转移性结直肠癌治疗的新进展mar2014课件

转移性结直肠癌化疗的新进展 中山大学肿瘤医院 内科 何友兼 教授 结 直 肠 癌 n西方国家中，结 直肠癌占癌症死亡第二位（ 10%-12%）。 n发病率每年递增4.2%。 n外科手术五年生存率：期90%、期70%- 75%、期35%-50%、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(treatment holiday)应个 体化处理 效力和毒性: FOLFIRI vs FOLFOX Efficacy/Toxicity5FU/LV Irinotecan Oxaliplatin RR(first line) 56% 54% OS(mo) 21.5 20.4 G3/4 neutropenia 24% 44% G3/4 febrile neutr. 7% 0% G3/4 mucositis 10% 1% G2/3 neurological 0% 71% G3/4 diarrhea 14% 11% Tournigand et al. JCO 2004. 22:229-237 III 期试验: FOLFOXIRI vs FOLFIRI 作者RR, %Median TTP/PFS, Mos Median OS, Mos Souglako s (n = 283) 43.0 vs 33.6 8.4 vs 6.921.5 vs 19.5 Falcone (n = 244) 60 vs 34*9.8 vs 6.9*22.6 vs 16.7* Souglakos J, et al. Br J Cancer. 2006;94:798-805. Falcone A, et al. J Clin Oncol. 2007;25:1670-1676. *Statistically significant difference. 用足三药.改善生存: Update 2005 11 Phase III Trials, 5768 Patients OS (mos) = 13.2 + (%3drugs x 0.1), R2 = 0.85 Grothey 78:237-248. mCRC: 主要的一线化疗效果 比较较方案中位 PFS, Mos 中位 OS, Mos IFL vs FOLFOX vs IROX16.9 vs 8.7 vs 6.5 15.0 vs 19.5 vs 17.4 FOLFIRI vs FOLFOX427.0 vs 7.014.0 vs 15.0 XELOX (CapeOx) vs FOLFOX43,4 7.3 vs 7.719.0 vs 18.9 FOLFIRI vs mIFL vs CapeIRI57.6 vs 5.9 vs 5.8 23.1 vs 17.6 vs 18.9 1. Goldberg RM, et al. J Clin Oncol. 2004;22:23-30. 2. Colucci G, et al. 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. mCRC : 分子靶点药 分子靶点药药结结构靶点临临床应应用 Cetuximab单单抗EGFR 化疗疗抗药药二线线表达EGFR后用 化疗疗20%.三线单药线单药 10%， 皮疹腹泻 (Erbitux,C225) (erbB-1) Panitumumab全人单单抗EGFRCet.无效时时可用,同上 Bevacizumab 单单抗VEGF-A一线线合用化疗疗，疗疗效提高 10%，生存延长长5个月 (Avastin) 分子靶药物 (in CRC): 以往临床研究结果 nCet(Pan), Bev与化疗联合均可增效.延长生存,可 用于各线(一.二.三)的治疗 nCet(Pan)单药有效, Bev必须与化疗联合使用,两个 单抗合用不增效 nBev.在一线进展后用仍可获生存效益 nCet(Pan)只能用于K-RAS野生型或G13d突变的 病人, Bev.的使用不须测靶 n首次皮疹程度反映Cet(Pan)的疗效,与K-RAS无关 nCet(Pan),Bev 用于术后辅助治疗均未证实有效 VEGF 和 VEGF-受体家族 VEGF regulates angiogenesis via interaction with receptor tyrosine kinases VEGFR-2/KDR and VEGFR-1/Flt-1 VEGFR-1 (Flt-1) VEGF-A Receptor isoforms Ligand isoforms VEGFR-2 (KDR) VEGF-B VEGFR-1s Angiogenesis VEGF-E VEGF-CVEGF-D VEGFR-3 (Flt-4) Lymph angiogenesis tumor metastases Extracellular Intracellular VEGF-A 165 NRP-1 PlGF Shinkaruk S, et al. Curr Med Chem Anti-Canc Agents. 2003;3:95-117. Luttun A, et al. Ann N Y Acad Sci. 2002;979:80-93. mCRC: 一线化疗/贝伐单抗 Comparative Regimens, Mos PFSOS IFL/Bev vs IFL110.6 vs 6.220.3 vs 15.6 FOLFOX4/XELOX/Bev vs FOLFOX4/XELOX2 9.4 vs 8.021.3 vs 19.9 FOLFOX/Bev vs FOLFIRI/Bev3 10.3 vs 10.223.7 vs 25.5 1. 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. 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 % Comments Grade 3 ATE 2.6 Risk of ATE increased in pts 65 yrs of age or older or with ATE history Grade 3/4 HTN 5-18* Patients should receive otherwise standard CV prophylaxis and have BP monitored and managed GI perforations 0.3-2.4 Grade 3 hemorrhagic event 1.2-4.6 Bev not recommended for pts with serious hemorrhage or recent hemoptysis Risk of major bleeding does not appear to be increased in pts receiving full-dose anticoagulation tx without other risk factors Wound complications 15 Discontinue 4-8 wks before surgery; resume 6-8 wks postsurgery Potential for increased VTE risk controversial; increased risk noted in 1 study but not in others.2,3 *Predominantly grade 3. May apply more to NSCLC. When surgery conducted during bev therapy. 