BMS-690514可以用于特罗凯耐药的病人

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BMS-690514 is an oral selective inhibitor of EGFR, HER2, and VEGFR1-3. Previous results from the phase I portion of this phase I/II study established 200 mg/day as safe and tolerable (ASCO 2008; abstr 2564). Methods: Erlotinib-naïve and erlotinib-resistant adult patients with advanced/metastatic, measurable NSCLC received BMS-690514 200 mg/d. Eligible patients had an ECOG PS ≤1 and adequate organ function. Objectives were to assess disease control rate (DCR; CR, PR, SD >4 months), safety, PK and potential predictive and PD biomarkers of BMS-690514. Response was assessed every 8 weeks (modified WHO criteria). Predictive biomarkers included EGFR copy number, and EGFR and KRAS mutations. PD biomarkers included immunohistochemistry of EGFR signaling proteins in skin biopsies, circulating sVEGFR2, blood pressure, skin rash and diarrhea. Results: For 60 patients treated, DCR were 11/28 (39%) and 7/32 (22%) for erlotinib-naive and -resistant patients, respectively. DCR was significantly higher among patients harboring an EGFR mutation (6/8) than those with WT EGFR (5/18). One erlotinib-naive patient had PR (57 wks) and subsequent surgical removal of remaining tumor. Regression (48%) was seen in one erlotinib-naive patient harboring a KRAS G13D mutation. One erlotinib-resistant patient had PR (66%, 31 wks). Two erlotinib-resistant patients with EGFR T790M mutations had SD with 6% and 31% decrease in tumor burden. Most frequent treatment-related AES were diarrhea (90%), skin rash (31%), asthenia (29%), anorexia (27%), hypertension (26%), and reversible acute renal insufficiency (11%). sVEGFR2 (14% decrease from baseline, n=14) and decreased pMAPK levels from skin biopsies (14 of 18 pts) were consistent with EGFR and VEGFR2 inhibition. Conclusions: BMS-690514 200 mg/d showed evidence of anti-tumor activity and disease control in patients with NSCLC, including erlotinib-resistant and those with WT EGFR, EGFR T790M or KRAS mutations. Predictive and PD clinical biomarkers confirmed inhibition of both EGFR and VEGFR signaling pathways by BMS-690514. A randomized phase II trial versus erlotinib in NSCLC is underway.

shy · 发表于 2011-3-11 15:49:28

本帖最后由 shy 于 2011-3-12 10:04 编辑

BMS-690514 是一种口服的选择性的（selective）EGFR, HER2, and VEGFR1-3抑制剂，早期的实验证明 200 mg/day是安全的和可以耐受的(ASCO 2008; abstr 2564).受测试的病人 ECOG PS ≤1并且有正常的器官功能。
目的是评估BMS - 690514的疾病控制率（DCR; CR, PR, SD >4 个月），安全性，PK和潜力预测以及局部的生物标志物。每8周对反应进行评估（修订的WHO标准）。预测生物标志物包括EGFR拷贝数，EGFR和KRAS基因突变。 PD的生物标志物包括免疫组织化学信号表皮生长因子受体蛋白在皮肤切片，循环sVEGFR2，血压，皮疹和腹泻对于60个接受治疗的患者，对于厄洛替尼有效的患者 DCR 为11/28（39％），对于厄洛替尼耐药的患者为7 / 32（22％）。 EGFR 突变的患者获得DCR的比例（6 / 8）明显高于EGFR野生的患者（5 / 18）。一个厄罗替尼有效的病人获得PR（57周），随后手术切除余下肿瘤。在一个厄洛替尼有效且有KRAS G13D基因突变的患者肿瘤减少了48%。一个埃罗替尼耐药的病人获得PR（66％，31周）。两个厄洛替尼耐药的病人获得SD患者，其肿瘤的负担减少6％和31％。最常见的治疗相关不良事件腹泻（90％），皮疹（31％），乏力（29％），厌食（27％），高血压（26％）和可逆的急性肾功能不全（11％）。sVEGFR2（从基线下降14％，n=14），降低皮肤切片pMAPK水平（14/18）均符合表皮生长因子受体和VEGFR2抑制作用。
结论：BMS-690514 200 mg/d 具有明显的肿瘤抑制能力，包括erlotinib耐药，以及 EGFR, EGFR T790M 野生或者 KRAS 突变的NSCLC病人。