转移性结直肠癌治疗的新进展_Mar_2014_

1、转移性结直肠癌化疗的新进展转移性结直肠癌化疗的新进展中山大学肿瘤医院中山大学肿瘤医院 内科内科何友兼何友兼 教授教授n西方国家中，结西方国家中，结 直肠癌占癌症死亡第二位直肠癌占癌症死亡第二位（10%-12%）。）。n发病率每年递增发病率每年递增4.2%。n外科手术五年生存率：外科手术五年生存率：期期90%、期期70%-75%、期期35%-50%、期期 推注nFOLFOX 的疗效大致与 FOLFIRI相当, 但毒性各异n三药方案(FOLFOXIRI)疗效和生存比二药略佳n合用靶向药可提高疗效, 改善生存n用足三药(5FU.L-OHP.IRI)者中位生存可超过2年n维持治疗或间歇休息(treat

2、ment holiday)应个体化处理效力和毒性效力和毒性: FOLFIRI vs FOLFOXTournigand et al. JCO 2004. 22:229-237III 期试验期试验: FOLFOXIRI vs FOLFIRIMosMosSouglakos(n = 283)43.0 vs 33.68.4 vs 6.921.5 vs 19.5 Souglakos J, et al. Br J Cancer. 2006;94:798-805. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676.*Statistically signific

3、ant difference.用足三药用足三药 改善生存改善生存: OS (mos) = 13.2 + (%3drugs x 0.1), R2 = 0.85Grothey & Sargent, JCO 20050 10 20 30 40 50 60 70 80Infusional 5-FU/LV + irinotecanInfusional 5-FU/LV + oxaliplatinBolus 5-FU/LV + irinotecanIrinotecan + oxaliplatinBolus 5-FU/LV LV5FU22221201918171615141312Median OS (

4、mo)Patients with 3 drugs (%)P =.0001First-Line TherapyMultivariate analysis:Effect on OSPFirst-line doublet0.69All 3 drugs0.005 mCRC: 一线治疗的中位生存一线治疗的中位生存06121824Median OS (Mos) 4-6 mos12-14 mos 15-16 mos20.3 mos19-20 mos5-FU/LVFOLFOX4 or CAPEOXIFL + BevacizumabIFL or FOLFIRI21.5 mosFOLFOX6FOLFIRI + B

5、evacizumab24 mos Gallagher DJ, et al. Oncology. 2010;78:237-248.mCRC: 主要的一线化疗效果主要的一线化疗效果比较方案比较方案中位中位 PFS, Mos中位中位 OS, MosIFL vs FOLFOX vs IROX16.9 vs 8.7 vs 6.515.0 vs 19.5 vs 17.4XELOX (CapeOx) vs FOLFOX43,47.3 vs 7.719.0 vs 18.91. Goldberg RM, et al. J Clin Oncol. 2004;22:23-30. 2. Colucci G, et a

6、l. J Clin Oncol. 2005;23:4866-4875. 3. Cassidy J, et al. J Clin Oncol. 2008;26:2006-2012. 4. Cassidy J, et al. Br J Cancer. 2011;105:58-64. 5. Fuchs CS, et al. J Clin Oncol. 2007;25:4779-4786.分子靶药物分子靶药物 (in CRC): 以往临床研究结果以往临床研究结果nCet(Pan), Bev与化疗联合均可增效与化疗联合均可增效.延长生存延长生存,可用可用于各线于各线(一一.二二.三三)的治疗的治疗nCe

7、t(Pan)单药有效单药有效, Bev必须与化疗联合使用必须与化疗联合使用,两个两个单抗合用不增效单抗合用不增效nBev.在一线进展后用仍可获生存效益在一线进展后用仍可获生存效益nCet(Pan)只能用于只能用于K-RAS野生型或野生型或G13d突变的病突变的病人人, Bev.的使用不须测靶的使用不须测靶n首次皮疹程度反映首次皮疹程度反映Cet(Pan)的疗效的疗效,与与K-RAS无关无关nCet(Pan),Bev 用于术后辅助治疗均未证实有效用于术后辅助治疗均未证实有效VEGF 和和 VEGF-受体家族受体家族VEGF regulates angiogenesis via interacti

8、on with receptor tyrosine kinases VEGFR-2/KDR and VEGFR-1/Flt-1VEGFR-1(Flt-1)VEGF-AReceptorisoformsLigandisoformsVEGFR-2(KDR)VEGF-BVEGFR-1sAngiogenesisVEGF-E VEGF-CVEGF-DVEGFR-3(Flt-4)Lymph angiogenesistumor metastasesExtracellularIntracellularVEGF-A 165NRP-1PlGFShinkaruk S, et al. Curr Med Chem Ant

9、i-Canc Agents. 2003;3:95-117. Luttun A, et al. Ann N Y Acad Sci. 2002;979:80-93.mCRC: 一线化疗一线化疗/贝伐单抗贝伐单抗IFL/Bev vs IFL110.6 vs 6.220.3 vs 15.6FOLFOX/Bev vs FOLFIRI/Bev310.3 vs 10.223.7 vs 25.51. Hurwitz H, et al. N Engl J Med. 2004;350:2335-2342. 2. Saltz LB, et al. J Clin Oncol. 2008;26:2013-2019. 3

10、. Bendell JC, et al. Oncologist. 2012;17:1486-1495.1. Bevacizumab package insert. South San Francisco, CA: Genentech; 2011. 2. Nalluri SR, et al. JAMA. 2008;300;2277-2285. 3. Hurwitz H, et al. J Clin Oncol. 2011;29:1757-1764.Adverse EventIncidence With Bev Across Indications,1 %CommentsGrade 3 ATE2.

11、6nRisk of ATE increased in pts 65 yrs of age or older or with ATE historyGI perforations0.3-2.4Wound complications15nDiscontinue 4-8 wks before surgery; resume 6-8 wks postsurgeryPotential for increased VTE risk controversial; increased risk noted in 1 study but not in others.2,3*Predominantly grade

12、 3.May apply more to NSCLC.When surgery conducted during bev therapy.贝伐单抗贝伐单抗 : 相关毒性相关毒性CRYSTAL1FOLFIRI/Cetux vs FOLFIRI9.9 vs 8.423.5 vs 20.0PRIME3-5FOLFOX4/Pmab vs FOLFOX49.6 vs 8.023.8 vs 19.4FOLFOX4/Pmab vs FOLFOX4 (KRAS/NRAS WT)10.1 vs 7.926.0 vs 20.2KRAS WT mCRC: 一线一线EGFR-靶向药靶向药nWorse PFS outc

13、ome with panitumumab + FOLFOX4 in mutant KRAS disease31. Van Cutsem E, et al. J Clin Oncol. 2011;29:2011-2019. 2. Bokemeyer C, et al. Ann Oncol. 2010;22:1535-1546. 3. Douillard JY, et al. J Clin Oncol. 2010;28:4697-4705. 4. Douillard JY, et al. ASCO 2013. Abstract 3620. 5. Douillard JY, et al. N Eng

14、l J Med. 2013;369:1023-1034. 6. Maughan TS, et al. Lancet. 2011;377:2103-2114. mCRC: 个体化治疗应考虑个体化治疗应考虑n病变范围病变范围n治疗目的治疗目的 (姑息姑息 vs 可能可能根治根治)n活动能力活动能力n年龄年龄n合并疾病合并疾病 n以往一年内的辅助治疗以往一年内的辅助治疗n分子标记分子标记n器官器官(肝肾肝肾,造血造血)功能功能n毒性风险毒性风险: 活动性出血活动性出血,蛋蛋白尿白尿,伤口不愈伤口不愈,神经病变神经病变,过敏过敏,n是否方便是否方便n花费花费/资源资源n病人意愿病人意愿NRA .mCR

15、C: 临床处理程序临床处理程序确定治疗目的确定治疗目的选择治疗策略选择治疗策略决定治疗强度决定治疗强度病人是否需要病人是否需要(渇望渇望)积极治疗积极治疗Yes85%No15%KRAS无法检测无法检测野生型野生型突变型突变型5FU/CAPECITABINE+/-Bevacizumab二联化疗二联化疗+Bevacizumab二联二联+Cet二联二联+Bev二联化疗二联化疗+BevacizumabKRAS WT mCRC: 一线一线EGFR vs VEGF单抗单抗nThe primary endpoint of ORR was not significantly different between

16、 treatment arms in the FIRE-3 study (62% vs 58%; P = .183)21. Schwartzberg LS, et al. ASCO GI 2013. Abstract 446. 2. Heinemann V, et al. ASCO 2013. Abstract LBA3506. *Statistically significant difference.PEAK1(N = 285)mFOLFOX6/Pmab vs mFOLFOX6/Bev10.9 vs 10.1NR vs 25.4FIRE-32(N = 592)FOLFIRI/Cetux v

17、s FOLFIRI/Bev10.0 vs 10.328.7 vs 25.0*mCRC: 其它的生物标志物其它的生物标志物nKRAS G13D1 综合有关预测和预后的资料综合有关预测和预后的资料 大型随机研究抗大型随机研究抗EGFR治疗无价值治疗无价值nBRAF2,3 预后结局很差预后结局很差 未见综合未见综合 一线治疗有关预测资料一线治疗有关预测资料nExpanded RAS analysis4,5 10% of KRAS 12/13 野生型肿瘤有其它野生型肿瘤有其它 RAS 突变突变nKRAS exons 3, 4nNRAS exons 2,3,4 抗抗-EGFR 单抗无效单抗无效1. Pe

18、eters M, et al. J Clin Oncol. 2013; 31:759-765. 2. Richman SD, et al. J Clin Oncol. 2009;27:5931-5937. 3. Van Custem E, et al. J Clin Oncol. 2011;29:2011-2019 4. Peeters M, et al. Clin Cancer Res. 2013;19:1902-1912. 5. Douillard JY, et al. N Engl J Med. 2013;369:1023-1034.III期期 80405 试验试验 : 一线化疗一线化疗

19、 Either Cetux or Bev in KRAS-WT mCRCnPrimary endpoint: OSnSecondary endpoints: ORR, PFS, TTF, duration of responsePatients with mCRC and KRAS WT, ECOG PS 0/1(N = 2900)FOLFOX or FOLFIRI + Bevacizumab q2w ClinicalT. NCT00265850.FOLFOX or FOLFIRI + Cetuximab q1wA third arm with CT + bevacizuma

20、b + cetuximab was closed to accrual in September 2009延续治疗策略上的考虑延续治疗策略上的考虑n增加病变得到长时间良好控制病人的数目n大多数新治疗研究到病人病变进展或毒性受限而终止n对病变得到良好控制病人的策略: 继续治疗到病变进展或毒性而终止 维持治疗 治疗停息(Treatment holidays)OPTIMOX : 维持维持 or 间歇休息间歇休息OPTIMOX11 Maintenance therapy(n = 620)FOLFOX 4 until progressionFOLFOX 7FOLFOX 7sLV5FU2OPTIMOX22

21、 Chemotherapy-free interval(n = 202)mFOLFOX 7mFOLFOX 7sLV5FU2mFOLFOX 7mFOLFOX 7Chemotherapy-Free Interval 1. Tournigand C, et al. J Clin Oncol. 2006;24:394-400. 2. Chibaudel B, et al. J Clin Oncol. 2009;27:5727-5733. OPTIMOX : 研究结果研究结果n疾控期疾控期, PFS, or OS 无明显差异无明显差异治疗休息治疗休息 n维持治疗的疾控期维持治疗的疾控期, PFS 明显为

22、好明显为好n但但 OS 无差异无差异 Tournigand C, et al. J Clin Oncol. 2006;24:394-400. Chibaudel B, et al. J Clin Oncol. 2009;27:5727-5733.维持贝伐单抗维持贝伐单抗 : MACRO TrialCapecitabine +Oxaliplatin +Bevacizumabx 6 cycles q3w(n = 241)Bevacizumabuntil progression Capecitabine +Oxaliplatin +Bevacizumabx 6 cycles q3w(n = 239)