贝伐单抗 : 相关毒性 TrialComparative RegimensMedian PFS, MosMedian OS, Mos CRYSTAL1FOLFIRI/Cetux vs FOLFIRI9.9 vs 8.423.5 vs 20.0 OPUS2FOLFOX4/Cetux vs FOLFOX48.3 vs 7.222.8 vs 18.5 PRIME3-5FOLFOX4/Pmab vs FOLFOX49.6 vs 8.023.8 vs 19.4 FOLFOX4/Pmab vs FOLFOX4 (KRAS/NRAS WT) 10.1 vs 7.926.0 vs 20.2 COIN6 FOLFOX/XELOX/Cetux vs FOLFOX/XELOX 8.6 vs 8.617.0 vs 17.9 KRAS WT mCRC: 一线EGFR-靶向药 nWorse PFS outcome with panitumumab + FOLFOX4 in mutant KRAS disease3 1. 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 Engl 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 n病变范围 n治疗目的 (姑息 vs 可能 根治) n活动能力 n年龄 n合并疾病 n以往一年内的辅助治疗 n分子标记 n器官(肝肾,造血)功能 n毒性风险: 活动性出血,蛋 白尿,伤口不愈,神经病变, 过敏, n是否方便 n花费/资源 n病人意愿 mCRC : 化疗有关的选择 可能切除不能切除 治疗疗目的 争取治愈,延长生 存 延长生存,改善 QoL 方案选择选择 二联、三联 二联、单药 序贯贯/联联合 联合 联合，也可序贯 加入靶向药药 有条件尽早加入 必要时后续加入 维维持与否 维持 CFI或间断 mCRC：化疗选择临床依据 u 无病间歇（DFI) , 缓解期 u PS（01，2） u 年龄（70，70） u 肿瘤分子生物学标记 ( TS.DDP.UGT.KRAS.NRAS.BRAF) u 化疗目的(新辅助, 辅助) u 患者取舍 mCRC: 临床处理程序 确定治疗目的选择治疗策略决定治疗强度 病人是否需要(渇望)积极治疗 Yes85% No15% KRAS 无法检测野生型突变型 5FU/CAPECITABINE +/-Bevacizumab 二联化疗 +Bevacizumab 二联+Cet 二联+Bev 二联化疗 +Bevacizumab KRAS WT mCRC: 一线EGFR vs VEGF单抗 nThe primary endpoint of ORR was not significantly different between treatment arms in the FIRE-3 study (62% vs 58%; P = .183)2 1. Schwartzberg LS, et al. ASCO GI 2013. Abstract 446. 2. Heinemann V, et al. ASCO 2013. Abstract LBA3506. *Statistically significant difference. TrialComparative Regimens PFS, Mos OS, Mos PEAK1 (N = 285) mFOLFOX6/Pmab vs mFOLFOX6/Bev 10.9 vs 10.1 NR vs 25.4 FIRE-32 (N = 592) FOLFIRI/Cetux vs FOLFIRI/Bev 10.0 vs 10.3 28.7 vs 25.0* mCRC: 其它的生物标志物 nKRAS G13D1 综合有关预测和预后的资料 大型随机研究抗EGFR治疗无价值 nBRAF2,3 预后结局很差 未见综合 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 RAS 突变 nKRAS exons 3, 4 nNRAS exons 2,3,4 抗-EGFR 单抗无效 1. Peeters 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 80405 试验 : 一线化疗 Either Cetux or Bev in KRAS-WT mCRC nPrimary endpoint: OS nSecondary endpoints: ORR, PFS, TTF, duration of response Patients with mCRC and KRAS WT, ECOG PS 0/1 (N = 2900) FOLFOX or FOLFIRI + Bevacizumab q2w ClinicalT. NCT00265850. FOLFOX or FOLFIRI + Cetuximab q1w A third arm with CT + bevacizumab + cetuximab was closed to accrual in September 2009 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 or 间歇休息 OPTIMOX11 Maintenance therapy (n = 620) FOLFOX 4 until progression FOLFOX 7FOLFOX 7 sLV5FU2 OPTIMOX22 Chemotherapy-free interval (n = 202) mFOLFOX 7mFOLFOX 7 sLV5FU2 mFOLFOX 7mFOLFOX 7 Chemotherapy-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 