晚期非小细胞肺癌维持治疗.ppt

1、晚期非小细胞肺癌维持治疗Why？ Who？,中山大学附属肿瘤医院 张力,新的治疗模式,EGFR TKI,chemo +/- 贝伐,EGFR mut +ve,EGFR mut ve or unknown,晚期 NSCLC,SD = stable disease,一线化疗后“等待”的结果（来自随机III期临床研究）： 50%患者在停止治疗后的2个月内疾病进展 到1/3的患者由于各种原因未能接受二线治疗,晚期肺癌治疗的模式,4个周期以后的化疗没有显著增加疗效,增加化疗周期没有显著提高缓解率并改善生存期,维持治疗,下一步,贝伐单抗（如果患者使用化疗贝伐单抗）,观察直到进展,维持治疗,TKI维持治疗,化

2、疗维持治疗,维持治疗Why？,IIIb/IV NSCLC n=562,Off Study n=245,Fidias：多西他赛维持治疗,Randomised,Treated,ORR 29%,Fidias et al, J Clin Oncol 2008,Fidias：多西他赛维持治疗,Fidias,etal.JCO2009,立即多西他赛(n=153),延迟多西他赛(n=156),JMEN：培美曲赛维持治疗,Stage IIIB/IV NSCLC PS 0-1 4 prior cycles of gem, doc, or tax + cis or carb, with CR, PR, or SD

3、Randomisation factors: gender PS stage best tumour response to induction non-platinum induction drug brain mets,2:1 Randomisation,Pemetrexed 500mg/m2 (d1,q21d) + BSC (n=441)*,Primary Endpoint = PFS,Placebo (d1, q21d) + BSC (n=222)*,*B12, folate, and dexamethasone given in both arms,Ciuleanu et al La

4、ncet 2009,Ciuleanu et al Lancet 2009,JMEN：培美曲赛维持治疗,IFCT-GFPC0502研究:试验设计,NSCLC 湿性IIIB期-IV期 PS0-1 18-70岁,主要终点：PFS,顺铂+ 吉西他滨 x4周期(N=834),如PD则出组,CR PR SD,R,观察组 N=155,吉西他滨组 N=154,特罗凯组 N=155,PD,PD,PD,进展后的 二线治疗,维持治疗,培美曲塞,培美曲塞,培美曲塞,N=464,PerolM,etal.ESMO:abstr370PD.,吉西他宾维持治疗:PFS in PS 01,PFS is measured from

5、 time of randomisation into the maintenance phase,M. Prol, et al. et al. 35th Annual Congress of the European Society for Medical Oncology, 812 October 2010, Milan, Italy. Abstract 370PD.,独立评审：特罗凯 vs. 观察组,2:1,Non-PD n=539,Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2, d1 q3d, x4 cycles,Placebo,PD,Pemetr

6、exed 500 mg/m2 d1 q3w,PD,Chemonaive Stage IIIB/IV NSCLC Non-squamous histology ECOG PS 01 (n=939),PARAMOUNT; S124; NCT00789373,First-line maintenance advanced NSCLC Phase III, randomised, double blind, placebo-controlled Primary endpoint PFS,Secondary endpoints OS ORR EQ-5D Resource utilisation Safe

7、ty,Paz-Ares LG et al. J Clin Oncol 2011;29 (suppl):abstract CRA7510.,2011年ASCO最新研究报道PARAMOUNT研究设计,Stratification NSCLC stage PS Response to induction,PARAMOUNT: Investigator Assessed PFS (from Maintenance),SATURN研究设计,Stratification factors: EGFR IHC (positive vs negativevs indeterminate) Stage (IIIB

8、 vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region,Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours Secondary endpoints: OS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC t

9、umours; biomarker analyses; safety; time to symptom progression; quality of life,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,Capuzzo et al Lancet Oncol 2010,特罗凯维持治疗PFS和OS,PFS probability,Ti

10、me (weeks),081624324048566472808896,Time (weeks),081624324048566472808896,HR=0.71 (0.620.82) Log-rank p0.0001,HR=0.81 (0.700.95) Log-rank p=0.0088,1.0 0.8 0.6 0.4 0.2 0,1.0 0.8 0.6 0.4 0.2 0,OS,PFS,Erlotinib (n=437) Placebo (n=447),Erlotinib (n=438) Placebo (n=451),OS probability,Capuzzo et al Lance

11、t Oncol 2010,Zhang L et al. J Clin Oncol 2011;29 (suppl):abstract LBA7511.,INFORM; C-TONG 0804; D7913L00071; NCT00770588,INFORM研究设计,1:1,Non-PD n=296,Platinum-based doublet chemotherapy* q3d, x4 cycles,Placebo,PD,Gefitinib 250md/day,PD,Chemonave Stage IIIB/IV NSCLC WHO PS 02 Chinese patients,First-li

12、ne maintenance advanced NSCLC Phase III, randomised, multicenter, parallel group, placebo-controlled Primary endpoint PFS,Secondary endpoints OS ORR DCR Health-related QoL Safety,*Cisplatin or carboplatin plus either gemcitabine, paclitaxel, docetaxel or vinorelbine,INFORM：PFS (ITT),Zhang L, et al.

