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本帖最后由 老马 于 2014-1-8 18:31 编辑
1 一线治疗方案选择化疗还是靶向?
一线治疗是选化疗还是靶向药对于多数家属是一个纠结的问题。
1.1 对未经选择的晚期NSCLC患者,一线厄洛替尼二线健择/顺铂方案的疗效差于一线健择/顺铂二线厄洛替尼方案。二线用TKI比一线用TKI有效率稍低,而一线TKI后二线化疗的有效率明显降低。
1.2 对于EGFR突变阳性的患者,一线TKI有效率明显高于化疗。而相对EGFR突变阴性的患者,EGFR突变阳性的患者一线化疗有效率及PFS也较高。西班牙Rosell研究显示一线化疗/二线TKI的总生存期会长于一线TKI/二线化疗组。
一线使用TKI的优点:TKI有效率明显高于化疗,无进展生存期也长的多,副作用也小的多,容易耐受。缺点:一线TKI,进展后PS状况变差,相当多的患者不愿意接受化疗。
1.3 对于ALK突变阳性的患者,一线TKI(克里唑蒂尼)有效率明显高于化疗。而相对ALK突变阴性的患者,ALK突变阳性的患者培美曲塞化疗方案有效率较高。
1.4 对于ALK和EGFR突变阴性的患者,一线TKI几乎接近无效,应首选化疗。
香港中文大学莫树锦对比分析EGFR TKI药物一二线治疗情况.pdf
(237.42 KB, 下载次数: 1631)
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本帖最后由 老马 于 2013-4-24 19:53 编辑
4 易瑞沙、特罗凯耐药后的选择
4.1 易瑞沙和特罗凯能换用吗?
(1)易瑞沙替换为特罗凯
易瑞沙治疗进展后,换为特罗凯是否有效。这一设想的根源在于,易瑞沙的临床使用剂量是250 mg/d,低于其最大耐受剂量(1000 mg/d),血浆稳态浓度不超过0.5 μmol/L;而特罗凯的临床使用剂量(150 mg/d)正是其最大耐受剂量,血浆稳态浓度超过1.5 μmol/L。因出现L747S突变而对易瑞沙耐药者,特罗凯可能有效。对易瑞沙耐药的EGFR突变阳性肿瘤大多伴有T790M突变或MET扩增,目前认为,这样的肿瘤对特罗凯也有交叉耐药,临床前体外研究显示,抑制含有T790M突变或MET扩增的EGFR突变阳性NSCLC细胞株的易瑞沙或特罗凯浓度须超过5 μmol/L。
(2)从特罗凯替换为易瑞沙
服用特罗凯肝毒性过大,或者得了间质性肺炎,经治疗后,换为服用易瑞沙,仍很有可能有效。
而特罗凯耐药后,换成易瑞沙,有效的可能性很小。应在二药之间插入化疗。
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4.3 继续吉非替尼或厄洛替尼联合单药化疗
适用于肺部缓慢进展的病人。
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本帖最后由 老马 于 2013-6-15 04:14 编辑
4.4 不可逆TKI抑制剂
BIBW2992(阿法替尼,afatinib)、Dacomitinib(PF00299804)、CO-1686、WZ4002等。
[用药讨论]BIBW2992
http://www.yuaigongwu.com/thread-771-1-1.html
BIBW 2992(阿法替尼)的服药说明
http://www.yuaigongwu.com/thread-6239-1-1.html
dacomitinib(PF00299804)试药讨论
http://www.yuaigongwu.com/thread-8735-1-1.html
Dacomitinib(PF-00299804)服药说明
http://www.yuaigongwu.com/thread-9099-1-1.html
CO-1686
http://www.yuaigongwu.com/forum.php?mod=viewthread&tid=8407
WZ4002试药讨论
http://www.yuaigongwu.com/thread-9039-1-1.html
WZ4002,延缓因T790M突变导致易、特、2992的耐药及耐药后的选择
http://www.yuaigongwu.com/thread-8373-1-1.html
T790M突变和cMet扩增
http://www.yuaigongwu.com/thread-8638-1-1.html
关于阿法替尼(Bibw 2992)耐药的一些理论和解决方案
http://www.yuaigongwu.com/thread-8492-1-1.html
XL184治疗NSCLC2期临床结果.PDF
(1.1 MB, 下载次数: 444)
Irreversible inhibitors of the EGF receptor may circumvent acquired resistance t.pdf
(584.24 KB, 下载次数: 156)
Resistance to an Irreversible Epidermal Growth Factor Receptor (EGFR) Inhibitor .pdf
(1.03 MB, 下载次数: 152)
The EGFR T790M Mutation in Acquired Resistance to an Irreversible Second-Generat.pdf
(907.96 KB, 下载次数: 142)
【华为网盘】Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor.pdf
Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors.
http://www.ncbi.nlm.nih.gov/pubmed/22961667
The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP-ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib-resistant EGFR-mutant non-small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1-amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials.
Optimization-of-dosing-for-EGFR-mutant-non–small-cell-lung-cancer-with-evolutio.pdf
(1.02 MB, 下载次数: 148)
Irreversible EGFR-TKIs: dreaming perfection
http://www.tlcr.org/article/view/819/1407
Kris et al. reported the results of the 1017 study of dacomitinib at the dose of 30-45 mg daily in NSCLC patients with EGFR mutations or HER-2 mutations (i.e., exon 20 insertions or point mutations) or HER-2 amplification (57). Endpoints included progression-free survival rate at 4 months (PFS at 4 M), PFS, partial response (PR) rate and safety. EGFR cohort included never or light-former smoker (<10 pack year) patients with metastatic non-pretreated adenocarcinoma or treatment-naïve patients with known EGFR mutations, while HER2 cohort enrolled subjects with HER2 mutations or amplification who received any number of prior therapy. In the EGFR cohort (Cohort A, N=89), 46 of patients harbored a classical mutation (exon 19, N=25; exon 21, N=21); in this subgroup, RR rate was 76% while PFS at 4M and PFS were 95.5% (95% CI, 83.2-98.9%) and 18.2 months (95% CI, 12.8-23.8 months) respectively. As expected, common side effects were diarrhea, skin toxicity and nail changes. Cohort B is still recruiting and in the first 22 enrolled patients (HER2 amplification, N=4; HER2 mutation, N=18) an interesting activity of 14% was observed, but limited to those patients carrying a HER-2 mutation.
Irreversible EGFR-TKIs dreaming perfection.pdf
(381.46 KB, 下载次数: 133)
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本帖最后由 老马 于 2013-4-24 19:41 编辑
4.7 空窗的风险有多大?
EGFR TKI耐药后停药很可能会出现爆发性反弹,临床实验数据显示,61个病人中有14人出现爆发性反弹,中位时间是停止TKI后的第8天(3-31天)。因此EGFR TKI耐药后选择空窗或者中医治疗风险极大。
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