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1、替吉奥治疗胃癌的进展,徐建明 军事医学科学院307医院肿瘤中心,试验背景替吉奥胶囊,替吉奥胶囊（S-1），是日本大鹏药品工业株式会社研制的一种口服氟脲嘧啶类衍生物。1999年在日本上市，在日本已取得胃癌、结直肠癌、头颈癌、肺癌、胰腺癌、乳腺癌、胆管癌等7个适应症。2005年，S-1获得SFDA批准进行胃癌、结直肠癌、头颈癌临床试验，其中胃癌临床试验已完成，将于近日获得进口批准。结直肠癌于2006年2007年完成I期临床试验，目前将进一步进行II期探索更佳治疗方案，为III期报批试验做准备。S-1治疗晚期结直肠癌的疗效：1994-2001年，单药一线治疗：ORR 16.7%37.4%，提示S-1
2、单药治疗不亚于奥沙利铂及CPT-11等药（单药疗效7.833.3%）2004-2007年，S-1/LV I/II期临床试验(日本)一线治疗：ORR 57.1%，TTP 203天，疗效良好，值得进一步探索。,S-1是一种口服氟尿嘧啶类衍生物，组成：替加氟(FT;5-FU前体药物)：吉美嘧啶(CDHP)：奥替拉西钾(Oxo)=1：0.4：1口服亚叶酸钙(LV)可增强S-1的抗肿瘤活性。,S-1/LV 的作用机制,随机 III期临床研究比较 S-1 单药、S-1+顺铂治疗晚期胃癌(The SPIRITS trial)SPIRITS:S-1 plus cisplatin vs S-1 in RCT i
3、n the treatment of stomach cancer,H.Narahara1,W.Koizumi2,T.Hara3,A.Takagane4,T.Akiya5,M.Takagi6,K.Miyashita7,T.Nishizaki8,O.Kobayashi9,S-1 Advanced Gastric Cancer(AGC)Clinical Trial Group;,1Osaka Medical Center for Cancer and CV Diseases,Osaka,JAPAN,2Kitasato University East Hospital,Kanagawa,JAPAN,
4、3Kouseiren Takaoka Hospital,Toyama,JAPAN,4Iwate Medical University,Iwate,JAPAN,5Gunma Prefectural Cancer Center,Gunma,JAPAN,6Shizuoka General Hospital,Shizuoka,JAPAN,7National Hospital Organization Nagasaki Medical Center,Nagasaki,JAPAN,8Matsuyama Red Cross Hospital,Ehime,JAPAN,9Kanagawa Cancer Cent
5、er,Kanagawa,JAPAN.,SPIRITS,ASCO 2007:#4514,背景-1,S-1 是:口服的氟嘧啶类药物，在日本已经广泛用于晚期胃癌.两个单独的II期临床研究表明，单药有效率 44-49%，MST 207-250 天 1,2,1:Y Sakata et al.Eur J Cancer 1998;34:1715-1720 2:W Koizumi et al.Oncology 2000;58:191-7,ASCO 2007:#4514,背景-2,JCOG92051),1):A.Ohtsu et al.J Clin Oncol 2003;21:54-59,FP 组比 5FU 组
6、明显更长的 PFS.(P0.001)两组的OS无显著差异,In Japan,recommended regimen for AGC was 5-FU alone,ASCO 2007:#4514,背景-3,JCOG9912,5-FU,S-1,CPT-11+CDDP,Non-inferiority,Boku et al.ASCO2007 abstract#:LBA4513,ASCO 2007:#4514,背景-4,S-1+CDDP Phase I/II Study1),S-1 40-60mg BID for 3wks,Day 1,Day 8,Day 15,Day 22,Day 29,Day 36,
7、CDDP 60mg/m2 on Day 8,S-1,1:W Koizumi et al.Br J Cancer 2003;89:2207-2212,S-1 给药剂量是依据患者的体表面积(BSA)BSA 1.25:40 mg BID 1.25-1.50:50 mg BID 1.50-BSA:60 mg BID,ASCO 2007:#4514,研究设计,AGCNo priorChemo.,R,S-1 aloneS-1:40-60 mg BID for 28 days q6wks,S-1+CDDPS-1:40-60 mg BID for 21 days q5wksCDDP:60 mg/m2 iv o
8、n day 8,Central Randomization(dynamic balancing)Adjustment Factors:Institute PS Unresectable vs Recurrent,ASCO 2007:#4514,研究终点,Primary Endpoint Overall Survival Estimated OS(S-1/S-1+CDDP):8/12 months N=142 in each arm for 90%power to establish superiority in OS(Two-sided log-rank a=0.05).Follow up:2
9、 years Secondary Endpoints Progression Free Survival Time to Treatment Failure Overall Response Safety,142 pts in each arm,ASCO 2007:#4514,入组标准,组织学证实的胃腺癌(unresectable/recurrent gastric cancer)以前没有化疗 PS(ECOG scale)0-2 Age 20-74 预期生存 3 months Adequate organ function(bone marrow,liver,renal function)知情
