肺癌adjuvant研究 ppt課件

1、Gefitinib (G) versus vinorelbine / cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-small-cell lung cancer (NSCLC) with EGFR activating mutation (ADJUVANT): A randomized, Phase III trial (CTONG 1104),Yi

2、-Long Wu,1 Wen-Zhao Zhong,1 Qun Wang,2 Song-Tao Xu,2 Wei-Min Mao,3 Lin Wu,4 Yi Shen,5 Yong-Yu Liu,6 Chun Chen,7 Ying Cheng,8 Lin Xu,9 Jun Wang,10 Ke Fei,11 Xiao-Fei Li,12 Jian Li,13 Cheng Huang,14 Zhi-Dong Liu,15 Ke-Ne

3、ng Chen,16 Hong-Hong Yan,1 Xue-Ning Yang1,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,June 5,2017,吉非替尼對比長春瑞濱/順鉑（VP）輔助治療II-IIIA（N1-N2）期伴有EGFR活化突變的非小細(xì)胞肺癌（ADJUVANT）：一

4、項隨機，III期研究（CTONG 1104）,研究背景,近20-25%確診NSCLC的患者適合通過外科切除達到治愈的目的1 ；N2期患者的中位DFS為12.2個月，3年DFS為23%2；以順鉑為基礎(chǔ)的輔助化療是II-IIIA期完全切除NSCLC的標(biāo)準(zhǔn)治療方案3；,DFS, disease free survival; N, lymph node; NSCLC, non-small-cell lung cancer; OS, o

5、verall survival,Arriagada R et al. Lancet 2010;375:1267-12772. Andre F et al. J Clin Oncol 2000;18:2981-29893. Burdett S et al. Cochrane Database Syst Rev 2015;CD011430,Abstract 8500 presented by Y-L Wu Guangdong Lung

6、 Cancer Institute，Guangdong General Hospital, China,研究背景,基于9項隨機對照臨床研究，EGFR TKIs是治療EGFR突變陽性進展期NSCLC的標(biāo)準(zhǔn)一線治療方案1；BR19和RADIANT研究中，EGFR TKIs作為可切除NSCLC的輔助治療方案，獲益有限2,3；ADJUVANT (NCT01405079) 研究是首個在完全切除且病理分期為II-IIIA（N1-N2）期的EGF

7、R突變陽性NSCLC患者中，對比吉非替尼與長春瑞濱聯(lián)合順鉑的輔助治療。,1. Ke EE, Wu YL. Trend Pharm Sci 2016; 11:887-9032. Goss GD et al. J Clin Oncol 2013; 31: 3320-33263. Kelly K et al. J Clin Oncol 2015; 33: 4007-4014,EGFR, epidermal growth factor r

8、eceptor; RCT, randomized control trial;TKI, tyrosine kinase inhibitor,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,統(tǒng)計學(xué)參數(shù)設(shè)計考量,現(xiàn)有證據(jù):第7版TNM分期：pN1, N2的中位OS為9-34個月1非T

9、KI輔助治療組的DFS為31個月2復(fù)發(fā)風(fēng)險比為 0.60 (95% CI 0.45, 0.79)3DFS提升基于以下標(biāo)準(zhǔn)判定：DFS提高≥40% (HR=0.6) 采用雙側(cè)檢驗，檢驗效能80%，顯著性界值為0.05對數(shù)秩檢驗需要約220名隨機患者（觀察到≥122個事件）,1. Rusch VW et al. J Thorac Oncol 2007;2:603-612 2. Janjigian YY et al.

10、J Clin Oncol 2009; 27 (15 suppl): abstr 7523 3. Winton T et al. N Engl J Med 2005; 352: 2589-2597,CI, confidence interval; HR, hazard ratio,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong G

11、eneral Hospital, China,,,ADJUVANT 研究設(shè)計,,易瑞沙250 mg/day 治療24個月或直到疾病進展或不可接受的毒性,完全切除且病理分期為II-IIIA (N1-N2)期 NSCLCEGFR活化突變 (exon 19 deletion or exon 21 L858R) ECOG PS 0-1年齡 ≥18 歲 且 <75 歲n=220,,,長春瑞濱 (25 mg/m2 第1、8天) 聯(lián)合

12、 順鉑 (75 mg/m2 第1填) q3w, 最多4個周期,DFS,主要終點:DFS次要終點:3年DFS率, 5年DFS率, OS, 5年OS率, 安全性, HRQoL (FACT-L, LCSS, TOI), 探索性生物標(biāo)志物終點,分層因素：EGFR 突變N分期,療效評估 ：每12周,ECOG PS, Eastern Cooperative Oncology Group Performance Status; DFS，

