肺癌脑转准备尝试拉帕替尼特别请jimmy进来看看

amei

求教大家关于拉帕替尼治疗肺癌脑转的有效率，我家人多发脑转，全放无效，现在打算用拉帕替尼尝试性治疗，请有相关信息的病友给点意见

[此贴子已经被作者于2008-5-7 13:57:09编辑过]

amei

有没有人给点意见呢？

jimmy112199

Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer.
Sub-category:
    
Metastatic Breast Cancer
Category:
    
Breast Cancer
Meeting:
    
2006 ASCO Annual Meeting
    
Printer Friendly
E-Mail Article
Abstract No:
    
503
Citation:
    
Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 503
Author(s):
    
N. U. Lin, L. A. Carey, M. C. Liu, J. Younger, S. E. Come, E. Bullitt, A. D. Van Den Abbeele, X. Li, F. H. Hochberg, E. P. Winer
Abstract:
    

Background: One-third of women with HER2+ metastatic breast cancer develop central nervous system (CNS) metastases. This study evaluated the safety and efficacy of lapatinib, an oral inhibitor of EGFR and HER2, in patients with HER2+ brain metastases. Patients and Methods: Eligible patients (pts) had HER2+ breast cancer, new or progressive brain metastases, and at least one measurable (LD >1.0cm) lesion. Pts received lapatinib 750 mg PO BID. Tumor response was assessed by MRI every 8 wks. FDG-PET scans were performed at baseline, and repeated at wks 1 and 8. The primary endpoint was objective response (CR+PR) in the brain by RECIST. Secondary endpoints included safety, quality-of-life (QOL), and PET changes. Sample size was calculated using a 2-stage design to distinguish objective response of 5% (H0) vs 20% (HA); > 4 objective responses were required to reject the null hypothesis. Results: 39 pts were enrolled, mean age 52 yrs (range 31-76). All pts developed CNS disease on trastuzumab; 38 progressed after prior radiation. Toxicity data are available for 38 pts; the most common AEs were diarrhea (grade 3, 21%), fatigue (grade 3, 16%), and rash (grade 3, 5%). Three pts remain on active treatment. Two pts achieved a PR by RECIST, and remained on study for 158 and 347 days. An additional pt achieved >30% decrease in LD of her CNS lesion but, upon central radiology review, did not meet RECIST criteria for measurable disease and was excluded from analysis of the primary endpoint. Five additional pts achieved SD>16 wks. Median time to treatment failure was 3.2 mo (95% CI 2.3 to 3.8). Preliminary volumetric analysis of 20/39 pts demonstrates 5 pts with >30% volumetric decline in CNS lesions, and an additional 3 pts with 15-30% volumetric decline. Analyses of QOL and correlation of PET with clinical outcomes will be presented. Conclusion: Lapatinib is well-tolerated in this population. Although the study failed to demonstrate the hypothesized level of activity as assessed by RECIST, there is sufficient evidence of clinical effect, albeit preliminary, to suggest that lapatinib can penetrate the CNS. Further investigation of lapatinib in HER2+ CNS disease is warranted and ongoing. Acknowledgements: AVON PFP award; NCI-SPORE in Breast Cancer at DF/HCC(CA89393), UNC(CA58223), Georgetown; ASCO YIA.

her2 +乳腺癌脑转移瘤患者apatinib 二期试药结果

子类别：
转移性乳腺癌
类别：
乳腺癌
会议：
2006年asco年度会议

摘要： 503
引文： 的Journal of Clinical肿瘤科， 2006年asco年度会议程序的一部分，一，卷24 ，第18 （ 6月20日补充） ， 2006 ： 503
作者：林，N. U，刘 ，Carey, M. C，等
摘要：

背 景： 1 -三分之一的妇女与her2 +转移性乳腺癌的发展，中枢神经系统（ CNS ）转移。这项研究评估的安全性和疗效lapatinib ，口腔表皮生长因子受体抑制剂和her2 ，在患者her2 +脑转移瘤。病人与方法：符合资格的病人（警校） her2 +乳腺癌，新的或进步的脑转移瘤，并至少有一个可衡量的（劳工处>一点〇厘米）病变。警校收到lapatinib 750毫克蒲出价。肿瘤的反应是评估的MRI每8周。葡萄糖- PET扫描分别于基线，并多次在乌溪沙的1条和第8 。主要终点是客观缓解（ CR +公关）在大脑中由recist 。辅助终点包括安全，生活质量（生活质量） ，与PET的变化。样本大小计算，使用二阶段设计，以区分客观的反应， 5 ％的（ h0 ）与20 ％ （公顷） ; > 4客观的反应，须拒绝零假设。
结果：
 39名试药，平均年 龄52岁（范  围31-76 ） 。所有的病人有 脑转移瘤对曲妥珠单抗; 38进展后，事先 辐射。毒性数据，可供   38的积分;最常见的AES人腹泻（三  级， 21 ％ ） ，疲    劳（三级， 16 ％ ） ，及出疹的病征， （三  级， 5 ％ ） 。三病人继续留在积极治疗。两个病人，取得了部分响  应 (recist) ，并保持 对研究为158和347天。另一病人取得> 30 ％的脑转跌幅，但是她的中枢神经系统病变，但经中央放射审查，不符合recist的标准衡量的疾病和被排除在外，从分析主要终点。 5额外的病人取得的SD > 16星期。中位数的时间到治疗失败的是3.2月（ 95 ％ CI为2。3月至3。8月） 。初   步容积分析三十九病人中二十 病人表明， 5病人> 30 ％ 体积下降，在中枢神经系统的病变，3病人15-30 ％ ，容积下降。分析生活质量和相关性PET与临床结果将提交。
结论：
 lapatinib是良好的容忍在这方面的人口。虽然这项研究未能证明该假设的活跃程度作为评估recist ，有足够证据的临床效果，虽然初步的，建议lapatinib能穿透中枢神经系统。进一步的调查lapatinib在her2 +神经退行性疾病，是必要和正在进行中。