10、同意,ASCO 2007:#4514,患者一般状况-1,Randomized:305 pts(S-1/S-1+CDDP:152/153)between Mar/2002 and Nov/2004 FAS:298 pts(S-1/S-1+CDDP:150/148),ASCO 2007:#4514,患者一般状况-2,ASCO 2007:#4514,Months,Estimated probability(%),11.0,13.0,总生存期,Log-rank p-value:0.0366HR:0.774 95%CI:0.608 0.985Median follow-up time(M):34.6,A
11、SCO 2007:#4514,无进展生存期,Log-rank p-value:0.0001HR:0.567 95%CI:0.437 0.734,Estimated probability(%),Months,6.0,4.0,ASCO 2007:#4514,到治疗失败的时间,Log-rank p-value:0.0089HR:0.699 95%CI:0.536 0.912,Estimated probability(%),Months,4.8,3.9,ASCO 2007:#4514,疗 效,Criteria:RECIST(Extramural Review),Fishers Exact Test
12、 p-value:0.0018,ASCO 2007:#4514,药物的副作用-1,Criteria:NCI-CTC ver.2.0,ASCO 2007:#4514,药物的副作用-2,No treatment-related death was observed,Criteria:NCI-CTC ver.2.0,ASCO 2007:#4514,AGC的III期临床研究,*TTP,3)Proc ASCO 2006;Vol 24,No.18S:LBA4018,1)J Clin Oncol 2006;24:4991 49972)Proc ASCO 2006;Vol 24,No.18S:LBA4017,
13、ASCO 2007:#4514,结 论,S-1+CDDP 的生存期长于 S-1 单药 S-1 中位生存 11.0 M,S-1+CDDP 13.0 M S-1+CDDP 耐受性好，无治疗相关的死亡 S-1+CDDP 方案可以当作 AGC 的一线治疗方案,ASCO 2007:#4514,N.Boku,S.Yamamoto,K.Shirao,T.Doi,A.Sawaki,W.Koizumi,H.Saito,K.Yamaguchi,A.Kimura,A.Ohtsu Gastrointestinal Oncology Study Groupof Japan Clinical Oncology Group
14、,5-FU 单药、CPT-11 顺铂(CP)、S-1 单药治疗晚期GC的随机 III期临床研究(JCOG9912),背 景,晚期胃癌无标准化疗方案.III期临床研究(JCOG9205)并未证明，5-FU+CDDP 比 5-FU 单药延长生存.II 期研究表明 S-1单药 和 CPT-11+CDDP 疗效好、毒性反应可以接受.(Sakata,Eur J Cancer 1998;Koizumi,Oncology 2000;Boku,J Clin Oncol 1999),(Ohtsu,J Clin Oncol 2003),Primary endpoint：总生存Secondary endpoints
15、：到治疗失败的时间(TTF)Non-hospitalized survival(NHS)Adverse Events(NCI-CTC ver.2)Response rate(RECIST,central review),与 5-FU 持续静滴(5-FUci)比较 CPT-11+CDDP的优效性 S-1的非劣效性,研究目的,Inclusion Criteria,1)组织学证实的不能手术切除的或复发的胃腺癌 2)能口服药物 3)Age:20,75 4)PS(ECOG)：0,1,2 5)主要脏器功能正常 6)未接受过放化疗 except adjuvant chemotherapy completed
16、 6 months before 7)不一定要有可测量的病灶 8)无严重的腹膜播散 9)Written informed consent,S-1 40 mg/m2,po,bid,days 1-28q 6 weeks,Stratified by(minimization)Institution PS 0/1/2 Unresectable/Recurrence with adjuvant Cx/Recurrence without adjuvant Cx,5-FUci,CPT-11+CDDP,S-1,Randomization,800 mg/m2/day,ci,days 1-5q 4 weeks,
17、CPT-11 70 mg/m2,div,days 1&15CDDP 80 mg/m2,div,day 1q 4 weeks,III 期研究(JCOG9912),Continued until disease progression,unacceptable toxicities,patients refusal,BSA 1.25 80 mg/body/day 1.25 BSA 1.5 100 mg/body/day 1.5 BSA 120 mg/body/day,患者一般状况,Adjuvant Cx-/+,Unresectable/Recurrent,0/1/2,PS,M/F,Gender,m
