospital, Yamaguchi, JAPAN
Abstract
Background Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. The inherent vascularity of HCC makes it a target for VEGF inhibitors and other molecular mediators of angiogenesis like FGFR and PDGFR. The current study established a MTD of lenvatinib for HCC patients with Child-Pugh A of 12 mg qd. The current presentation is a report on the efficacy and safety of lenvatinib.
Methods Between July 9, 2010 and June 22, 2011, 46 pts with advanced HCC and Child-Pugh A status were enrolled in Japan (n = 43) and Korea (n = 3). Pts may have received up to one prior treatment regimen including sorafenib. Pts were treated with a starting dose of lenvatinib 12 mg once daily in 28 day cycles until disease progression or development of unmanageable toxicities. Response was assessed by RECIST 1.1 (modified to evaluate viable lesions) by independent radiologist review (IRR).
Results 46 pts were enrolled (med age: 67; M: 72%) and were evaluable for response. 76% of pts required dose adjustments for management of toxicity. The most common adverse events were hypertension 76% (Gr3: 54%), palmar-plantar erythrodysaesthesia syndrome 65% (Gr3: 9%), anorexia 59% (Gr3: 2.2%), proteinuria 54% (Gr3: 17%), fatigue 54% (Gr3: 0%), and thrombocytopenia 52% (Gr3: 33%). A higher level of toxicity was observed in pts weighing < 60 kg compared to pts ≥ 60 kg correlating with differences in drug exposure. ORR based on IRR is (PR = 32.6%, SD = 45.7%). Median Time to progression (TTP) is 7.49 mo (95% CI: 5.45 - 9.43)(based on minimum 6 mo. f/u, with 56.5% progression events) based on IRR. Median overall survival (OS) is 13.9 mo (95% CI: 11.8 -) (based on minimum 8 mo. f/u, with 46% death events). OS data has not yet matured and will be reported in the future.
Conclusions In this Phase I/II study, lenvatinib administered to patients with advanced HCC was not associated with any new toxicities associated with TKI class and was managed by dose adjustments. A weight-based starting dose (<60 Kg: 8 mg qd, vs ≥60kg: 12 mg qd) may be appropriate to minimize toxicity due to higher drug exposure in pts < 60 kg. The observed OS and TTP indicate lenvatinib has activity in patients with advanced HCC and may be a new therapeutic option.

---------------2014年asco，3期招募中。期望比Sorafenib延长2.5月的生存期
A multicenter, open-label, phase 3 trial to compare the efficacy and safety of lenvatinib (E7080) versus sorafenib in first-line treatment of subjects with unresectable hepatocellular carcinoma.

Subcategory:
Hepatobiliary Cancer
Category:
Gastrointestinal (Noncolorectal) Cancer
Meeting:
2014 ASCO Annual Meeting
Session Type and Session Title:
General Poster Session, Gastrointestinal (Noncolorectal) Cancer
Abstract Number:
TPS4153

Citation:
J Clin Oncol 32:5s, 2014 (suppl; abstr TPS4153)

Author(s):
Richard S. Finn, Ann-Lii Cheng, Kenji Ikeda, Masatoshi Kudo, Toshiyuki Tamai, Corina E. Dutcus, Steven Younger, Kwang-Hyub Han, Shukui Qin, Eric Raymond; Geffen School of Medicine at UCLA, Los Angeles, CA; Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan; Toranomon Hospital, Tokyo, Japan; Department of Gastroenterology and Hepatology, Kinki University School of Medicine, Osaka, Japan; Eisai, Tokyo, Japan; Eisai, Woodcliff Lake, NJ; Severance Hospital, Yonsei University, Seoul, South Korea; PLA Cancer Center of Nanjing Bayi Hospital, Nanjing, China; Hopital Saint-Antoine, Paris, France


Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures

Abstract:

Background: Lenvatinib (L, E7080) is an oral multi-targeted tyrosine kinase inhibitor of VEGFR1-3, FGFR1-4, PDGFRβ, RET and KIT. Given the role of angiogenesis in hepatocellular carcinoma (HCC), a phase 1/2 open-label study evaluated the safety and efficacy of L in 46 patients with advanced disease and Childs-Pugh (CP) A liver function status (Kudo ILCA 2013). Patients were treated with a starting dose of L 12 mg qd (28-d cycles) until disease progression or development of unmanageable toxicities. Median time to progression (TTP) was 12.8 months (mo; 95% confidence interval [CI] 7.23–14.7) and median overall survival (OS) was 18.7 mo (95% CI 12.8–25.1). The most common adverse events were hypertension 76% (Gr3 54%), palmar-plantar erythrodysesthesia syndrome 61% (Gr3 7%), proteinuria 59% (Gr3 20%), anorexia 57% (Gr3 2%), thrombocytopenia 50% (Gr3 33%), and fatigue 48% (Gr3 0%). Overall response rate (ORR) was 37%; 45.7% had stable disease. Methods: Based on these phase 2 data, a global, randomized, open-label phase 3 trial was designed to determine if L is non-inferior or superior compared to sorafenib (S) in advanced HCC. Eligible patients (N=940) with Barcelona Clinic Liver Cancer Stage B or C HCC, CP A status, and ECOG 0-1 will be randomized 1:1 to either L 12 mg or 8 mg orally qd (based on body weight [BW]) or S 400 mg orally bid. Patients will be stratified by region; macroscopic portal vein invasion, extrahepatic spread, or both; ECOG-PS; and BW (<60 vs ≥60 kg). The primary endpoint is OS. Secondary endpoints include progression-free survival, TTP, ORR (modified RECIST criteria), safety and PK/PD. Given an estimated median OS for S of approximately 10 mo, a 2.5 mo improvement was derived to achieve a hazard ratio (HR) of 0.8. Statistical study power (using a non-inferiority test by the 95% CI lower-limit method on log HR for OS) was determined based on this HR and a non-inferiority margin of 1.08, corresponding to 60% retention of S effect vs placebo. Based on these assumptions, the study power to declare non-inferiority or superiority is approximately 97% and 82%, respectively. The overall false positive rate is 0.05 (2-sided). Clinical trial information: NCT01761266.

