EGFR突变患者TKI治疗与化疗联用

EGFR突变患者TKI治疗与化疗同时进行的疗效评价,小组成员：丁宁、节梦梦、谢晓东、刘亮、王浩强,内容,同步联用（concurrent combination），化疗和TKI药物拮抗，效果降低；作用条件：前期TKI耐药；序贯联用（ intercalated combination ），选择方案较多，效果显著维持治疗（maintenance therapy ）,同步联用Concurrent Combination,EGFR突变发现之前三组独立实验：Giaccone et al. 2004; Herbst et al. 2004, 2005; Gatzemeier et al. 2007 ；实验对照： concurrent combination of EGFR-TKIs and platinum-based doublet chemotherapy VS chemotherapy alone实验人群：未筛查EGFR突变,concurrent combination,Failed,Heymach et al. 2007 荟萃分析:3918名患者,结论：在突变未筛查人群中EGFR-TKI 与化疗同时使用效果不显著,两者联用无优势的原因,First, by lack of patient molecular selection:EGFR TKIs only induce apoptosis in EGFR-mutant but not in wild type EGFR lung cancer cell lines;EGFR-TKIs仅对突变型有效，引发细胞凋亡，对野生型无效,化疗可能降低患者的EGFR基因突变发生率,Second, by a probably antagonistic effect between EGFR TKI and chemotherapy:EGFR TKI induces G1-phase cell cycle arrest that protects cancer cells from the lethal effect of cell cycle phase-dependent cytotoxic chemotherapy which arrest cells at the mitotic cell cycle phase.EGFR TKI使细胞停滞在G1期，而细胞周期依赖的化疗药物仅对M期的细胞起作用,两者联用无优势的原因,EGFR-TKI + 化疗-耐药后的治疗选择,入组患者N=78,化疗+厄罗替尼N=34,化疗N=44,EGFR 突变状态:70名(90%)患者突变TKI中位治疗时间15个月(范围4-51个月)8民患者突变状态未知TKI中位治疗时间11个月(范围5-16个月),实验一：化疗+厄罗替尼,化疗 特罗凯治疗获得性耐药的患者,风险比0.20 (0.05-0.78)P=0.02,EGFR-TKI存在获得性耐药 (Jackman标准) 的患者接受后续化疗或化疗+特罗凯治疗化疗必须在EGFR-TKI停药的4周内启动由独立评估者对治疗应答进行评估，对评估者实施治疗方案盲法,HR 0.79(0.48-1.29)P=0.34,耐药后继续TKI同步化疗可能会成为有价值的治疗策略尤其是对症状有进展的患者能获得更高缓解率,化疗 + 特罗凯,相比基线的改善百分比 (%),40,20,0,20,40,60,80,PD or SDPR,化疗,40,20,0,20,40,60,80,PR,PD/SD,PR,PD/SD,实验二：,目的：比较对EGFRTKI耐药患者采用化疗联合EGFRTKI与单化疗的疗效及不良反应。方法：符合入组标准的l8例患者中，8例接受化疗联合EGFRTKI(CE组)，lO例接受单化疗(c组)，21 d为1个周期，至少完成2个周期化疗的患者进行疗效及不良反应评价结果：18例患者均可评价疗效； CE组疾病控制率(DCR)为875，中位无进展生存期(PFS)为3.5个月，C组DCR为30，中位PFS为2.4个月，两组比较差异有统计学意义(P=0046，P=O05)结论：EGFR突变阳性的NSCLC患者，在EGFRTKI耐药后继续使用EGFRTKI并联用化疗可延缓疾病进展，是EGFRTKI治疗失败的NSCLC患者的一项治疗策略。,序贯联用Intercalated Combination,一线化疗联用TKI治疗有效延长病人生存时间,死亡,死亡,一线TKI,二线化疗,一线化疗,维持 TKI,A,B,理论生存期,进展,进展,进展,进展,三线TKI,四线化疗,二线化疗,三线TKI,进展,First-line Asian Sequential Tarceva and Chemotherapy Trial (FASTACT),154名患者随机分组,序贯联用PFS显著提高具有临床应用价值,化疗与TKI一线交替使用,维持治疗Maintenance Therapy,一线化疗后TKI维持-SATURN带来生存获益,参考文献,1 Linda Leung, Tony S.K. Mok and Herbert Loong , Combining chemotherapy with epidermal growth factor receptor inhibition in advanced non-small cell lung cancer, Ther Adv Med Oncol (2012) 4(4) 173181 2 Davies AM, Ho Ch, Lara PN, et al. Pharmacodynamic separation of epidermal growth factor receptor tyrosine kinase inhibitors and chemotherapy in nonsmall cell lung cancer. Clinical Lung Cancer 2006; 6: 3858. Gefitinib induces apoptosis in the EGFR-L858 non-small cell lung cancer cell line H3255. Cancer Res 2004;64:72414.3 Solit DB, She Y, Lobo J, et al. Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res 2005;11:19839.4 J. Remon, T. Morn, N. Reguart, M. Majem, E. Carcereny, P. Lianes ,Beyond EGFR TKI in EGFR-mutant Non-Small Cell Lung Cancer patients:Main challenges still to be overcome Cancer Treatment Reviews 40 (2014) 7237295 Mok, T.S., Wu, Y.L., Thongprasert, S., Yang, C.H., Chu, D.T., Saijo, N. et al. (2009a) Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma