2014ASCO年会摘要发布

悠悠子佩 · 发表于 2014-5-21 15:30:25

版主一人辛苦，造福大家，谢谢了

shany · 发表于 2014-5-21 23:33:10

26楼

Phase (Ph) 1/2 study of TSR-011, a potent inhibitor of ALK and TRK, including crizotinib-resistant ALK mutations.
TSR-011的1/2期临床研究。TSR-011是一种ALK和TRK的强力抑制剂，对克里唑替尼耐药的ALK突变也有抑制作用。

Abstract:

Background: Ultimately, the majority of anaplastic lymphoma kinase (ALK) rearranged (+) non-small cell lung cancers (NSCLC) are either unresponsive to crizotinib or develop resistance mutations. Similarly, gene rearrangements in NTRK1 have been identified as a potentially actionable oncogenic aberration. TSR-011 inhibits ALK and tropomyosin-related kinase (TRK) A, B, and C receptor activity with IC50 values < 3 nM and exhibits inhibition of oncogenic echinoderm microtubule associated protein like 4 (EML4)-ALK and tropomyosin (TPM)-TRKA dependent tumor growth in mice.
背景：大部分ALK重排的非小细胞肺癌最终会失去对克里唑替尼的响应或获得耐药突变。与ALK类似，NTRK1的重排已被发现是一种可能起关键作用的致癌基因畸变。TSR-011抑制ALK及TRK A、B、C受体的活性，IC50值<3nM，在小鼠中显示出对(EML4)-ALK及(TPM)-TRKA依赖的肿瘤具有生长抑制作用。

Methods: A Ph 1-2a dose escalation and cohort expansion study is underway to evaluate safety, tolerability, PK, and preliminary efficacy of TSR-011. Ph 1 is evaluating unselected patients with advanced solid tumors and lymphomas. The recommended Ph 2 dose will be evaluated in Ph 2a in patients with ALK+ or TRK ligand/receptor + tumors (defined by immunohistochemistry or fluorescent in-situ hybridization) including those with NSCLC progressing on, or naïve to, ALK inhibitor therapy.
方法：一项评估TSR-011的安全性，耐受性，药代动力学和初步评估疗效的1-2a期剂量递增队列扩展研究正在进行中。1期评估未经选择的晚期实体瘤或淋巴瘤患者。2a期将在ALK+或TRK配体/受体+（由免疫组化或FISH确定）的患者中评估2期推荐剂量，对象包括未接受过ALK抑制剂治疗或治疗中进展的非小细胞肺癌患者。

Results: Twenty-three patients with advanced cancer have been enrolled at oral total daily doses between 30 and 480 mg, including NSCLC (n=10, including 5 ALK+), pancreatic (3), ovarian (2), salivary gland (2) and 1 each with papillary thyroid, cholangiocarcinoma, bladder, carcinoid, colon & leiomyosarcoma. Bi-exponential PK was observed, with dose proportional Cmax and AUC and t1/2 of 12-24 h. Dose-limiting toxicities included dysaesthesia and QTc prolongation; MTD has been defined. PK modeling revealed that a fractionated dose of 60 mg daily (dose expansion cohort) minimizes peak exposure and achieves sustained trough concentrations well above the IC50 for ALK inhibition. Of 5 patients with ALK+ NSCLC, 3 (all crizotinib-resistant) achieved PR (1 met RECIST criteria and 2 had non-measurable disease, so not formally RECIST-classified) 1 is early (not imaged yet), and 1 discontinued for DLT. Stable disease was observed in ALK- papillary thyroid, pancreatic and colorectal patients.
结果：已入组23名晚期癌症患者，接受30到480mg的口服每日总剂量治疗，患者包括非小细胞肺癌（n=10，其中5名ALK+），胰腺癌（3），卵巢癌（2），唾液腺癌（2）以及甲状腺乳头状癌、胆管癌、膀胱癌、类癌、直肠癌和平滑肌肉瘤各一。观察到双指数药代动力学，与剂量线性相关的Cmax和AUC，半衰期12-24小时。剂量限值毒性包括感觉迟钝和QT延长；已确定最大耐受剂量。药代动力学模型显示分次给予每日60mg剂量（剂量扩增队列）可最小化峰值暴露并达到持续的明显高于ALK抑制的IC50的谷浓度。5名ALK+的非小细胞肺癌患者中，3名（均为克里唑替尼耐药）达到部分缓解（1名满足RECIST标准，2名无实体瘤故无法根据RECIST分类），1名新入组（尚未行影像学评估），1名因剂量限值毒性中断。在ALK-的甲状腺乳头状癌、胰腺癌和结直肠癌患者观察到稳定疾病。