18、edian(range),Age,No.of patients,233/1,188/46,151/80/3,175/59,64(39-75),234*,S-1,235/1,190/46,151/81/4,180/56,63(32-75),236,CPT-11+CDDP,233/1,189/45,152/79/3,176/58,63(24-75),234,5-FUci,*One patient was ineligible;adenosquamous cell carcinoma.,患者肿瘤情况,Target lesion-/+,intestinal/diffuse,Histological t
19、ype*,0/1,2/3,4,5,Macroscopic type*,No.of patients,Peritoneal metastasis,165/69,59/175,110/124*,5/68/161,234,S-1,102/101/31,55/181,102/134,5/73/155,236,CPT-11+CDDP,160/76,100/105/31,59/175,111/121,5/63/164,234,5-FUci,147/87,103/90/41,No.of metastatic sites,0,1/2/3,-/+,*Japanese Classification of Gast
20、ric Carcinoma*Lauren classification,no data available in 2 pts*1 pt with adenosquamous type included,No.of patients,6个月内 Gr.3 AE(1),5.6,3.8,3.9,0.9,41.5,0,5.6,65.0,1.3,12.8,39.3,15.5,1.3,4.7,0.4,0.4,7.7,0,0,9.4,0,S-1,CPT-11+CDDP,5-FUci,234,236,234,Treatment related death*,0.4,1.3,0,Leukocytes,Neutro
21、phils,Hemoglobin,Platelets,Infection without neutropenia,Infection with Gr.3 or 4 neutropenia,Febrile neutropenia,*Judged by Data and Safety Monitoring Committee,1.7,0,3.0,Stomatitis,5.6,20.5,6.9,Nausea,7.7,9.0,0.4,Diarrhea,12.4,32.9,12.5,Anorexia,5.1,10.3,1.7,Fatigue,4.7,2.6,4.7,AST,3.4,2.6,3.4,ALT
22、,4.3,1.3,3.0,Bilirubin,0.9,2.1,0,Creatinine,5.2,22.6,6.5,Hyponatremia,6个月内 Gr.3 AE(2),No.of patients,S-1,CPT-11+CDDP,5-FUci,234,236,234,PFS和有效率,Response rate-in pts with target lesion-,CR and PR were confirmedby central review,0.001,0.59-0.85,0.71,4.0M,234,S-1,0.014,-,P-value,0.67-0.98,-,95%C.I.,-,2
23、.3M,234,5-FUci,0.81,3.7M,236,CPT-11+CDDP,HR,Median,n,:one-sided log-rank test(superiority),到治疗失败的时间,治疗失败的原因,Other,Death,Refusal not related to toxicity,Refusal related to toxicity,Toxicities,Disease progression,Continuing at final analysis,No.of patients,2,1,0,8,14,203,6,S-1,234,9,1,8,39,36,143,0,CP
24、T-11+CDDP,236,6,1,9,9,9,199,1,5-FUci,234,Overall Survival,P-value,0.034,0.055,-,0.68-1.01,0.70-1.04,-,95%C.I.,-,44.0%,10.8M,234,5-FUci,0.83,47.9%,11.4M,234,S-1,0.85,52.5%,12.3M,236,CPT-11+CDDP,HR,1-yr,MST,n,:one-sided log-rank test(superiority),non-inferiority 0.001,:multiplicity adjusted by Holms m
25、ethod,Significancelevel,0.05,0.025,0.025,0.003,0.62-0.92,0.76,9.2M,234,S-1,0.027,-,0.68-1.00,-,95%C.I.,-,7.2M,234,5-FUci,0.82,9.5M,236,CPT-11+CDDP,HR,Median,n,P-value,:one-sided log-rank test(superiority),Non-hospitalized Survival,=overall survival time hospitalized days,*type unknown were excluded
26、from the analysis,生存期的亚组分析-Hazard Ratio to 5-FUci and 95%Confidence Interval-,Hazard ratio,Age 65(n=372),65(n=332),PS 0(n=454),1,2(n=250),Unresectable(n=567),Recurrent(n=137),Intestinal(n=323)*,Diffuse(n=379),(-)(n=173),Target lesion(+)(n=531),No.of met sites 0,1(n=305),2(n=399),Peritoneal mets(-)(n