nOPTIMOX1 (维持 vs 继续治疗) n疾控期, PFS, or OS 无明显差异 nOPTIMOX2 (治疗休息 vs 维持治疗) n维持治疗的疾控期, PFS 明显为好 n但 OS 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 : MACRO Trial Capecitabine + Oxaliplatin + Bevacizumab x 6 cycles q3w (n = 241) Bevacizumab until progression Capecitabine + Oxaliplatin + Bevacizumab x 6 cycles q3w (n = 239) Capecitabine + Oxaliplatin + Bevacizumab until progression Patients with newly diagnosed mCRC and ECOG PS 2 Diaz-Rubio E, et al. Oncologist. 2012;17:15-25. MACRO : OS (ITT) XELOX- BevBev Patients, n239241 Events, n (%)175 (73)174 (7%) Censored, n (%) 64 (27)67 (28) Median (95% CI) 23.2 (19.79,- 26.01) 19.99 (17.98- 23.25) Mos XELOX-Bev Bev Patients at Risk, n 241 239 Survival Probability 0 0.25 0.50 0.75 1.00 0 0 2 39 19 13 33 26 23 30 39 40 27 54 60 24 77 85 21 101 120 18 132 146 15 159 170 12 193 191 9 210 208 6 226 227 3 8 6 36 Bev XELOX-Bev Diaz-Rubio E, et al. Oncologist. 2012;17:15-25. HR: 1.05 (95% CI: 0.851-1.295) 间歇休息 : GISCAD Trial CR, PR, SD Previously untreated mCRC R A N D O M I Z A T I O N FOLFIRI x 2 mos 2:1 FOLFIRI x 2 mos E V A L U A T E Progression: Off Trial Break x 2 mos then FOLFIRI x 2 mos FOLFIRI x 4 mos Labianca R, et al. Ann Oncol. 2011;22:1236-1242. 146 147 75 70 25 27 10 9 146 147 95 101 39 43 10 13 Pts at Risk, n Continuous Intermittent Mos 0 Patients (%) 061218 Mos 100 80 60 40 20 0 Patients (%) 61218243036 130 124 60 68 19 29 Labianca R, et al. Ann Oncol. 2011;22:1236-1242. OS PFS 100 80 60 40 20 0 间歇休息 : GISCAD Trial Continuous arm Intermittent arm Events 145 143 Totals 146 147 Continuous arm Intermittent arm Events 145 143 Totals 146 147 Arm C Bevacizumab (n = 243) Arm A FOLFOX4 + Bevacizumab (n = 286) Arm B FOLFOX4 (n = 291) Patients with previously treated mCRC; no previous bevacizumab (N = 820) FOLFOX4 Oxaliplatin 85 mg/m2 on Day 1 q2w 5-FU 400 bolus/600 mg/m2 IV on Days 1 and 2 q2w LV 200 mg/m2 on Days 1 and 2 q2w Bevacizumab 10 mg/kg on Day 1 q2w Giantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544. Stratified by ECOG performance score 0 vs 1 or 2; previous XRT E3200: 二线用贝伐单抗 for mCRC Alive, nDead, nMedian, MosTotal, n A: FOLFOX4 + bevacizumab2862543212.9 B: FOLFOX42912642710.8 C: Bevacizumab2432192410.2 Giantonio BJ, et al. J Clin Oncol. 2007;25:1539-1544. E3200: 在以前治疗过的 mCRC FOLFOX + Bev 改善 OS OS (Mos) Probability 0 0.2 0 0.4 0.6 0.8 1.0 61218243036 HR: 0.76 A vs B: P = .0018 B vs C: P =.95 ML18147 (TML): 进展后继续用贝伐单抗 nA randomized, open-label phase III intergroup study Standard 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 or irinotecan based) (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: OS ML18147 (TML): 改善 OS (ITT) OS (%) Mos CT (n = 410) BEV + CT (n = 409) 100 80 60 40 20 0 0 6 12 18 24 30 36 42 48 9.8 9.8 mosmos11.2 11.2 mosmos Unstratified* 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 last dose of BEV ( 42 days, 42 days), ECOG PS at baseline (0, 1). Bennouna J, et al. Lancet Oncol. 