13、disease-free survival; FACT-L, Functional Assessment of Cancer Therapy – Lung; HRQoL, health-related quality of life; LCSS, Lung Cancer Symptom Scale; OS, overall survival; R, randomization; TOI, Trial Outcome Index,,R

14、1:1,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,CONSORT 流程圖（易瑞沙對比化療）,評估患者合格性(n=483),不合格患者 (n=1; EGFR 假陽性)拒絕治療(n=23),終止治療(n=70) 疾病復(fù)發(fā)(n=56)患者死亡 (n=3)不良事件 (n=1)

15、醫(yī)學(xué)/倫理依從性差(n=10),ITT人群(N=111)安全性人群(N=87),拒絕治療(n=5),終止治療(n=76)疾病復(fù)發(fā)(n=58)患者死亡(n=7)依從性不好(n=11),ITT人群 (N=111)安全性人群(N=106),ITT, intent-to-treat,繼續(xù)治療(n=17),繼續(xù)治療(n=30),分配至VP組(n=111),分配至吉非替尼組(n=111),接受化療 (n=87),接受吉非替尼(n=106

16、),患者隨機分配 (n=222),未隨機化的患者(n=261)不符合納入標(biāo)準(zhǔn) (n=55)EGFR野生型或中心實驗室無法測定EGFR 突變狀態(tài)(n=206),Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,ADJUVANT 研究Site,Presented by:,基線人口統(tǒng)計學(xué)特

17、征 (ITT人群),?Sex was not available for two patients in the gefitinib arm and one patient in the vinorelbine plus cisplatin arm,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital,

18、China,基線人口統(tǒng)計學(xué)特征 (ITT人群),Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,10,藥物暴露,<6,6.1–12,12.1–18,>18.1,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer

19、Institute，Guangdong General Hospital, China,主要終點: DFS (ITT人群),,,,,,,,,,,,,100,80,60,40,20,0,0,12,24,36,48,組吉非替尼（易瑞沙）長春瑞濱+順鉑,N111111,事件6559,中位, 月 (95% CI)28.7 (24.9, 32.5)18.0 (13.6, 22.3),復(fù)發(fā)HR = 0.6095% CI 0.42,

20、 0.87; p=0.005,Disease-free survival (%),時間 (月),8854,5726,105,10,No. 風(fēng)險患者:吉非替尼長春瑞濱+順鉑,111111,,60,0,3年DFS 率34% vs 27%,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital,

21、China,? 10.7 m,,DFS亞組分析 (ITT人群),,,,,,,,0,1,1,.,5,0,.,5,吉非替尼更好,長春瑞濱/順鉑更好,0.60 (0.33, 1.09),0.58 (0.40, 0.83),0.58 (0.37, 0.92),0.61 (0.40, 0.92),0.56 (0.27, 1.19),0.55 (0.33, 0.92),0.62 (0.37, 1.04),0.89 (0.45, 1.76),0.52

22、 (0.34, 0.80),0.58 (0.40, 0.84),0.85 (0.16, 4.46),,,,,,,,,,,,0.003,0.094,0.020,0.018,0.132,0.024,0.071,0.743,0.003,0.004,0.852,222,89,130,167,52,115,106,77,143,207,11,總體,總體cox風(fēng)險比,男,女,吸煙,模型,性別,EGFR 突變狀態(tài),淋巴結(jié),病理,否,是,EGFR e

23、xon19 deletion,EGFR exon21 L858R,N1,N2,腺癌,非腺癌,0.754,0.896,0.701,0.232,0.506,亞組,患者數(shù),DFS,HR(95%CI),P value,P for interaction,,,,,,,,,,,,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General

24、Hospital, China,不良事件 (≥10%，安全性人群),AE, adverse event; ALT, alanine aminotransferase; AST, aspartate transaminase,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdong General Hospital, China,HRQoL,O

25、R, odds ratio,研究期間出現(xiàn)臨床相關(guān)改善的患者比例(%),p=0.025OR 0.48(95% CI 0.25, 0.91),p=0.041OR 0.47(95% CI 0.23, 0.97),p=0.002OR 0.34(95% CI 0.18, 0.67),,,,Abstract 8500 presented by Y-L Wu Guangdong Lung Cancer Institute，Guangdo

26、ng General Hospital, China,結(jié)論,ADJUVANT 達到主要終點:吉非替尼（易瑞沙）療效優(yōu)于VP，具有統(tǒng)計學(xué)意義, 中位DFS: 28.7 vs 18.0個月(HR 0.60, P=0.005) ；3年DFS率: 34% vs 27%；吉非替尼不良事件與既往報道一致；未出現(xiàn)間質(zhì)性肺病；吉非替尼2年的輔助治療時間是合理安全的；OS 數(shù)據(jù)尚不成熟；吉非替尼輔助治療或可成為可切除II-IIIA EGFR突