27、=472),(+)(n=232),All randomized(n=704),CPT-11+CDDP,S-1,生存期的亚组分析,P-value,S-1,5-FUci,12,24,36(months),0,50,(%)100,0.070,175,0.015,-,175,181,n,P-value,10.5M,9.0M,12.1M,MST,3.8M,2.2M,4.8M,PFS,-Target Lesion(+)-,-Target Lesion(-)-,0.18,18.1M,59,0.54,-,13.5M,59,14.4M,55,MST,n,:one-sided log-rank test(supe
28、riority),S-1,5-FUci,CPT-11+CDDP,CPT-11+CDDP,0,50,(%)100,12,24,36(months),结 论,S-1 的生存期明显不劣于 5-FUci，毒性较低 RR,TTF,NHS and PFS 更好 各个亚组的生存期都比5-FUci 组长 CPT-11+CDDP 生存期并不优于 5-FUci，且毒性大导致更多 的治疗失败 但 RR,TTF,NHS and PFS 更好 在TL(+)亚组的生存比 5-FUci 长 在TL(-)和腹膜转移(+)者的生存更短 S-1 should be considered for the standard chem
29、otherapy of unresectable or recurrent gastric cancer.,S-1单药、S-1/CDDP(SP)、5-FU/CDDP(FP)治疗晚期胃癌(AGC)的随机 III 期临床试验(SC-101 study),Maolin Jin1,Youjian He2June 3rd,2008 1-Beijing Cancer Hospital;2-Sun Yet-Sen University Cancer CenterASCO 2008,Chicago,Abstract No.#4533;Poster No.#21,背 景,40%初次诊断的胃癌患者是晚期,4060
30、 术后复发.AGC 无标准治疗方案.S-1治疗 GC有效.无论是单药还是 SP 在日本广泛用于AGC 治疗*.S-1 在中国无经验,中国是GC发病率最高的国家之一.,*:S-1 is manufactured and supplied by Taiho Pharmaceutical Co.,Ltd.Tokyo,Japan,研究目标,Primary endpoint:Response Rate(RR)#1Secondary endpoint:Time to Treatment Failure(TTF)Overall Survival(OS)Toxicity/safety#2,#1:RECIST
31、guideline,used IRC evaluation results.#2:NCCN CTCAE version 3.0,研究设计,不可切除的晚期或转移性 GC,Central randomization(dynamic balance)Stratification：Performance Status;Number of metastatic sites;Gastrectomy,S-1,5-FU/CDDP,S-1/CDDP,60 patients,60 patients,60 patients,If failed,can switch to S-1,治疗方案,Arm A(S-1):S-
32、1,42 days/cycle,S-1 40 mg/m2,Bid,oral,Rest 14 days,d1d28(4 weeks),d29d42(2 weeks),Arm B(SP):S-1+CDDP,35 days/cycle,S-1 40 mg/m2,Bid,oral,Rest 14 days,d1d21(3 weeks),d22d35(2 weeks),CDDP,60mg/m2,d8,infusion3hrs,Arm C(FP):5-FU+CDDP,28 days/cycle(4 weeks),5-FU+CDDP,Rest 23 days,d1d5,d6d28,CDDP,20mg/m2,
33、infusion0.5hr5-FU,600mg/m2,infusion24hrs,入组标准,组织学证实的胃腺癌不可切除,晚期或转移性病灶对转移灶既往未放化疗.辅助和/或新辅助结束6个月以上者可以入选Age 18 or aboveECOG performance status 0 to 2Adequate hematological,renal and liver function,患者分配,230 pts randomized(Jul.2005Oct.2006),S-1 n=80,SP n=76,FP n=74,FAS n=77,FAS n=74,FAS n=73,Without target
34、 lesion,n=1Inclusion criteria violationn=1,Without target lesionn=1,Without target lesionn=3,一般状况（FAS=224）,There is no significant difference between the three arms in FAS.,RR 比较(FAS),Remarks：a)CMH-test,adjusted by stractifications,two-sides significance level=2.5%.b)Difference compared with S-1/CDD
35、P arm.c)Odds Ratio:FP vs.SP=0.387(95%CI0.1770.847,p=0.0176);d)Odds Ratio:S-1 vs.SP=0.597(95%CI0.284-1.256,p=0.1741).,S-1 second-line treatment,41 of 73 pts switched to S-1 monotherapy after failed in FP,OS,*Until January 15,2007,224 patients were followed up,94 died(42%),115 alive,15 lost follow-up.
