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2015年肿瘤治疗资料集中贴

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97128 128 老马 发表于 2015-3-11 16:53:56 |
老马  博士一年级 发表于 2015-5-27 20:23:33 | 显示全部楼层 来自: 浙江温州
ARIAD Presents Updated Clinical Data on Brigatinib in Patients with ALK+ Non-Small Cell Lung Cancer
GENEVA & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Apr. 17, 2015-- ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced updated clinical data on its investigational tyrosine kinase inhibitor, brigatinib (AP26113), in patients with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC) from an ongoing Phase 1/2 trial. The new results include an analysis of safety and efficacy for patients treated at select doses of brigatinib and an evaluation of intracranial central nervous system (CNS) antitumor activity.

The updated results were presented at the 2015 European Lung Cancer Conference (ELCC) being held in Geneva, Switzerland.

Phase 2 Dose Sub-Analysis

The data presented at ELCC focused on the 98 patients treated at doses of 90 mg/day (n=18), 90 mg/day for 1 week followed by escalation to 180 mg/day (n=32), and 180 mg/day (n=48) in the Phase 2 portion of the trial. All patients receiving these doses were evaluated for safety, and patients with ALK+ NSCLC (n=65) were evaluated for efficacy. The presentation at ELCC is based on patient data as of January 19, 2015 with a median follow-up of 40 weeks (range, 0.1 – 150+ weeks).

“The updated data on select doses from the Phase 1/2 trial show robust anti-tumor activity of brigatinib in patients with crizotinib-resistant ALK+ NSCLC, with responses now approaching one year,” stated Rafael Rosell, M.D., Director, Cancer Biology & Precision Medicine Program Catalan Institute of Oncology, Germans Trias i Pujol Health Sciences Institute and Hospital in Barcelona, Spain. “Importantly, by starting at the 90 mg dose, we have seen a reduction of early-onset pulmonary events observed at the higher starting doses.”

Key data from the study update include:

Safety Summary

The most common adverse events (AEs) of any grade, regardless of treatment relationship, were nausea, diarrhea, and fatigue and were similar in incidence across all three dose-cohorts, as follows:
At 90 mg/day (n=18): nausea (44%), headache (44%), diarrhea (39%), fatigue (39%), cough (39%), and increased amylase (33%)
At 90 mg to 180 mg/day (n=32): diarrhea (44%), nausea (41%), fatigue (38%), headache (28%), cough (28%), and increased amylase (28%)
At 180 mg/day (n=48): nausea (63%), diarrhea (38%), fatigue (31%), headache (31%), cough (25%), and increased amylase (15%)
Serious AEs, regardless of treatment relationship, occurring in 4% or more patients, were dyspnea, hypoxia, and pneumonia, as follows:
At 90 mg/day (n=18): dyspnea (1 patient, 6%), hypoxia (2 patients, 11%), and pneumonia (2 patients, 11%)
At 90 mg to 180 mg/day (n=32): dyspnea (2 patients, 6%), hypoxia (1 patient, 3%), and pneumonia (1 patient, 3%)
At 180 mg/day (n=48): dyspnea (2 patients, 4%), hypoxia (2 patients, 4%), and pneumonia (2 patients, 4%)
As previously observed and reported, fewer early-onset pulmonary events, including dyspnea, hypoxia, and new pulmonary opacities, were reported with a starting dose of 90 mg (2/50 patients, 4%) vs. 180 mg (6/44 patients, 14%). Importantly, no early-onset pulmonary events were observed in the 32 patients started at 90 mg and escalated to 180 mg after 7 days.
Response Summary

The median time on study for patients dosed at 90 mg/day was 33.5 weeks (range, 0.7-150+ weeks), 50.3 weeks (range, 0.1-70+ weeks) for the 90 mg to 180 mg/day cohort, and 31.4 weeks (range, 0.1-135+ weeks) for the 180 mg/day cohort.
Brigatinib was active at each of the three dosing regimens with similar efficacy among the cohorts:
Objective response rate (ORR) among the 14 evaluable ALK+ NSCLC patients dosed at 90 mg/day was 79% (11 patients, 7 confirmed).
Among the 26 evaluable ALK+ NSCLC patients dosed at 90 mg/day for 1 week followed by 180 mg/day, ORR was 81% (21 patients, 19 confirmed), including 3 patients (12%) with a complete response (CR).
Among the 25 evaluable ALK+ NSCLC patients dosed at 180 mg/day, ORR was 68% (17 patients, 16 confirmed), including 2 patients (8%) with a CR.
Median duration of response was 11.2 months for the 90 mg/day cohort, not yet reached for the 90 mg to 180 mg/day cohort, and 9.2 months for the 180 mg/day cohort.
Median progression-free survival (PFS) was 12.9 months for the 90 mg /day cohort, not yet reached for the 90 mg to 180 mg/day cohort, and 11.1 months for the 180 mg/day cohort.
Phase 1/2 Analysis of CNS Antitumor Activity