-----------------------------甲状腺癌研究显著改善无进展生存期
卫材酪氨酸激酶抑制剂Lenvatinib III期甲状腺癌研究显著改善无进展生存期
作者：tomato来源：生物谷2014-6-4 8:59:29
关键词： 卫材 酪氨酸激酶抑制剂 lenvatinib 分化型甲状腺癌



2014年6月4日讯 /生物谷BIOON/ --卫材（Eisai）近日公布了实验性抗癌药物lenvatinib（E7080）III期SELECT研究的数据。该研究是一项多中心、随机、双盲、安慰剂对照III期研究，调查了口服lenvatinib（24mg）治疗放射性碘131抵抗的分化型甲状腺癌(RR-DTC)的疗效，主要终点为无进展生存期（PFS），次要终点包括总缓解率（ORR），总生存期（OS）和安全性。

数据表明，与安慰剂组相比，lenvatinib治疗组无进展生存期（PFS）显著延长（18.3个月 vs 3.6个月，p＜0.0001），达到了研究的主要终点。目前，该研究的总生存期（OS）数据尚未获得。相关数据已提交至美国临床肿瘤学会（ASCO）第50届年会。

Lenvatinib是一种口服多受体酪氨酸激酶（RTK）抑制剂，具有新颖的结合模式，除抑制参与肿瘤增殖的其他促血管生成和致癌信号通路相关RTK外，还能够选择性抑制血管内皮生长因子（VEGF）受体的激酶活性。（生物谷Bioon.com）


--------------------向EMA和FDA提交甲状腺癌新药lenvatinib上市申请
2014年8月19日讯 /生物谷BIOON/ --卫材（Eisai）8月18日宣布，已分别向美国食品和药物管理局（FDA）和欧洲药品管理局（EMA）提交了抗癌药lenvatinib的监管文件，寻求批准用于放射性碘难治性分化型甲状腺癌（RR-DTC）的治疗。此前，卫材已于今年6月向日本劳动卫生福利部（MHLW）提交了lenvatinib的监管申请。在日本、美国、欧盟，lenvatinib均被授予孤儿药地位；同时，EMA已授予lenvatinib加速评估资格。从治疗创新的角度思考，lenvatinib将成为一种具有重大公共卫生利益的新药。

Lenvatinib是一种口服多受体酪氨酸激酶（RTK）抑制剂，具有新颖的结合模式，除抑制参与肿瘤增殖的其他促血管生成和致癌信号通路相关RTK外，还能够选择性抑制血管内皮生长因子（VEGF）受体的激酶活性。目前，卫材也正在评估lenvatinib用于其他癌症的治疗。

Lenvatinib在日本、美国、欧盟提交的申请文件，是基于III期SELECT研究的积极顶线数据。该研究是一项多中心、随机、双盲、安慰剂对照III期研究，调查了口服lenvatinib（24mg）治疗放射性碘131抵抗的分化型甲状腺癌(RR-DTC)的疗效，主要终点为无进展生存期（PFS），次要终点包括总缓解率（ORR），总生存期（OS）和安全性。数据表明，与安慰剂组相比，lenvatinib治疗组无进展生存期（PFS）显著延长（18.3个月 vs 3.6个月，p＜0.0001），达到了研究的主要终点。（生物谷Bioon.com）

这药我知道一个参加临床的，吃了一个月，AFP下降一大半，另两个病友用YC，吃了20天左右查血，AFP也有较明显的降幅。

小P 发表于 2014-11-27 13:57
这药我知道一个参加临床的，吃了一个月，AFP下降一大半，另两个病友用YC，吃了20天左右查血，AFP也有较明显 ...

是YL

终于又有好消息了，坚持就有希望。

终于又有好消息了，坚持就有希望。

求方式，甲状腺

肺癌有效吗？

7080近期效果在许多人身上是表现不错，特别是用药一个月到两个月期间，但是这个药用到4个月以上时，需要小心观察，AFP水平会出现平台期或者出现上升趋势，这个时候能做的就是加量，按照1mg/次（观察控制在半个月左右），如果持续有效则维持当前剂量，如果出现上升，则继续剂量，目前有据可查的，最多有用到20mg的，不过需要密切注意副作用。另外一个做法就是加雷利度胺，5-10mg，E7080剂量维持当前不变，加服雷利度胺。也是一种方法。