精品晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳课件

NSCLC,Progress in the treatment,晚期非小细胞肺癌表皮生长因子受体酪氨酸抑制剂的最佳治疗易瑞沙与特罗凯的比较,蔡 俊 明 台北榮民總醫院 胸腔部 胸腔腫瘤科 陽明大學 醫學院 內科學系,三十年来晚期非小细胞肺癌的治疗成果,Tumour cell proliferation,PI3K,MAPK,Tumour cell survival,Akt,mTOR,STAT 3/5,Grb-2,Ras,Raf,MEK,ATP,Anti-EGFR Abs Cetuximab, Panitumumab, Matuzumab, h-R3, MDX-447 Anti-HER1,HER2,HER4 TKIs Gefitinib, Erlotinib, BIBW-2992, PKI-166, GW-572016, CI-1033, AEE788 RAS farnesyltransferase inhibitors MMS214662, R115777, SCH66336 RAF inhibitors Sorafenib, L-779450 MEK inhibitors CI-1040, U-0126 mTOR inhibitors Temsirolimus, RAD001,ATP,SOS,Small molecule tyrosine kinase inhibitors,表皮生长因子受体讯息传递的生物标记与抑制剂,肺腺癌的表皮生长因子受体突变,Response Rate vs. Clinical Background,Clinical Background vs. EGFR Mutations,EGFR mutation (%),RR (%),Asian,Non-Asian,Female,Male,Never,Ever,Adeno,Non-Adeno,Asian,Non-Asian,Female,Male,Never,Ever,Adeno,Non-Adeno,Mitsudomi, IJCO, 2006,T854A,E884K,L747S,D761Y,敏感性突变,Sharma, et al. Nat Rev Cancer 2007,生长因子受体易瑞沙与特罗凯的敏感性突变,抗药性突变,428,100 55 125 288 283 TAX317 TAX320 JMEI,19,30,29,32,30,BSC,Docetaxel,Docetaxel,Pemetrexed,4.6,7.9,7,5.7,8.3,1-yr Survival (%) MS (m) DCR (%),47.3,63.4,46.6,53.1,54.1,9.1,8.8,6.7,5.8,Docetaxel,117,60,27,10,40,428,非小细胞肺癌的救援性治疗 Comparison of Docetaxel, Pemetrexed & EGFR-TKIs,Gefitinib,BR.21 versus ISEL 以安慰剂为对照组的研究,Favours EGFR TKI,Favours placebo,HR,0.40,0.60,0.80,1.00,1.20,特罗凯 Erlotinib (BR.21)1 30% reduction in risk of death p=0.001,易瑞沙 Gefitinib (ISEL)2 11% reduction in risk of death Not significant,1Shepherd FA, et al. N Engl J Med 2005;353:12332 2Thatcher N, et al. Lancet 2005;366:152737,何以易瑞沙失败 ? BR21 vs ISEL,病人选择与纳入条件,Criteria for inclusion in ISEL and BR21 clinical trials,ISEL: development of progressive disease within 90 days of the preceding round of chemotherapy (early relapse) BR21: no selection for early relapse,428,100 55 125 288 283 TAX317 TAX320 JMEI,19,30,29,32,30,BSC,Docetaxel,Docetaxel,Pemetrexed,4.6,7.9,7,5.7,8.3,1-yr Survival (%) MS (m) DCR (%),47.3,63.4,46.6,53.1,54.1,9.1,8.8,6.7,5.8,Docetaxel,Gefitinib,117,60,27,10,40,428,非小细胞肺癌的救援性治疗 Comparison of Docetaxel, Pemetrexed & EGFR-TKIs,BR.21 and ISEL对照组群的存活曲线显示它们是相似的组群,Proportion surviving,1.0 0.8 0.6 0.4 0.2 0,0 2 4 6 8 10 12 14 16 18 20 22 24 26 28,Time (months),1Shepherd FA, et al. N Engl J Med 2005;353:12332 2Thatcher N, et al. Lancet 2005;366:152737,药物剂量,何以易瑞沙失败 ? BR21 vs ISEL,易瑞沙 与 特罗凯 结构相似，活性不同?,易瑞沙与特罗凯结构上的差异使得两者在血浆、肿瘤和正常组织中分布浓度不同，其代谢作用、活体外活性也不同，使得药物所产生的临床效果和毒性不同。,特罗凯,易瑞莎,cLogP = 3.30,cLogP = 3.87,易瑞沙之亲脂性约比特罗凯高三倍,易瑞莎较易被代谢、由胆汁排出、易与蛋白质结合、血浆中药物浓度较低。