jimmy112199

Lapatinib in brain metastases associated with breast cancer

One-third of women with HER2-positive metastatic breast cancer currently develop brain metastases.

Once the disease advances to this stage, overall disease prognosis is
poor with the average one-year survival from diagnosis estimated at
about 20 percent.


Results from an ongoing, multicenter Phase II study suggest that
Lapatinib ( Tykerb ) has clinical activity in pretreated patients with
brain metastases from HER2-positive breast cancer.


Patients ( n=241 ) enrolled in this study had radiographically
documented progressive brain lesions following prior therapy with
Trastuzumab (Herceptin ) and cranial radiotherapy.


Results from an independent radiology review show that 19 patients ( 7%
) treated with Lapatinib monotherapy experienced a partial response,
defined by greater than or equal to 50% volumetric reduction in brain
lesions with no progression of tumor outside the brain, no increase in
steroid requirements or worsening of neurological symptoms.

Forty-six patients ( 19% ) experienced greater than or equal to 20% volumetric reduction in brain lesions.


An additional 102 patients ( 42% ) achieved stable disease for at least
eight weeks based on a protocol defined composite response criteria.

Twenty-two percent of all patients had no disease progression within the first six months on Lapatinib monotherapy.


An exploratory analysis in a previous, Phase III study found that
numerically fewer patients on Lapatinib plus Capecitabine ( Xeloda )
developed brain metastases as compared to Capecitabine alone.

As a result, this Phase II study was amended to allow patients whose
disease progressed in the brain and/or non-CNS on monotherapy Lapatinib
to then receive the combination of Lapatinib and Capecitabine.

In patients ( n=40 ) treated with Lapatinib in combination with
Capecitabine, 8 ( 20% ) experienced greater than or equal to 50% volume
reduction in brain metastases, and 16 ( 40% ) experienced greater than
or equal to 20% volume reduction.


The most common adverse events included diarrhoea ( 13% Grades 3 and 4
), skin rash ( 3% Grades 3 and 4 ), nausea ( 3% Grade 3 ), vomiting (
4% Grade 3 ), fatigue ( 3% Grade 3 ) and anorexia ( 1% Grade 3 ).


Source: American Society of Clinical Oncology ( ASCO ) – Annual Meeting, 2007

XagenaMedicine2007

结果：
7%病人脑癌减小50%，19%病人脑癌减小20%，42%病人稳定8星期以上，22%病人半年无进展

[此贴子已经被作者于2008-5-10 1:03:31编辑过]

amei

谢谢，jimmy，有没有拉帕提尼治疗肺癌的资料呢？我查了一下拉帕提尼是双靶点同时抑制her1,her2生长因子突变的酪氨酸激酶抑制剂，因为her2基因在肺癌患者中多为低表达，大约只有4%的肺癌患者此项为阳性，有10%的腺癌患者是阳性。但是her1/egfr基因在肺癌患者中却是高表达的，这也是易瑞沙以及特罗凯的作用靶点。不知拉帕提尼是否会对肺癌患者有效呢？ 补充说明一点，我妈妈易瑞沙，特罗凯均耐药。

[此贴子已经被作者于2008-5-9 11:02:46编辑过]

jimmy112199

1) 拉帕提对NSCLC试药效果不好已结束，
A phase
 II study of lapatinib in NSCLC has been closed to accrual due
 to a low overall response rate in a subset comprising patients
 with pure bronchioloalveolar carcinoma, adenocarcinoma with
 bronchioloalveolar carcinoma features, or no smoking history

2)拉帕提尼+力比泰正在试药尚无结果

3)  结合拉帕提尼和爱比妥的细胞毒作用，加强对吉非替尼耐药性肺癌细胞

Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells

Hwang-Phill Kim¹, Sae-Won Han², Sung-Hak Kim¹, Seock-Ah Im^1,2, Do-Youn Oh^1,2, Yung-Jue Bang^1,2 and Tae-You Kim^1,2

¹ Cancer Research Institute, ² Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea

Requests for reprints: Tae-You Kim, Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu, Seoul 110-744, Korea. Phone: 82-2-2072-3943; Fax: 82-2-762-9662. E-mail: kimty@snu.ac.kr