A separate evaluation of the efficacy and safety of brigatinib in ALK+ NSCLC patients with intracranial CNS metastases at baseline was also presented at the ELCC meeting. In an independent central radiological review of brain Magnetic Resonance Imaging (MRI) scans, 49 of 79 ALK+ NSCLC patients in the Phase 1/2 trial were identified to have intracranial CNS metastases at baseline. Of these 49 patients, 16 had measurable intracranial CNS metastases (15 evaluable) and 33 patients had only non-measurable intracranial CNS metastases (30 evaluable).

AEs in patients with CNS metastases occurred at a similar incidence as in the broader study population.
In this post-hoc analysis of centrally reviewed brain MRI, brigatinib demonstrated intracranial CNS antitumor activity with responses in ALK+ NSCLC patients with intracranial CNS metastases at baseline.
Objective response rate (ORR) was 53% in evaluable patients with measurable lesions (n=15), including 1 (7%) CR.
In evaluable patients with non-measurable lesions (n=30), ORR defined as disappearance of all lesions was 30% (9 patients).
For patients with a response and at least one follow-up MRI scan (n=16), median (Kaplan-Meier [KM] estimate) duration of intracranial response was 18.9 months. For patients with a follow-up MRI scan (n=45), median (KM estimate) intracranial PFS was 22.3 months.
Median time on study for ALK+ NSCLC patients with intracranial CNS metastases at baseline was 56.1 weeks (range, 0.1-150+ weeks).
Pivotal Phase 2 ALTA Trial Enrolling Patients

A separate, pivotal global Phase 2 trial of brigatinib (AP26113) in patients with locally advanced or metastatic ALK+ NSCLC who have progressed on crizotinib continues to enroll patients. The ALTA (ALK in Lung Cancer Trial of AP26113) trial is designed to determine the safety and efficacy of AP26113 in refractory ALK+ NSCLC patients. The trial will enroll approximately 220 patients including those with brain metastasis. Patients are randomized 1:1 to receive either 90 mg of brigatinib once per day continuously or a lead-in dose of 90 mg/day for 7 days followed by 180 mg/day continuously.

“We are on track for full patient enrollment in the ALTA trial in the third quarter of this year,” stated Frank G. Haluska, M.D., Ph.D., senior vice president of clinical research and development and chief medical officer at ARIAD. “We are encouraged by the CNS anti-tumor activity, now exceeding 18 months in the Phase 1/2 brigatinib trial, and look forward to the evaluation of activity on brain metastasis in the ALTA trial.”

ARIAELCC 2015_Rosell_Phase 2 doses Oral Pres_Final_10April2015 (for Discussant).pdf

137.83 KB, 下载次数: 89

个人公众号:treeofhope
妈妈长寿  博士二年级 发表于 2015-5-27 20:43:40 | 显示全部楼层 来自: 广东广州
ALK+ Non-Small Cell Lung Cancer
只看懂这个
妈妈长寿  博士二年级 发表于 2015-5-27 20:43:48 | 显示全部楼层 来自: 广东广州
ALK+ Non-Small Cell Lung Cancer
只看懂这个
konglingsheng  初中三年级 发表于 2015-5-29 09:45:25 | 显示全部楼层 来自: 中国
期盼964

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konglingsheng  初中三年级 发表于 2015-5-29 09:56:20 | 显示全部楼层 来自: 中国
感谢分享,正准备用药
老马  博士一年级 发表于 2015-5-31 12:59:41 | 显示全部楼层 来自: 浙江温州
最新消息施贵宝的Opdivo (nivolumab)NSCLC临床效果不如默克的Keytruda®(pembrolizumab),周五尾盘,bmy股票大跌,默克大涨。
个人公众号:treeofhope
老马  博士一年级 发表于 2015-5-31 13:07:54 | 显示全部楼层 来自: 浙江温州
Cardiovascular events in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors: A systematic review and meta-analysis.