,特罗凯,易瑞莎,主要代谢产物的活性不同,Li J, et al. Clin Cancer Res 2007;13:37317 McKillop D, et al. Xenobiotica 2006;36:2939,Gefitinib,CI,F,N,O,NH,N,O,O,NH,O,O,N,H,Desmethyl-gefitinib,Erlotinib,O,O,O,O,NH,N,N,OSI-420,H,MW 429.2,MW 446.9,特罗凯,易瑞莎,Dose-proportional Cmax and AUC Repeated daily dosing does not result in drug accumulation High plasma exposure at 150mg/day p.o.,Hidalgo M, et al. J Clin Oncol 2001;19:326779 Ranson M, et al. J Clin Oncol 2002;20:224050,Cmax (ng/mL),AUC024 (nghour/L),Erlotinib 150mg/day,Gefitinib 225mg/day,Gefitinib 525mg/day,Gefitinib 700mg/day,2,500 2,000 1,500 1,000 500 0,45,000 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0,药物动力学比较 (每日剂量 ),Paez, Science 2004,Gefitinib induces apoptosis in the H3255,表皮生长因子受体 L858R突变对 EGFR-TKI 较野生型敏感,* A: adenocarcinoma; AS: adenosquamous carcinoma; BAC: bronchioloalveolar cell carcinoma; LC: large cell carcinoma; S: squamous cell carcinoma * Mitsudomi, et al. Oncogene 1991.,非小细胞肺癌细胞株的生物特性,非小细胞肺癌细胞株：EGFR 基因突变与药物敏感性,侵犯脑膜对特罗凯具有抗性之肺癌细胞对易瑞沙敏感 EGFR突变之角色,70 y/o Japanese-American woman, never smoked Stage IV adenocarcinoma, RML with rib metastases 2002/02 Mediastinoscopic LN biopsy 2002/04 TRIBUTE trial (TXL+Ca+erlotinib) 42% 2003/11 WBRT due to brain mets 2004/08 Hemiparesis, diplopia, incontinence (bowel & bladder), wheelchair bound Brain & spine MRI: leptomengeal carcinomatosis 2004/10 Could not tolerated temozolomide+CPT-11 in progression. ECOG PS 4 2004/10 On gefitinib Symptoms: significantly improved in 3 wks 2005/02 Ambulating independently with a walker 2005/04 ECOG PS 2 2005/06 Aspiration pneumonia and died.,Prior to gefitinib 2 ms,Choong NW, Nature CP Oncol 3:50, 2006,Prior to gefitinib 2 ms 4.5 Ms,EGFR突变对上皮生长因子受体嗜酪酸塩抑制剂之敏感性与抗药性的影响 (一),Choong NW, Nature CP Oncol 3:50, 2006,Costa, JCO, 26:1182, 2008,EGFR突变对上皮生长因子受体嗜酪酸塩抑制剂之敏感性与抗药性的影响 (二),Costa, JCO, 26:1182, 2008,EGFR突变对上皮生长因子受体嗜酪酸塩抑制剂之敏感性与抗药性的影响 (二),Screen 47 known kinase inhibitors for ability to inhibit H1975 proliferation 85% inhibition at 2 M,Identification 3 compounds CL-387,785; EKB-569; CI-1033,Determine IC50,Measure EGFR Autophos inhibition,Ambit Biosciences,Compound IC50 (M) CI-1033 0.023 EKB-569 0.033 CL-387,785 0.051 SU-11464 0.450 ZD6474 1.900 GW572016 3.500 Gefitinib 6.600 PKI-166 7.700 Erlotinib 10.000 Inhibition of H1975 cell proliferation,克服T790M抗药性药物之研究,易瑞沙与特罗凯：副作用表列,易瑞沙与特罗凯做为晚期非小细胞肺癌 后线治疗的比较 逆溯性配对研究,Sungkyunkwan University, School of Medicine Samsung Medical Center,Myung-Ju Ahn, M.D.,Gfitinib: 2002-2005; Erlotinib: 2006-2008 Gefitinib: 316 vs Erlotinib: 257 (Matched Age, Sex, PS, Smoking, No of PriorTx),Ahn et al, Unpublished data,病患基本资料,36% 72% 50-56%,肿瘤反应,Ahn et al, Unpublished data,Total OS; Median 10.7 months,(B) Gefitinib OS; Median 10.0 months Erlotinib OS; Median 12.4 months (p=0.07),Ahn et al, Unpublished data,A) 整体存活曲线 B) 分別接受易瑞沙与特罗凯治疗病患之存活曲线,研究图示 Statistics Target N =48 for each group Simons optimal two-stage design P0=10%, P1=25%, -error 5%, -error 20%, 10% drop-out rates 1st stage: responders 2/18 2nd stage: additional 25 pts,方 