Abstract

Although non-small cell lung cancer (NSCLC) cells with somatic mutations in their epidermal growth factor receptors (EGFR) initially show a dramatic response to tyrosine kinase inhibitor (TKI), these cells eventually develop resistance to TKI. This resistance may be caused by a secondary T790M mutation in the EGFR tyrosine kinase, which leads to the substitution of methionine for threonine in 790. In this study, we show that a combination of lapatinib and cetuximab overcomes gefitinib resistance in NSCLC with the T790M mutation. We observed that T790M lung cancer cells were resistant to gefitinib, and Stat3 was persistently activated in the resistant cells. A reversible EGFR and HER2 TKI, lapatinib, decreased Stat3 activation by blocking heterodimerization of EGFR and HER2, which led to a modest increase in the inhibitory effect on gefitinib-resistant T790M cells. In addition to lapatinib, the anti-EGFR antibody, cetuximab, induced down-regulation of EGFR and apoptotic cell death in T790M cells. Finally, combined lapatinib and cetuximab treatment resulted in significantly enhanced cytotoxicity against gefitinib-resistant T790M cells in vitro and in vivo. Taken together, these data suggest that treatment with a combination of lapatinib and cetuximab, which induces dimeric dissociation and EGFR down-regulation, appears to be an effective strategy for treatment of patients with EGFR TKI-resistant NSCLC. [Mol Cancer Ther 2008;7(3):607–15]

[此贴子已经被作者于2008-5-9 11:55:10编辑过]

amei

谢谢，jimmy

jimmy112199

本文介绍了5个NSCLCL病人用Lapatin后稳定。

Phase I Safety, Pharmacokinetics, and Clinical Activity Study of Lapatinib (GW572016), a Reversible Dual Inhibitor of Epidermal Growth Factor Receptor Tyrosine Kinases, in Heavily Pretreated Patients With Metastatic Carcinomas

Howard A. Burris, III, Herbert I. Hurwitz, E. Claire Dees, Afshin Dowlati, Kimberly L. Blackwell, Bert O'Neil, Paul K. Marcom, Matthew J. Ellis, Beth Overmoyer, Suzanne F. Jones, Jennifer L. Harris, Deborah A. Smith, Kevin M. Koch, Andrew Stead, Steve Mangum, Neil L. Spector

From the Sarah Cannon Research Institute, Nashville, TN; Division of Hematology/Oncology, University of North Carolina at Chapel Hill, Chapel Hill; Duke University Medical Center, Durham; GlaxoSmithKline Inc, Research Triangle Park, NC; and Case Western Reserve University, Cleveland, OH

Address reprint requests to Howard A. Burris III, The Sarah Cannon Research Institute, 250 25th Avenue N, Suite 110, Nashville, TN 37203; e-mail: hburris@tnonc.com.


       ABSTRACT
TOP
ABSTRACT
INTRODUCTION
PATIENTS AND METHODS
RESULTS
DISCUSSION
Authors' Disclosures of...
REFERENCES
 
PURPOSE: This study (EGF10004 assessed the safety/tolerability, pharmacokinetics, and clinical activity of daily oral dosing with lapatinib (GW572016) in patients with ErbB1-expressing and/or ErbB2-overexpressing advanced-stage refractory solid tumors.

PATIENTS AND METHODS: Heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers were randomly assigned to one of five dose cohorts of lapatinib administered once daily. Pharmacokinetic samples were obtained on days 1 and 20. Clinical response was assessed every 8 weeks.

RESULTS: Sixty-seven patients with metastatic solid tumors were treated with lapatinib. The most frequently reported drug-related adverse events were diarrhea (42%) and rash (31%). No grade 4 drug-related adverse events were reported. Five grade 3 drug-related toxicities (gastrointestinal events and rash) were experienced by four patients. Drug-related interstitial pneumonitis or cardiac dysfunction associated with other ErbB-targeted therapies was not reported. Four patients with trastuzumab-resistant metastatic breast cancer鍟wo of whom were classified as having inflammatory breast cancerad partial responses (PRs). Twenty-four patients with various other carcinomas experienced stable disease, of whom 10 received lapatinib for ? 6 months. The relationships between lapatinib dose or serum concentration and clinical response could not be adequately characterized due to the limited response data. The incidence of diarrhea increased with increasing dose, whereas the incidence of rash was not related to dose.

CONCLUSION: Lapatinib was well tolerated at doses ranging from 500 to 1,600 mg once daily. Clinical activity was observed in heavily pretreated patients with ErbB1-expressing and/or ErbB2-overexpressing metastatic cancers, including four PRs in patients with trastuzumab-resistant breast cancers and prolonged stable disease in 10 patients.

The median duration of treatment for patients with PR was 5.5 months (range, 3 to 8 months). Stable disease (SD) was reported in 24 patients (10 breast cancer, five non mall-cell lung cancer (NSCLC), three colorectal cancer, three head and neck cancer, one ovarian cancer, one adenocarcinoma of unknown primary, and one granular cell carcinoma).

[此贴子已经被作者于2008-5-9 12:12:49编辑过]