非小细胞肺癌治疗进展 Competition in NSCLC Competition in NSCLC Competition in NSCLC E4599 and Avail 入组病人的基本情况研究结果：主要研究终点Competition in NSCLC Competition in NSCLC Competition in NSCLC 肺癌个体化治疗，我们的选择应该是……我们的选择应该是……谢谢大家Cisplatin 75 mg/m2 day 1 plus Gemcitabine 1250 mg/m2 days 1 & 8 RandomizationFactors Stage PS Gender Histo vs cyto Brain mets  R Cisplatin 75 mg/m2 day 1 plus Pemetrexed 500 mg/m2 day 1 Vitamin B12, folate, and dexamethasone given in both arms Each cycle repeated q3 weeks up to 6 cycles Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008 Primary endpoint: survival; non-inferiority design JMDB: 培美曲赛对比吉西它滨 用于一线进展期NSCLC （III 期研究）Pemetrexed+Cisplatin Median OS: 11.0 mos Gemcitabine+Cisplatin Median OS: 10.1 mos  HR=0.844 (95% CI: 0.74–0.96) p=0.011  Pemetrexed+Cisplatin Median OS: 9.4 mos Gemcitabine+Cisplatin Median OS: 10.8 mos  HR=1.229 (95% CI: 1.00–1.51) p=0.051 非鳞癌* (n=1252) 鳞癌(n=473) Survival Time (months) Survival Time (months) Survival Probability Survival Probability Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008 JMDB: 培美曲赛对比吉西它滨 用于一线进展期NSCLC （III 期研究）JMDB AVAiL  FLEX IPASS Design 2- arms1st-line 4-arms1st-line 2-arms1st-line 2-arms1st-line Primary endpoint OS PFS OS PFS Agents PemetrexedGemcitabineCisplatin Bevacizumab GemcitabineCisplatin CetuximabVinorelbineCisplatin  GefitinibCarboplatinPaclitaxel No. of Pts. 1700 1043 1100 1200 Outcome PE: met PE: met PE: met   PE: exceeded EGFR-TKI Bevavizumab EGFR 突变患者从易瑞沙治疗中高度获益Cetuximab 3周内发生皮疹患者从爱必妥治疗中高度获益高度选择人群可从贝伐治疗中获益培美曲赛在腺癌患者中疗效优于吉西他滨Pemetrexed JMDB AVAiL  FLEX IPASS Design 2- arms1st-line 4-arms1st-line 2-arms1st-line 2-arms1st-line Primary endpoint OS PFS OS PFS Agents PemetrexedGemcitabineCisplatin Bevacizumab GemcitabineCisplatin CetuximabVinorelbineCisplatin  GefitinibCarboplatinPaclitaxel No. of Pts. 1700 1043 1100 1200 Outcome PE: met PE: met PE: met   PE: exceeded EGFR-TKI Bevavizumab Pemetrexed EGFR 突变患者从易瑞沙治疗中高度获益Cetuximab 3周内发生皮疹患者从爱必妥治疗中高度获益高度选择人群可从贝伐治疗中获益培美曲赛在腺癌患者中疗效优于吉西他滨*** EGFR 突变患者** 优先选择爱必妥（因为3 周发生皮疹患者中位生存期15 个月），并且安全性好*  贝伐适合患者群EGFR 状态组织学亚型化疗方案单抗NSCLC: 2009 年非小细胞肺癌一线治疗选择NSCLC PS 0-1 非鳞癌鳞癌培美曲赛/顺铂GP 爱必妥**  贝伐单抗*  爱必妥EGFR 突变EGFR-TKIs ***  ？