23、Capecitabine +Oxaliplatin +Bevacizumabuntil progression Patients with newly diagnosedmCRC and ECOG PS 2 Diaz-Rubio E, et al. Oncologist. 2012;17:15-25.MACRO : OS (ITT)MosXELOX-BevBevPatients at Risk, n 241 239Survival Probability00.250.500.751.00002391913332623303940275460247785211011201813214615159

24、170121931919210208622622738636BevXELOX-Bev Diaz-Rubio E, et al. Oncologist. 2012;17:15-25.HR: 1.05 (95% CI: 0.851-1.295)间歇休息间歇休息 : GISCAD TrialCR, PR, SDPreviously untreated mCRCRANDOM I ZAT I ONFOLFIRI x 2 mos2:1FOLFIRI x 2 mosEVALUATEProgression: Off TrialBreak x 2 mos then FOLFIRI x 2 mosFOLFIRI

25、x 4 mos Labianca R, et al. Ann Oncol. 2011;22:1236-1242.146147757025271091461479510139431013Pts at Risk, nContinuousIntermittentMos0Patients (%)061218Mos100806040200Patients (%)6121824303613012460681929 Labianca R, et al. Ann Oncol. 2011;22:1236-1242.OSPFS100806040200间歇休息间歇休息 : GISCAD TrialContinuou

26、s armIntermittent armEvents145143Totals146147Continuous armIntermittent armEvents145143Totals146147Arm CBevacizumab (n = 243)Arm AFOLFOX4 + Bevacizumab(n = 286)Arm BFOLFOX4(n = 291)Patients with previously treated mCRC; no previous bevacizumab(N = 820)FOLFOX4Oxaliplatin 85 mg/m2 on Day 1 q2w5-FU 400

27、 bolus/600 mg/m2 IV on Days 1 and 2 q2wLV 200 mg/m2 on Days 1 and 2 q2wBevacizumab10 mg/kg on Day 1 q2wGiantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544.Stratified by ECOG performance score 0 vs 1 or 2; previous XRTE3200: 二二线用贝伐单抗线用贝伐单抗 for mCRCAlive, nDead, nMedian, MosTotal, nA: FOLFOX4 + bevac

28、izumab2862543212.9B: FOLFOX42912642710.8C: Bevacizumab2432192410.2Giantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544.E3200: 在以前治疗过的在以前治疗过的 mCRC FOLFOX + Bev 改善改善 OSOS (Mos)Probability00.81.061218243036HR: 0.76A vs B: P = .0018B vs C: P =.95ML18147 (TML): 进展后继续用贝伐单抗进展后继续用贝伐单抗nA randomized

29、, open-label phase III intergroup studyStandard second-line CT (oxaliplatin or irinotecan based) until PD(n = 411)BEV 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or irinotecan-based) until PD(n = 409)Progressive mCRC after BEV + standard first-line CT (either oxaliplatin oririnotecan based)(

30、n = 820)Bennouna J, et al. Lancet Oncol. 2013;14:29-37.Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS ( 9 or 9 mos), time from last BEV dose ( 42 or 42 days),ECOG PS at baseline (0/1 or 2)Primary endpoint: OSML18147 (TML): 改善改善 OS (ITT)OS (%)MosCT (n = 410)BEV + CT (n

31、= 409)1008060402000 6 12 18 24 30 36 42 48Unstratified* HR: 0.81 (95% CI: 0.69-0.94; log-rank P = .0062)Stratified HR: 0.83 (95% CI: 0.71-0.97; log-rank P = .0211)*Primary analysis method. Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS ( 9 mos, 9 mos), time from la

32、st dose of BEV ( 42 days, 42 days), ECOG PS at baseline (0, 1).Bennouna J, et al. Lancet Oncol. 2013;14:29-37.100806040200PFS (%)0 6 12 18 24 30 36 42MosUnstratified* HR: 0.68 (95% CI: 0.59-0.78; log-rank P .0001)Stratified HR: 0.67 (95% CI: 0.58-0.78; log-rank P .0001)一线治疗后继续用血管生成抑制剂一线治疗后继续用血管生成抑制剂

