非小细胞肺癌治疗展望课件.ppt

1、非小细胞肺癌治疗展望,吴一龙 广东省肺癌研究所 广东省人民医院 广东省医学科学院,Tarceva六周年庆/济南,Therapeutic Advances in the Last 5-10 Years,Biomarker-driven therapy for EGFR-mutant ALK-positive NSCLC and targeted therapy (EGFR TKIs & Crizotinib),No major advances,NSCLC (Advanced Stage),Unmet Needs to Advance Personalized Therapy in NSCLC

2、Recognition of lung cancer complexity at the genomic level -including inter- and intra patient tumor heterogeneity Integration of this genomic complexity into clinical decision-making process,Future,Traditional View,Inter-patient Tumor Heterogeneity,Models for Inter- and Intra-Patient Tumor Heteroge

3、neity,Intra-patient Tumor Heterogeneity,Evolution over time with therapy,or,EGFR MT+,ALK+,EGFR MT+,EGFR MT-,Resistance Mutation T790M,Evolutionary Biology & Tumor Resistance,Intra-tumor heterogeneity is present at baseline Reducing sensitive clones by therapy permits unopposed growth of less fit res

4、istant clones or emergence of a new clone (“Tumor Darwinism”) Separating new “drivers” from emergent “passengers” is becoming increasingly complex,Evolution over time with therapy,“Driver” Oncogene,New “Driver”,Evolution over time with therapy,“Driver” Oncogene,New “Driver”,Scenario 1,Scenario 2,fro

5、m Gandara et al: Clin Lung Cancer, 2012,血液分子标志物研究: 更好的全貌，更容易的方法？,Detection of EGFR activating mutations from plasma DNA as a potent predictor of survival outcomes in FASTACT 2 study: A randomized phase III study on intercalated combination of erlotinib (E) and chemotherapy (C),Mok T, Wu YL et al ASC

6、O 2013,-,EGFR 突变状态对治疗选择的影响,A phase II trial comparing pemetrexed with gefitinib as the second-line treatment of non-squamous NSCLC patients with wild-type EGFR (CTONG0806),N 157,Primary endpoint: PFS Second endpoint: OS, RR, QoL,NCT00891579,EGFR野生型患者的治疗,CTONG 0806: CONSORT diagram showing patient di

7、sposition,The results will release at ASCO 2013,CTONG0806 Patients Characteristic,Randomized phase III trial of erlotinib (E) versus docetaxel (D) as second- or third-line therapy in patients with advanced non-small cell lung cancer (NSCLC) who have wild-type or mutant epidermal growth factor recept

8、or (EGFR): Docetaxel and Erlotinib Lung Cancer Trial (DELTA).,Okano Y, ASCO 2013 Abstract 8006,Primary Endpoint: PFS & OS,？,OS密码,EGFR突变患者一线治疗的4种模式,IPASS模式 SATURN、INFORM模式 FAST-ACT模式 化疗模式,哪一种更优？,1. Chemo 2. FAST-ACT 3. INFORM 4. IPASS 5. OPTIMAL 6. SATURN,吴氏法则：按字母顺序排列,需要更多的研究！,Potential targets and d

9、rugs,Phase II, open-label, single-arm study of efficacy and safety of crizotinib in East Asian NSCLC with ALK(-) and ROS1(+),N=100,Crizotinib 250 mg p.o. b.i.d. continuous dosing schedule,Key eligibility criteria: ALK-Negative and a translocation or inversion in ROS1 gene aNSCLC 3 previous treatment

10、 regimen,Treatment,Primary endpoint: ORR Secondary endpoint: DR, TTR, DCR at 8 weeks, PFS, OS, QoL, etc ALK status determined by Abbott ALK FISH, Ventana IHC, or RT-PCR(Amoy) ROS1 rearrangement determined by RT-PCR assay,1970 1980 1990 2000 2005 2010 2015,Besse et al. JCO 2013,靶向化疗的历史进展,ERCC1 target

11、ed trial (NCT00801736),Stages IIIB to IV 1,272 cases,Phase III,High ERCC1 non-SCC: pemetrexed plus paclitaxel SCC: gemcitabine plus paclitaxel Low ERCC1 non-SCC: pemetrexed plus cisplatin SCC: gemcitabine plus cisplatin,Predictive value of ERCC1 regarding cisplatin based chemotherapy v nonplatinum t

12、reatment,Primary endpoint: OS,Besse et al. JCO 2013,Interim analysis of the Spanish Lung Cancer Group (SLCG) BRCA1-RAP80 Expression Customization (BREC) randomized phase III trial of customized therapy in advanced non-small cell lung cancer (NSCLC) patients (p) (NCT00617656/GECP-BREC). - Moran et al

13、. 2013 ASCO,Potential Algorithm for Therapy of Advanced NSCLC: 2015 & Beyond?,Targeted agent assignment based on molecular markers,No targeted agent applicable (default to chemotherapy),Potential future treatment Algorithm,DNA Damage Repair Capacity ERCC1, RRM1, BRCA,Pemetrexed sensitivity TS, DHFR, GARFT,Biomarkers determine doublet: platinum? pemetrexed?,Maintenance based on prior therapy,Second line based on prior therapy,Influence by histology, toxicity + Bevacizumab for eligible non-SC