法,RANDOMI ZAT ION,Gefitinib 250mg/d Q4wKs,Erlotinib 150mg/d Q4wks,REEVALUAT ION,REEVALUAT ION,Until Disease progression or Intolerable toxicities,4 weeks,8 weeks,At least 2 of 3 Adenoca. Female Never smoker or EGFR mutant,病患基本资料,Numbers of treatment cycles : median 5 (range, 0.5-20), total 605 cycles Gefitinib group: median 6 (range, 0.5-19), total 331 cycles Erlotinib group: median 4 (range, 0.5-20), total 274 cycles,肿瘤反应,整体与无恶化存活曲线,Median follow-up duration: 11.5 months (range, 6.7-20.8),Gefitinib Erlotinib,PFS by Treatment,P=0.167,OS and PFS,OS PFS,毒性副作用, Except 3 mortalities from pneumonia. (2 of gefitinib and 1 of erlotinib),表皮生长因子受体突变患者的 临床后果 非小细胞肺癌患者接受表皮生长因子受体 酪氨酸抑制剂或化疗的集体分析 L Paz-Ares, et al. ESMO/ECCO Berlin 2009 J Cell Mol Med 2010 14:51-69,论文搜集策略摘要,Reports identified from broad literature search (n=564),Studies retained for full paper review (n=175),Studies identified from ASCO 20089 search (+n=42),Excluded based on abstract or title: no clinical data related to question (- n=431),Excluded (n=121) PFS/TTP/n not reported for pts with mutations (n=96) EGFR-TKIs given sequentially or as maintenance or adjuvant therapy (n=10) Data duplicated in another publication (n=15),Studies included (n=54),资料搜集策略摘要,个别研究之疾病无恶化期 90% accuracy intervals (any line of therapy),Erlotinib,Gefitinib,Chemotherapy,Pooled median PFS (95% accuracy interval),13.2 (12.014.7),9.8 (9.210.4),5.9 (5.36.5),Permutation test for estimated pooled median PFS (1,000 iterations) EGFR TKI vs chemotherapy p=0.000 (two-sided),Erlotinib N = 365 (2/12),Gefitinib N = 1069 (19/39),Chemotherapy N = 375,Pooled studies,表皮生长因子受体突变阳性 各种治疗疗效,SATURN 研究設計,Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region,1:1,Chemonave advanced NSCLC n=1,949,Non-PD n=889,4 cycles of 1st-line platinum-based doublet*,Placebo,PD,Erlotinib 150mg/day,PD,Mandatory tumour sampling,*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel EGFR = epidermal growth factor receptor; IHC = immunohistochemistry,Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary endpoints: Overall survival (OS) in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL),晚期非小细胞肺癌含铂两药方案后以易瑞沙治疗或持续化疗之随机第三相研究: WJTOG试验结果 LBA#8012,全 部,WJTOG 0203 - OS,非鳞状细胞癌,SATURN - OS,全 部,WJTOG0203: 整体存活依临床特质之亚群分析,0.4,0.6,0.8,1.0,1.2,Favours erlotinib,Favours placebo,HR,Male Female Caucasian Asian Adenocarcinoma Squamous-cell Never smoker Former smoker Current smoker,HR (95% CI) n 0.88 (0.741.05) 659 0.64 (0.460.91) 230 0.86 (0.731.01) 746 0.66 (0.421.05) 131 0.77 (0.610.97) 403 0.86 (0.681.10) 360 0.69 (0.451.05) 152 0.75 (0.561.00) 244 0.88 (0.721.08) 493,All,0.81 (0.700.95),889,SATURN: 整体存活依临床特质之亚群分析,SATURN: 疾病无恶化期 (野生型 vs.鳞状细胞癌 ),Log-rank p=0.0148,HR=0.76 (0.600.95),鳞状细胞癌,1.0 0.8 0.6 0.4 0.2 0,Time (weeks),0 8 16 24 32 40 48 56 64 72 80 88