13、2011 ASCO Abstract 7511.,化疗x46 Cycle,维持治疗,为什么需要维持治疗,化疗x46 Cycle,观察,维持治疗改善PFS！,化疗x46 Cycle,维持治疗,2/3线治疗,Death,为什么需要维持治疗,化疗x46 Cycle,观察,2/3线治疗,Death,化疗x46 Cycle,维持治疗,2/3线治疗,Death,维持治疗改善PFS，也改善OS？,Fidias,etal.JCO2009,立即多西他赛(n=153),延迟多西他赛(n=156),Fidias：多西他赛维持治疗,JMEN: Overall Survival*, by AD Patients (N=

14、663),Survival Time (months),The planned preliminary analysis assessed OS with a nominal 1-sided alpha level of 0.00001. *Nonsquamous = Any NSCLC histology other than predominantly squamous cell carcinoma,只有19%的对照组病人接受培美曲塞，对照组不公平！,SATURN研究：OS (ITT),Cappuzzo F et al, WCLC 2009.,只有1%的对照组病人接受Tarceva，对照组

15、不公平！,SATURN: EGFR mut+,Significantly improved PFS with erlotinib vs placebo in patients with EGFR mut+ disease,OS data not yet mature (N.B. 67% of patients with EGFR mut+ disease in placebo arm received a second-line EGFR TKI),Time (weeks),08162432404856647280 88 96,PFS probability,HR=0.10 (0.040.25

16、)Log-rank p0.0001,Cappuzzo et al. Lancet Oncol 2010; Brugger, et al. WCLC 2009,0369121518212427303336,1.0 0.8 0.6 0.4 0.2 0,Time (months),HR=0.83 (0.342.02)Log-rank p=0.6810,1.0 0.8 0.6 0.4 0.2 0,PFS,OS,Erlotinib (n=22) Placebo (n=27),Erlotinib (n=22) Placebo (n=27),OS probability,INFORM: OS (ITT),Z

17、hang L, et al. 2011 ASCO Abstract 7511.,化疗x46 Cycle,维持治疗,2/3线治疗,Death,为什么需要维持治疗,化疗x46 Cycle,观察,2/3线治疗,Death,维持治疗改善PFS！,化疗x46 Cycle,维持治疗,2/3线治疗,Death,维持治疗改善PFS，也改善OS？,？,化疗x46 Cycle,维持治疗,2/3线治疗,为什么需要维持治疗,化疗x46 Cycle,观察,2/3线治疗,维持治疗改善 OS ?,4-5线治疗,-线治疗,N线？,LUX-Lung 1: Trial design,29,Randomization 2:1 (D

18、ouble Blind),Oral afatinib 50 mg once daily plus BSC,Oral placebo once daily plus BSC,Primary endpoint: Overall survival (OS) Secondary: PFS, RECIST response, QoL (LC13 central lab) Serum EGFR mutational analysis (all patients),Patients with: Adenocarcinoma of the lung Stage IIIB/IV Progressed after

19、 one or two lines of chemotherapy (incl. one platinum-based regimen) and 12 weeks of treatment with erlotinib or gefitinib ECOG 02 N=585,PFS by independent review,30,Primary analysis: Overall survival,31,OS: Pts with No Subsequent Systemic Therapy,Randomized studies on first line EGFR TKI in patient

20、s with EGFR mutation,Mok et al NEJM 2009, Lee et al WCLC 2009, Mitsudomi et al Lancet Oncology 2010, Maemondo NEJM 2010 Zhou et al ESMO 2010，Rosell et al ASCO 2011,IPASS: 2010 Comparison of post-discontinuation treatments,C / P,Gefitinib20 patientsongoing#,# % exclude the 20 patients in the gefitini

21、b arm with ongoing randomised treatment (3 M+, 1 M-, 16 M unknown) *Patients may have also received other chemotherapy and/or EGFR TKI during the study Radiotherapy, surgery, medical procedures and other treatments excluded; *categories are not mutually exclusive,78%,Mutation + (N=261),Mutation - (N=176),Mutation unknown (N=780),77%,观察,一线EGFR TKIs治疗,2/3线治疗,Death,为什么需要维持治疗,化疗x46 Cycle,观察,2/3线治疗,Death,2/3线治疗,Death,一线EGFR TKIs治疗改善PFS，也改善OS？,观察,一线EGFR TKIs治疗,？,他是谁？,他是谁？,他是谁？,你能分的出来在哪里出现主要要变化吗？,维持治疗Why Not !,维持治疗Who？,JMEN: Overall Survival*, by AD Patients (N=663),Survival Time (months)