Conclusions: TSR-011 is a well-tolerated promising second-generation agent for ALK-dependent and crizotinib resistant NSCLC, and is being explored in ALK+ and TRK+ tumors. Clinical trial information: NCT02048488.
结论：TSR-011是一种针对ALK依赖及克里唑替尼耐药的非小细胞肺癌耐受性良好前景广阔的二代药物。对其在ALK+及TRK+肿瘤中疗效的研究正在进行中。

mmjs1999 · 发表于 2014-5-22 08:35:48

多谢楼主，辛苦了

期待春天 · 发表于 2014-5-22 10:18:15

好贴，期待赶快翻译出来，早日浏览，让外语专家费点心。

决不放弃11 · 发表于 2014-6-2 22:40:25

辛苦了

老马 · 发表于 2014-6-5 14:46:50

【ASCO2014】中国研究：INC280联合吉非替尼治疗NSCLC患者的疗效
http://news.medlive.cn/cancer/info-progress/show-62321_53.html
2014年美国临床肿瘤学会年会将于当地时间5月30日-6月3日在芝加哥召开，根据大会的会议日程，我国肿瘤专家吴一龙教授在6月3日上午有一项研究在“Poster Highlights Session”中展出，下面和大家提前分享这项精彩研究。医脉通小编们今年也将继续奔赴ASCO年会现场，及时将各项最新研究进展整理、发布，欢迎大家保持关注！

很多EGFR突变的NSCLC患者尽管对EGFR-TKI药物有比较高的应答率，但是最终会复发。MET通路的失调在耐药机制上起着一定的作用，这发生在15-20%的病例中。INC280是一种高选择性的口服MET抑制剂，研究发现其与EGFR-TKI药物联合在EGFR突变/MET活化的NSCLC中具有临床前活性。

研究方法

这是一项针对INC280联合吉非替尼的Ib/II期、开放标签、剂量逐步增加的研究，病人年龄≥18岁，ECOG PS≤2，EGFR突变的NSCLC患者，之前接受过EGFR-TKI药物治疗，后疾病出现进展，已经确认是MET失调（扩增[FISH≥5 CN]或者过表达[IHC 2/3+]）。

主要目的（Ib期）是确认MTD，推荐INC280联合吉非替尼的II期剂量；次要目的是安全性、疗效、药效学和药代学。通过过量控制指导下的剂量递增，使用一种自适应的贝叶斯logistic回归模型确定MTD。

研究结果

到2013年12月2日，41例病人进入Ib期研究（59%女性，平均年龄58岁）。INC280分为100-800mg QD和200-600mg BID的7个剂量队列，联合吉非替尼 250mg QD。剂量限制毒性（QLT）在两个病人中发生：头晕（800mg QD）和呼吸困难（600mg BID）。最常见的药物相关不良反应（任何等级）为恶心（27%），呕吐，腹泻和皮疹（所有为22%）。最常见的3/4级不良反应为脂肪酶增加（7%），淀粉酶增加（5%）。有一人死亡，未排除INC280的原因。

初步数据分析未发现INC280与吉非替尼有药代动力学相互作用。在6/41病人（15%）中出现局部缓解，包括3个在400mg BID组，其中有5个人在入组前EGFR-TKI药物是最后的治疗。所有的应答者都是高MET状态。

结论

口服INC280联合吉非替尼耐受性良好，II期推荐剂量还未定。初步临床活性支持对INC280联合吉非替尼在TKI耐药的MET阳性NSCLC患者中的进一步评估。临床试验信息：NCT01610336