未知或野生PS 2 男性鳞癌或1周2周3周有皮疹无皮疹继续爱必妥联合治疗继续爱必妥联合治疗停爱必妥，保留化疗化疗联合其他靶向药物患者评估1~3 级* * Synovate 2007 * Synovate 2007 * *  *  *  * JMDB AVAiL  FLEX IPASS Design 2- arms1st-line 4-arms1st-line 2-arms1st-line 2-arms1st-line Primary endpoint OS PFS OS PFS Agents PemetrexedGemcitabineCisplatin Bevacizumab GemcitabineCisplatin CetuximabVinorelbineCisplatin  GefitinibCarboplatinPaclitaxel No. of Pts. 1700 1043 1100 1200 Outcome PE: met PE: met PE: met   PE: exceeded EGFR-TKI Bevavizumab Pemetrexed Cetuximab IPASS: Gefitinib vs Carbo /Pac in advanced NSCLC Gefitinib (250 mg / day) Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m2) 3 weekly# 1:1 randomisation * Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years; #limited to a maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progressionPS, performance status; EGFR, epidermal growth factor receptor Patients Chemona ve Age ≥18 years Adenocarcinoma histology Never or light ex-smokers* Life expectancy≥12 weeks PS 0-2 Measurable stage IIIB / IV disease Primary Progression-free survival  (non-inferiority) Secondary Objective response rate Overall survival  Quality of life Disease-related symptoms  Safety and tolerability  Exploratory Biomarkers EGFR mutation EGFR-gene-copy number  EGFR protein expression Endpoints Mok et al ESMO LBA 2, 2008 IPASS: Comparison of PFS by mutation status within treatment arms Hazard ratio <1 implies a lower risk of progression in the M+ group than in the M- groupM+, mutation positive; M-, mutation negative Mok et al ESMO LBA 2, 2008 Gefitinib, HR=0.19, 95% CI 0.13, 0.26, p<0.0001No. events M+ = 97 (73.5%)No. events M- = 88 (96.7%) Carboplatin / paclitaxel , HR=0.78, 95% CI 0.57, 1.06, p=0.1103No. events M+ = 111 (86.0%)No. events M- = 70 (82.4%) 0 4 8 12 16 20 24 Time from randomisation (months) 0.0 0.2 0.4 0.6 0.8 1.0 Probabilityof PFS Gefitinib EGFR M+ (n=132) Gefitinib EGFR M- (n=91) Carboplatin / paclitaxel EGFR M+ (n=129) Carboplatin / paclitaxel EGFR M- (n=85) 结论：EGFR 突变的患者选择EGFR-TKIs 治疗EGFR 状态未知的患者选择化疗JMDB AVAiL  FLEX IPASS Design 2- arms1st-line 4-arms1st-line 2-arms1st-line 2-arms1st-line Primary endpoint OS PFS OS PFS Agents PemetrexedGemcitabineCisplatin Bevacizumab GemcitabineCisplatin CetuximabVinorelbineCisplatin  GefitinibCarboplatinPaclitaxel No. of Pts. 1700 1043 1100 1200 Outcome PE: met PE: met PE: met   PE: exceeded EGFR-TKI EGFR 突变患者从易瑞沙治疗中高度获益Gatzemeier et al. JTO 3, 11, 4, (Abstr. 8), 2008 FLEX : 1st-cycle rash CT + Erbitux  FLEX : 1st-cycle rash CT + ErbituxS econdary endpoints Any grade (n=290) Grade 0 (n=228) RR 44% 28% PFS 5.4 months 4.3 months Gatzemeier et al. JTO 3, 11, 4, (Abstr. 