2013;14:29-37. 100 80 60 40 20 0 PFS (%) 0 6 12 18 24 30 36 42 Mos Unstratified* 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) 4.1 mo4.1 mo 5.7 mo5.7 mo 一线治疗后继续用血管生成抑制剂 ? nBevacizumab nziv-aflibercept (阿帕西普) (阿帕西普) III期 VELOUR 研究: FOLFIRI ziv- Aflibercept 二线治疗 mCRC nPrimary endpoint: OS nSecondary endpoints: PFS, ORR, safety, immunogenicity nNo correlatives Patients with mCRC progressing on first-line oxaliplatin-based chemotherapy* (planned N = 1226) FOLFIRI + ziv-Aflibercept 4 mg/kg q2w (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) VELOUR 研究 : 生存结果 Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. OS (%) 100 80 60 40 20 0 Mos 0369 12 15 18 21 24 27 30 33 36 39 Stratified HR: 0.817 (95.34% CI: 0.713 -0.937; log-rank P = .0032) Placebo/FOLFIRI Median: 12.06 mos Aflibercept/FOLFIRI Median: 13.50 mos PFS (%) 100 80 60 40 20 0 Mos 036912151821 2427 30 Stratified HR: 0.758 (95% CI: 0.661- 0.869; log-rank P .0001) Placebo/FOLFIRI Median: 4.67 mos Aflibercept/FOLFIRI Median: 6.90 mos (阿帕西普)(阿帕西普) VELOUR 研究 : 按贝伐单抗分层OS Tabernero J, et al. Eur J Cancer. 2013;Epub ahead of print. OS (%) 100 80 60 40 20 0 Mos 0369 12 15 18 21 24 27 30 33 36 39 HR: 0.862 (95.34% CI: 0.673-1.104) Placebo/FOLFIRI Median: 11.7 mos Aflibercept/FOLFIRI Median: 12.5 mos Pts at Risk, n Placebo AFL 187 186 170 178 138 150 115 121 81 89 54 59 37 36 22 22 13 13 Previous Bevacizumab OS (%) 100 80 60 40 20 0 Mos 0369 12 15 18 21 24 27 30 33 36 39 HR: 0.788 (95.34% CI: 0.699-0.927) Placebo/FOLFIRI Median: 12.4 mos Aflibercept/FOLFIRI Median: 13.9 mos Pts at Risk, n Placebo AFL 427 426 403 388 347 348 286 295 205 222 139 157 94 112 65 82 38 62 No Previous Bevacizumab (阿帕西普) (阿帕西普) ziv-Aflibercept (阿帕西普): 毒性 Increased Grade 3/4 AEs in Aflibercept Arm, % FOLFIRI + Aflibercept (n = 611) FOLFIRI + Placebo (n = 605) Any83.562.5 Diarrhea19.37.8 Asthenia16.910.6 Stomatitis/ulceration13.75.0 Infection12.36.9 Palmar-plantar erythrodysesthesia2.80.5 Anti-VEGFassociated events Hypertension19.31.5 Hemorrhage2.91.7 Arterial thromboembolic events1.80.5 Venous thromboembolic events7.96.3 Neutropenia36.729.5 Complicated neutropenia5.72.8 Thrombocytopenia3.31.7 Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. (阿帕西普) mCRC : 二线EGFR 单抗治疗 TrialComparative RegimensPFS, Mos OS, Mos EPIC1 Irinotecan/Cetux vs Irinotecan 4.0 vs 2.6* 10.7 vs 10.0 1812 FOLFIRI/Pmab vs FOLFIRI 5.9 vs 3.9* 14.5 vs 12.5 SPIRIT T3 FOLFIRI/Pmab vs FOLFIRI/Bev 7.7 vs 9.2 18.0 vs 21.4 1. Sobrero 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) CORRECT: 所有治疗肠癌方案失效后用 Regorafenib(瑞格非尼) nPrimary endpoint: OS nApproximately 50% of patients with 4 systemic therapies All patients had received bevacizumab Patients with progression after all available standard therapy (N = 760) Arm A: Regorafenib 160 mg PO QD + BSC 3 wks on, 1 wk off (n = 505) Arm B: Placebo + BSC 3 wks on, 1 wk off (n =