小P · 发表于 2014-6-5 14:57:00

老马兄好！INC280分为100-800mg QD意思是一天一次，但之前的说是一天二次。我现在280联合瑞格。280是一天二次每次200MG，要改为一天一次吗？谢谢！

cccrow · 发表于 2014-7-18 16:19:28

怎么添加不了附件？刚好有2014年的ASCO摘要全集-pdf版本。。。

cccrow · 发表于 2014-7-18 16:23:41

http://pan.baidu.com/s/1ntI8dIT
放在百度网盘里面了

costa_na · 发表于 2014-7-21 12:11:35

本帖最后由 costa_na 于 2014-7-21 12:19 编辑

EGFR mutation status in cerebrospinal fluid of NSCLC patients who developed leptomeningeal metastasis after EGFR-TKI treatment.
柔脑膜转移NSCLC患者脑脊液中EGFR突变状态

Abstract:
摘要：

Background: Prognosis for these patients with leptomeningeal metastasis (LM) is very poor due to the lack of therapeutic options. It was suggested that the leptomeningeal space is protected from the systemic chemotherapy as well as EGFR-TKIs. Therefore, it would be interesting to explore the EGFR mutation status in CSF of the NSCLC patients who developed LM after the initial response to EGFR-TKI. In this study, we attempted to address two questions: 1. what is the EGFR mutation status in CSF of this group of patients? 2. what is the difference of EGFR mutation status in CSF as compared to that in the concurrent plasma samples?
背景：由于缺乏有效治疗策略，柔脑膜转移（LM）的肿瘤患者预后很差。人们一直认为全身化疗和人类表皮生长因子受体酪氨酸酶抑制剂（EGFR-TKIs）不能作用于柔脑膜腔。所以，对接受EGFR-TKI治疗响应后发生柔脑膜转移的非小细胞肺癌患者脑脊液（CSF）中EGFR突变水平的研究是非常有意义的。试图解决两个问题：一为发生柔脑膜转移的非小细胞肺癌患者脑脊液中 EGFR突变状态，另一个为这些患者脑脊液和血浆中EGFR突变水平差异。

Methods: A highly sensitive droplet digital PCR (ddPCR) method was used to detect EGFR mutation in 7 CSF samples which were collected from seven patients with NSCLC who initially responded to EGFR-TKI and developed LM afterwards. Concurrent plasma samples were collected and analyzed as well for comparison.
方法：研究人员采用高灵敏度液滴数字PCR（ddPCR）方法对7份脑脊液样本中EGFR突变水平进行了检测，这些样本来自于7例初始接受EGFR-TKI治疗响应后发生柔脑膜转移的非小细胞肺癌患者。同时采集了患者同一时期的血浆样本进行分析、对比。

Results: EGFR-sensitive mutations were detected in CSF of all 7 patients (4 of 19-del and 3 of L858R), one of which (1/7, 14.3%) carried T790M mutation as well (19-del&T790M). EGFR mutations were not detected in plasma from 5 of these 7 patients (5/7, 71.4%). In additional plasma samples from remaining 2 patients, who were positive for EGFR E19-del in CSF, E19-del and T790M double mutations were detected.
结果：所有7例患者的脑脊液中均检测到EGFR基因敏感性突变（4例患者为19-del突变，3例为L858R突变），其中1例患者（1/7，14.3%）携带T790M突变（19-del及T790M突变）。5例患者（5/7，71.4%）的血浆标本中没有检测到EGFR基因突变。余下的2例患者血浆标本中检测到E19-del和T790M双基因突变，其脑脊液样本为EGFR E19-del突变阳性。

Conclusions: With development of LM after EGFR-TKI treatment, CSF remained positive for EGFR mutations dominant by sensitive mutations only, even though the plasma were either negative for EGFR mutations or carried TKI-resistant T790M mutation. This is supportive of the protection of EGFR mutation positive tumor cells within leptomeningeal space from the exposure to current EGFR-TKIs.
结论：数据显示，经EGFR-TKI治疗后出现柔脑膜转移的非小细胞肺癌患者，无论血浆中EGFR突变为阴性还是携带TKI-耐药的T790M突变，脑脊液中均出现EGFR突变（主要是敏感突变）。该结论验证了研究人员 “柔脑膜腔内EGFR突变阳性的肿瘤细胞更可能出现可EGFR-TKIs耐药”这一观点。

EGFR mutation status of matched CSF and plasma samples from NSCLC patients who developed LM after initial response to EGFR-TKI treatment.[td]