Sub-category:
Leukemia

Category:
Leukemia, Myelodysplasia, and Transplantation

Meeting:
2015 ASCO Annual Meeting

Abstract No:
7056

Poster Board Number:
Board #45

Citation:
J Clin Oncol 33, 2015 (suppl; abstr 7056)

Author(s): Chatree Chai-Adisaksopha, Christopher Michael Hillis, Wilson Lam; McMaster University, Hamilton, ON, Canada; Juravinski Cancer Centre, Hamilton, ON, Canada; University of Calgary, Calgary, AB, Canada

Abstract Disclosures

Abstract:
Background: Tyrosine kinase inhibitors (TKIs) have dramatically improved survival for patients with chronic myelogenous leukemia (CML). However, there are growing evidences that TKIs may be associated with an increased risk of cardiovascular events. Methods: We searched MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) databases. Included studies were: (1) randomized controlled trials or cohort studies of adult patients ( ≥ 18 years) treated with TKIs for chronic phase or accelerated phase CML, (2) studies that reported at least one cardiovascular outcome (peripheral arterial occlusive disease (PAOD), ischemic heart disease or stroke/TIA). The primary outcome of this review were a composite of major cardiovascular events. The pooled incidences of cardiovascular events with corresponding 95% confidence intervals [CI] were performed using a single-proportion random-effects model. The pooled risk ratio (RR) with 95% CIs was calculated using a Mantel-Haenszel random-effects model to compare the effect between nilotinib and imatinib. Results: We identified 32 studies enrolling 16,218 patients (20 studies investigated nilotinib, 12 imatinib, 4 ponatinib, 1 dasatinib and 1 bosutinib). The pooled incidence rates (95% CI) of cardiovascular events were 8% (6-10%) for nilotinib, 1% (0-1%) for imatinib, 2% (1-2%) for dasatinib, 10% (5-16%) for ponatinib and 13% (11-16%) for bosutinib and 6% (3-10%) for non-TKI studies. The direct comparison between nilotinib and imatinib suggested that nilotinib treatment was associated with a significantly increased risk of the cardiovascular events (RR 1.6; 95%CI 1.4-1.8). Conclusions: Here, we evaluated the pooled estimates of the incidence of cardiovascular events in CML patients treated with TKIs. The pool proportions suggested that, when compared to non-TKI treated patients, patients who received imatinib and dasatinib had lesser cardiovascular events, whereas the incidence was greater among patients receiving nilotinib, ponatinib and bosutinib.
个人公众号:treeofhope
老马  博士一年级 发表于 2015-5-31 14:42:10 | 显示全部楼层 来自: 浙江温州
ACSO 2015部分内容
一、非小细胞肺癌
(1)Rociletinib/ CO-1686
Rociletinib的3期临床(与化疗药物对比,二线治疗)在进行中,已经报批FDA,估计年底或者明年初上市。Rociletinib的3期剂量为每天二次,一次625mg,与食物同服或者饭后半小时内服用。
https://clinicaltrials.gov/show/NCT02322281
http://abstracts.asco.org/156/AbstView_156_149724.html
http://abstracts.asco.org/156/AbstView_156_149636.html
http://abstracts.asco.org/156/AbstView_156_152181.html
(2)AZD9291
AZD9291的3期临床(与特罗凯或者易瑞沙对比,一线治疗)在进行中,已经报批FDA,估计年底或者明年初上市。AZD9291的3期剂量为每天一次,一次80mg,适当时可减量到40mg每天,最大剂量为160mg每天。
https://clinicaltrials.gov/ct2/show/NCT02296125
http://abstracts.asco.org/156/AbstView_156_148945.html