33、 ?(阿帕西普阿帕西普)(阿帕西普阿帕西普)III期期 VELOUR 研究研究: FOLFIRI ziv-Aflibercept 二线治疗二线治疗 mCRCnPrimary endpoint: OSnSecondary endpoints: PFS, ORR, safety, immunogenicitynNo correlativesPatients with mCRC progressing on first-line oxaliplatin-based chemotherapy*(planned N = 1226)FOLFIRI + ziv-Aflibercept 4 mg/kg q2w

34、(n = 612)FOLFIRI + Placebo q2w(n = 614)*30% had previous bevacizumab.Stratified by previous bevacizumab (yes vs no),ECOG PS (0 vs 1 vs 2) Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. ClinicalT. NCT00561470.(阿帕西普阿帕西普)VELOUR 研究研究 : 生存结果生存结果 Van Cutsem E, et al. J Clin Oncol. 2012;30:

35、3499-3506.OS (%)100806040200Mos0369 12 15 18 21 24 27 30 33 36 39Stratified HR: 0.817 (95.34% CI: 0.713-0.937; log-rank P = .0032)Placebo/FOLFIRIMedian: 12.06 mosAflibercept/FOLFIRIMedian: 13.50 mosPFS (%)100806040200Mos036912151821 2427 30Stratified HR: 0.758 (95% CI: 0.661-0.869; log-rank P .0001)

36、Placebo/FOLFIRIMedian: 4.67 mosAflibercept/FOLFIRIMedian: 6.90 mos(阿帕西普阿帕西普)(阿帕西普阿帕西普)VELOUR 研究研究 : 按贝伐单抗分层按贝伐单抗分层OS Tabernero J, et al. Eur J Cancer. 2013;Epub ahead of print.OS (%)100806040200Mos0369 12 15 18 21 24 27 30 33 36 39HR: 0.862 (95.34% CI: 0.673-1.104)Placebo/FOLFIRIMedian: 11.7 mosAfli

37、bercept/FOLFIRIMedian: 12.5 mosPts at Risk, n PlaceboAFL18718617017813815011512181895459373622221313Previous BevacizumabOS (%)100806040200Mos0369 12 15 18 21 24 27 30 33 36 39HR: 0.788 (95.34% CI: 0.699-0.927)Placebo/FOLFIRIMedian: 12.4 mosAflibercept/FOLFIRIMedian: 13.9 mosPts at Risk, n PlaceboAFL

38、4274264033883473482862952052221391579411265823862No Previous Bevacizumab(阿帕西普阿帕西普)(阿帕西普阿帕西普)ziv-Aflibercept (阿帕西普阿帕西普): 毒性毒性Increased Grade 3/4 AEs in Aflibercept Arm, % FOLFIRI + Aflibercept(n = 611)FOLFIRI + Placebo(n = 605)Any83.562.5Diarrhea19.37.8Asthenia16.910.6Stomatitis/ulceration13.75.0Infe

39、ction12.36.9Palmar-plantar erythrodysesthesia2.80.5Neutropenia36.729.5Thrombocytopenia3.31.7 Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.(阿帕西普阿帕西普) mCRC : 二线二线EGFR 单抗治疗单抗治疗EPIC1Irinotecan/Cetux vs Irinotecan4.0 vs 2.6*10.7 vs 10.0SPIRITT3FOLFIRI/Pmab vs FOLFIRI/Bev7.7 vs 9.218.0 vs 21.41. S

40、obrero AF, et al. J Clin Oncol. 2008;26:2311-2319. 2. Peeters M, et al. J Clin Oncol. 2010;28:4706-4713. 3. Hecht JR, et al. ASCO 2013. Abstract 335. *Statistically significant difference.(瑞格非尼瑞格非尼)CORRECT: 所有治疗肠癌方案失效后用所有治疗肠癌方案失效后用Regorafenib(瑞格非尼瑞格非尼)nPrimary endpoint: OSnApproximately 50% of patients with 4 systemic therapies All patients had received bevacizumab