36、*:Logrank test,*FPs survival include 41 pts contribution who switched to S-1,Hazard:S-1 vs.SP=2.262(95%CI1.327-3.856)FP vs.SP=1.908(95%CI1.089-3.341),TTF,Hazard:S-1 vs.SP=1.709(95%CI1.145-2.552)FP vs.SP=2.673(95%CI1.755-4.071),*:Logrank test.,药物主要的副作用,小 结,从 2005.7月 2006.10月，80 pts in S-1,76 pts in S
37、P and 74 pts in FP 入组.三组患者的一般状况无显著差异.独立评估委员会评估的结果,RR 24.7%in S-1,37.8%in SP and 19.2%in FP.SP 有效率优于FP(CMH p=0.021).FP 组41例患者交替到 S-1组 后的RR 14.6%,说明 S-1 2nd-line 治疗有效.SP 组的生存明显长于FP 组(Log-rank p=0.038)和 S-1组(Log-rank p0.001).S-1/SP/FP 最常见的 3/4 毒性反应(%):贫血,2.5/5.3/5.4;白细胞下降,1.3/13.2/9.5;中性粒减少,3.8/17.1/16
38、.2;PLT 减少,0/6.6/12.2;恶心,0/2.6/5.4;呕吐,1.3/6.6/12.2;腹泻,3.8/6.6/0.S-1 和 SP 组均能很好耐受.,结 论,S-1 和 SP 均有效、耐受性好.SP 有可能成为晚期中国胃癌患者的标准治疗方案.,Primary endpoint:Superiority in OSN=1000 non-Asian AGC for 1st line palliative chemotherapy,FLAGS Trial:S-1+CDDP vs 5-FU+CDDP,5-FU 1,000 mg/m2/d CIV D1-5Cisplatin 100 mg/m2
39、 iv D1,every 4 weeks,S-1 25 mg/m2 po bid D1-21Cisplatin 75 mg/m2 iv D1,every 4 weeks,R,Ajani,et al.ASCO GI 2009,FLAGS:OS,Ajani,et al.ASCO GI 2009,%存活率,1009080706050403020100,随机后时间（月）,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,Log-rank Test:p=0.1983相对危险度:0.92(95%CI:0.80,1.05)中位总生存时间:CS:8.6 mont
40、hsCF:7.9 monthsCS（顺铂/S1）CF（顺铂/5-Fu）,N at riskS-1:5-FU:,521,479,402,341,276,212,172,124,90,69,48,36,24,14,6,4,0,0,508,452,385,326,250,199,156,116,79,56,35,26,19,12,8,3,1,0,FLAGS:PFS,Ajani,et al.ASCO GI 2009,%无进展生存率,1009080706050403020100,Log-rank Test:p=0.9158相对危险度:0.99(95%CI:0.86,1.14)CS:4.8 monthsC
41、F:5.5 monthsCS（顺铂/S1）CF（顺铂/5-Fu）,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,521,365,237,152,91,41,24,17,12,9,8,5,1,0,508,335,235,149,75,36,22,16,11,6,4,N at riskS-1:5-FU:,随机后时间（月）,FLAGS:3/4 度血液学毒性,Ajani,et al.ASCO GI 2009,患者比例(%),706050403020100,贫血,中性粒细胞减少,血小板减少,白细胞减少,中性粒细胞减少性发热*,*,*,*,*,CSCF,*P0.01,FL
42、AGS:肝肾相关毒性,Ajani,et al.ASCO GI 2009,患者比例(%),50454035302520151050,肌酐 1.5 x ULN,肌酐清除率 50 mL/min,肾相关不良事件(所有分级),肾损害,胆红素1.5 x ULN,肝相关不良事件(所有分级),肝功能损害,肾毒性,肝毒性,*,*,*,*,*,CSCF,*P0.05*P0.01,*,FLAGS:结论,与顺铂/5-Fu相比，顺铂/S1并不提高OS次要终点指标：有效性：顺铂/S1与顺铂/5-Fu 无差异顺铂/S1 在安全性上比顺铂/5-Fu更好.然而，顺铂/S1 方案中顺铂剂量是顺铂/5-Fu方案 的75%，且S-1