http://abstracts.asco.org/156/AbstView_156_144153.html
http://abstracts.asco.org/156/AbstView_156_145109.html
(3)AZD3759
AZD3759,阿斯利康的非小肺癌脑转新药,针对egfr突变耐药病人,50mg-100mg*2每天,无明显副作用,目前1期临床(与160mg每天的AZD9291对比治疗脑转效果,入组病人为egfr耐药的脑转非小细胞肺癌)。值得关注。
AZD3759的入脑特性:具有非常高的被动渗透率(29.5x10-6 cm/sec),不是跨膜糖蛋白(Pgp)和乳腺癌耐药蛋白(BCRP)的底物,在免子、小鼠和猴子体内的Kpuu,brain和 Kpuu,CSF > 0.5。
初步临床结果:4位脑转NSCLC病人,3位50mg*2每天,1位100mg*2每天,其中2位可评估病人中,1位肿瘤缩小,1名稳定,他们的脑脊髓液中药物浓度为7.7nM和6nM,约等于AZD3759的pEGFR IC50。临床中没有发现剂量限制副作用,有2位病人1级皮疹。
注:多药转运体如 PGP、MRP、LRP 和 BCRP,能够使细胞内药物外排增加或囊泡隔离导致细胞内药物浓度降低或药物分布改变。
Kpuu:血浆分配系数。
https://clinicaltrials.gov/show/NCT02228369
http://abstracts.asco.org/156/AbstView_156_146873.html
http://abstracts.asco.org/156/AbstView_156_147526.html
AZD9291的入脑数据:
AZD9291在脑脊髓液中药物浓度约是易瑞沙的10倍。
http://www.poster-submission.com ... oster/37/26856/456P
易瑞沙和特罗凯的入脑数据:
http://repository.kulib.kyoto-u. ... 0280-012-1929-4.pdf
特罗凯在脑脊髓液中药物浓度为68.2nM(pEGFR IC50=40nM),易瑞沙为7.2nM(pEGFR IC50=33nM)。特罗凯和易瑞沙都是PGP的底物,但不是BCRP的底物。
(4)PF-06463922
PF-06463922,辉瑞的ALK/ROS1新药,半衰期20–28小时,中等强度的CYP3A4诱导剂。1期临床收入18位ALK阳性和4位ROS1阳性病人,其中17位病人脑转,19名病人至少经过一种ALK/ROS1药物治疗(crizotinib 或 ceritinib),临床剂量从100mg-200mg每天一次,有效率为40%,最常见的副作用是高胆固醇血症23%(3级以上14%),周围神经病变23%。2期临床剂量和最大耐受剂量仍待确定,目前建议使用100mg每天一次。
https://clinicaltrials.gov/show/NCT01970865
http://abstracts.asco.org/156/AbstView_156_144494.html
http://abstracts.asco.org/156/AbstView_156_143329.html
(5)Deltarasin
Deltarasin是一种小分子抑制剂,抑制KRAS-PDEδ相互作用,治疗KRAS突变新药。
http://abstracts.asco.org/156/AbstView_156_153354.html
(6)Cabozantinib/XL184/Cometriq/卡博替尼
a.Cabozantinib(60mg每天)单药或者联合特罗凯(150mg每天)对比特罗凯单药治疗egfr野生NSCLC病人,Cabozantinib单药和联合方案相对特罗凯的无进展生存期和总生存期有提高。
b.Cabozantinib(60mg每天)或Crizotinib单药治疗Met阳性的NSCLC病人,3位Crizotinib治疗的病人有效缓解(CT),1位Cabozantinib治疗的病人CT检查稳定,PET检查完全缓解。
c. Cabozantinib(60mg每天)单药治疗Ret阳性的NSCLC病人,有效缓解率33%,无进展生存期为7个月。
http://abstracts.asco.org/156/AbstView_156_147467.html
http://abstracts.asco.org/156/AbstView_156_147349.html
http://abstracts.asco.org/156/AbstView_156_152055.html
http://abstracts.asco.org/156/AbstView_156_145500.html
https://clinicaltrials.gov/show/NCT01639508
(7)司美替尼/Selumetinib/AZD6244
Selumetinib联合化疗或AZD9291或凡德他尼治疗NSCLC,具体数据等大会报告。
http://abstracts.asco.org/156/AbstView_156_142892.html
http://abstracts.asco.org/156/AbstView_156_150914.html
http://abstracts.asco.org/156/AbstView_156_148945.html
(8)INC280
INC280诺华的Met抑制剂,1期临床中。
INC280(100-600mg*2)联合特罗凯(100-150mg),18位NSCLC病人入组,其中部分病人有met阳性,8位egfr阳性,12位特罗凯耐药。主要的副作用是腹泻(47%)和皮疹(47%),乏力(40%),肝转氨酶升高(27),恶心,厌食和甲沟炎(各27%),3级以上副作用是厌食,肝转氨酶升高和中性粒细胞减少症(各7%)。12位可评估病人中,6位稳定,2位egfr突变病人肿瘤缩小10-29%。
http://abstracts.asco.org/156/AbstView_156_145819.html
(9)特罗凯脉冲方案
CSF pharmacokinetics of high-dose pulsatile tyrosine kinase therapy in brain cancer patients.
http://abstracts.asco.org/156/AbstView_156_153130.html
特罗凯150mg每天一次方案,脑中浓度是血药浓度的2%,使用脉冲方案:4000(第1天4粒,第2-4天停药),脑中浓度是血药浓度的24%;药物停药时间不宜超过6天。
(10)Ceritinib/Zykadia/LDK378/色瑞替尼的剂量调整
http://abstracts.asco.org/156/AbstView_156_148133.html
Ceritinib与食物同服,血药浓度可提高50%。可尝试剂量减半后与食物同服,疗效相近,胃肠道副作用大大减轻。
(11)Brigatinib/AP26113
http://abstracts.asco.org/156/AbstView_156_148225.html
Brigatinib 90mg每天一次,一周后提高到180mg每天一次。