8), 2008 +16% +1.1 月JMDB AVAiL  FLEX IPASS Design 2- arms1st-line 4-arms1st-line 2-arms1st-line 2-arms1st-line Primary endpoint OS PFS OS PFS Agents PemetrexedGemcitabineCisplatin Bevacizumab GemcitabineCisplatin CetuximabVinorelbineCisplatin  GefitinibCarboplatinPaclitaxel No. of Pts. 1700 1043 1100 1200 Outcome PE: met PE: met PE: met   PE: exceeded EGFR-TKI EGFR 突变患者从易瑞沙治疗中高度获益Cetuximab 3周内发生皮疹患者从爱必妥治疗中高度获益Bevacizumab Bevacizumab  AVAiL: Cis /Gem PD PD PD Bevacizumab 15mg/kg + CG Bevacizumab 7.5mg/kg + CG Placebo + CG Previously untreated, stage IIIB, IV or recurrent non-squamous NSCLC RANDOMISE Placebo + CG 2 2 1 1 Previously untreated stage IIIB/IV non-squamous NSCLC CP Avastin (15mg/kg) every 3 weeks + CP  PD PD Avastin every 3 weeks until progression ECOG 4599: Carbo/Taxol NSCLC: Bevacizumab following Standard Triplet CT E4599 AVAiL CP CP+BEV15 GP GP+BEV7.5 GP+BEV15 OS (mos) 10.3 12.3 13.1 13.6 13.4 PFS (mos) (HR) 4.5-- 6.20.66 6.1-- 6.70.68 6.50.74 RR (%) 15 35 20 34 30 71 / 29 69 / 31 58 / 42 50 / 50 男/女％60 32 59 31 无44 无42 中位年龄岁大于65 岁％49 33 46 34 88 0 88 0 组织学亚型％腺癌鳞癌21 60 18 24 60 17 40 60 0 40 60 0 ECOG  ％0  1  2 6 94 6 94 13 74 12 78 疾病分期％湿性IIIB IV 568 557 433 417 病人数VC VC ＋Erbitux PC PC + Bevacizumab 方案FLEX E4599 　注意：P=0.03 E4599 入组病人疾病分期中化疗联合Avastin 组有14 ％为复发病人E4599 排除标准包括：鳞癌、脑转移、咯血咳血、ECOG> ＝1、有出血倾向、常规使用阿司匹林或非甾体类消炎药或其他可能抑制血小板功能药物、21 天前做过放疗、28 天前进行过手术、、明显的心血管疾病、不可控制高血压……10.1 10.3 8.9 11.3 腺癌：12.0 鳞癌：10.2 10.3 12.3 OS 　　15 23 2年生存率％42 47 44 51 1年生存率％0.871 腺癌：0.815 鳞癌：0.794 0.79  HR 0.044 0.003  P 值VC VC ＋E PC PC + Bevacizumab  方案FLEX E4599 　27 VC 17 VC ＋E FLEX E4599 17.8 16.4 Post-study treatment  ％EGFR-TKI PC PC + Bevacizumab  　注意：E4599 入组的人群的基本状况较好，以腺癌为主并且ECOG<=1 ，则两组的OS 和生存率如何直接对比？二线治疗，E4599 中两组用EGFR-TKI 的比例相当；但FLEX 研究中化疗组二线用EGFR-TKI 比例比联合组高10 ％，两组有统计学差异（P<0.05 ），这样会压缩两组间的生存期差异Avastin in ECOG 4599 and AVAiL - Advice for Current Practice - 剂量15 mg/kg ：paclitaxel/carboplatin 7.5mg/kg ：gemcitabine/cisplatin  治疗维持时间Good arguments for treatment until progression 联合的化疗方案Phase III –study regimens Registration label  JMDB AVAiL  FLEX IPASS Design 2- arms1st-line 4-arms1st-line 2-arms1st-line 2-arms1st-line Primary endpoint OS PFS OS PFS Agents PemetrexedGemcitabineCisplatin Bevacizumab GemcitabineCisplatin CetuximabVinorelbineCisplatin  GefitinibCarboplatinPaclitaxel No. of Pts. 1700 1043 1100 1200 Outcome PE: met PE: met PE: met   PE: exceeded EGFR-TKI Bevavizumab EGFR 突变患者从易瑞沙治疗中高度获益Cetuximab 3周内发生皮疹患者从爱必妥治疗中高度获益高度选择人群可从贝伐治疗中获益