43、 剂量也低于日本研究的剂量,Ajani,et al.ASCO GI 2009,Sakuramoto et al.N Engl J Med 2007;357:1810-20,研究目标,探讨II/III 胃癌D2 术后，S-1 单药辅助治疗的有效性Primary endpointOverall survivalSecondary endpointsRelapse-free survivalSafety of S-1,Sakuramoto et al.N Engl J Med 2007;357:1810-20,入组标准,组织学证实的胃癌D2 术后 术后分期II/III(Japanese classi
44、fication)R0 resection(curability A or B)Negative peritoneal cytologyAge 20-80 years既往未做辅助治疗Adequate organ functionWritten informed consent,Sakuramoto et al.N Engl J Med 2007;357:1810-20,研究设计,Curative gastrectomy(D2),Central Randomization(dynamic balancing)Adjustment factors:stage*(II,IIIA,IIIB),Inst
45、itution,within 6 weeks after surgery,S-1 80-120 mg/day*4 wks administration with 2wks off in each course for 12 months,Surgery alone(No further therapy),*Japanese Classification of Gastric Carcinoma,13th ed,1999,*Body surface area(m2)=1.5120mg/day,Sakuramoto et al.N Engl J Med 2007;357:1810-20,统计学考虑
46、,5-year OS for surgery alone=70%Improvement by S-1 at a hazard ratio of 0.7(5y OS:77.9%)Follow up:5 yearsTwo-sided=0.05,statistical power=80%485 patients in each group*Calculated by the method of Freedman,Two interim analyses1 and 3 years after completion of the enrollmentAlpha spending function:OBr
47、ien&Fleming type,Sakuramoto et al.N Engl J Med 2007;357:1810-20,Accrual,Opened:October 2001Closed:December 2004Randomized:1059 pts(S-1:529,Surgery alone:530)Eligible:1034 pts(S-1:515,Surgery alone:519)Institutions:109 Japanese institutions,Sakuramoto et al.N Engl J Med 2007;357:1810-20,一般状况(1),Sakur
48、amoto et al.N Engl J Med 2007;357:1810-20,一般状况(2),Sakuramoto et al.N Engl J Med 2007;357:1810-20,一般状况(3),Sakuramoto et al.N Engl J Med 2007;357:1810-20,一般状况(4),Sakuramoto et al.N Engl J Med 2007;357:1810-20,依从性:S-1,Reasons for discontinuation by 12 monthsPatients withdrawal(adverse events etc.)71 pt
49、sDoctors decision(adverse events or complications)72 ptsRelapse or second cancer27 pts,Sakuramoto et al.N Engl J Med 2007;357:1810-20,不良事件(1),Sakuramoto et al.N Engl J Med 2007;357:1810-20,不良事件(2),Sakuramoto et al.N Engl J Med 2007;357:1810-20,第一次中期分析,First interim analysis was carried out on June 2
50、006,using the follow-up data of December 2005(Median follow-up:2.0 yrs)OBrien-Fleming stopping boundary:p=0.0011Overall survivalAll randomized:p=0.0016Eligible:p=0.0008Relapse-free survival:p=0.0002Predictive power(OS):99.3%,Sakuramoto et al.N Engl J Med 2007;357:1810-20,DSMC 推荐,On June 20th,2006,af