Brigatinib临床组中有48名脑转病人,有效率为75%,无进展时间为12.9月;脑转病人中有2名Ceritinib耐药病人,脑部转移缩小,肺部稳定。
二、乳腺癌
(1)Abemaciclib/LY2835219
Abemaciclib是礼来的CDK4/6抑制剂,3期临床中。
http://abstracts.asco.org/156/AbstView_156_143933.html
http://abstracts.asco.org/156/AbstView_156_143970.html
http://abstracts.asco.org/156/AbstView_156_143933.html
(2)Ribociclib /LEE011
Ribociclib是诺华的CDK4/6抑制剂,3期临床中。
http://abstracts.asco.org/156/AbstView_156_145167.html
(3)Buparlisib/BKM120
Buparlisib是诺华的PI3K抑制剂,3期临床中。
http://abstracts.asco.org/156/AbstView_156_146016.html
(4)S-222611
Phase I expansion of S-222611, a reversible inhibitor of EGFR and HER2, in advanced solid tumors, including patients with brain metastases.
http://abstracts.asco.org/156/AbstView_156_148414.html
临床入组76人,其中41位HER2阳性(26位乳腺癌,13位食管-胃交界部癌,2位头颈部癌)。HER2阳性病人中,1位完全缓解(食管-胃交界部癌),5位部分缓解(乳腺癌),这些病人之前均接受过至少一次HER2药物治疗。乳腺癌HER2阳性病人中有5人脑转,其中1人部分缓解。S-222611的推荐剂量为800mg每天一次,常见副作用是血清胆红素升高和腹泻。
(5)Tesevatinib/KD019
Tesevatinib是Kadmon公司的HER2抑制剂,1期临床中。
Tesevatinib (formerly KD019) is a TKI with potent activity against EGFR, HER2, and SRC
http://abstracts.asco.org/156/AbstView_156_150396.html
https://www.clinicaltrials.gov/ct2/show/NCT02154529
Tesevatinib可完全穿透血脑屏障,脑中浓度与体内血药浓度相当,单药最大剂量为300mg每天一次,联合曲妥珠单抗的临床剂量为150mg-250mg每天一次,250mg组的副作用为2级腹泻,300mg组在进行中。
三、肾癌
(1)Tivozanib/TIVO-1
Tivozanib是AVEO的抗血管生成抑制剂,3期临床中,今年打算在欧洲申请批准。
http://abstracts.asco.org/156/AbstView_156_149655.html
个人公众号:treeofhope
老马  博士一年级 发表于 2015-6-2 19:00:19 | 显示全部楼层 来自: 浙江温州
BMY.jpg
老马  博士一年级 发表于 2015-6-2 19:04:42 | 显示全部楼层 来自: 浙江温州
Dr Shaw: Even crizotinib has some CNS activity, but CNS is main site of criz failure in ALK+ pts so big need.
JCO-2015-Costa-JCO.2014.59.0539(克药脑转).PDF (289.75 KB, 下载次数: 84)
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