晚期胃癌系列研究解读 --REAL-2 研究 P-XLD-2014.01-002 Valid Until 2016.01 仅供医学、药学专业人士参考

主要内容 研究背景 研究设计及结果 研究意义

REAL-2 研究的背景 在英国，ECF 方案广泛用于晚期食管癌的治疗 两项纳入800名患者的随机临床试验证实了其活性1–3 总体缓解率（ORR）: ~40% 总体生存期（OS） ~9 个月 1年生存: ~40% Cochrane荟萃分析支持5-Fu联合顺铂加蒽环类治疗胃癌4 ECF was developed at the Royal Marsden Hospital (UK), based on the single-agent activity of the three drugs in upper gastrointestinal cancer and on the synergy between 5-FU and cisplatin in animal models [1]. An anthracycline was included to enhance the efficacy of the combination, and epirubicin was preferred to doxorubicin because of its lower toxicity. In a multicentre randomised study, ECF was compared with the standard FAMTX regimen for the treatment of oesophagogastric cancer (n=274) [2,3]. ECF resulted in response and survival advantage (ORR: 46% versus 21%, p<0.0005; OS: 8.7 versus 6.1 months, p=0.0005). Patients treated with ECF experienced significantly more grade 3/4 nausea/vomiting (17% versus 5%) and alopecia (56% versus 42%), and significantly less leucopenia (12% versus 39%), neutropenia (36% versus 58%) and infections (8% versus 20%). When compared with the combination of mitomycin, cisplatin and 5-FU (MCF), ECF resulted in similar ORR (42% vs 44%) and overall survival (9.4 vs 8.7 months) (n=574) [4]. There was significantly more grade 3/4 neutropenia with ECF, whereas thrombocytopenia and hand-foot syndrome were more frequent with MCF. The global quality of life (QoL) scores were maintained with ECF but declined with MCF, and differences in QoL were detected at both 3 months (p<0.001) and 6 months (p=0.015). A Cochrane meta-analysis indicated that the addition of anthracyclines to 5-FU/cisplatin combinations prolongs OS (HR: 0.77; 95% CI: 0.62–0.91) [5]. Similarly, addition of cisplatin to 5-FU/anthracyclines results in improved overall survival (HR=0.83; 95% CI: 0.76–0.91). In particular, ECF should be preferred to cisplatin plus epirubicin plus bolus 5-FU/LV (PELF), as it results in a more acceptable safety profile. 1. Cunningham et al. Proc ASCO 1991 2. Webb et al. J Clin Oncol 1997 3. Waters et al. Br J Cancer 1999 4. Ross et al. J Clin Oncol 2004 5. Wagner et al. Cochrane Database Syst Rev 2005 1. Webb et al. J Clin Oncol 1997 2. Waters et al. Br J Cancer 1999 3. Ross et al. J Clin Oncol 2002 4. Wagner et al. Cochrane Database Syst Rev 2005

REAL-2临床研究: 希罗达® vs 5-氟尿嘧啶, 奥沙利铂 vs 顺铂 局部晚期或转移性胃食管癌 (n=1002) 随机化 ECF† 表柔比星 顺铂 5-FU EOF* 表柔比星 奥沙利铂 5-FU ECX 表柔比星 顺铂 希罗达 EOX 表柔比星 奥沙利铂 希罗达 REAL-2: randomised, multicentre Phase III study evaluating the role of Xeloda and oxaliplatin as first-line therapy in previously untreated patients (prior radiotherapy only in the adjuvant setting) with oesophagogastric metastatic or locally advanced carcinoma, using a 2x2 factorial design [1,2]. Patients were eligible if they were aged ≥18 years with measurable disease (RECIST criteria), Eastern Cooperative Oncology Group (ECOG) PS of 0–2 and adequate renal, hepatic and haematological function. Patients were stratified by centre, PS, extent of disease and oesophageal/OGJ vs gastric cancer. The primary endpoint of the trial was non-inferiority in overall survival between the two platinum-containing regimens and between the two fluoropyrimidine-containing regimens. Secondary analysis was for overall survival superiority in three test arms versus ECF control. The first 80 patients recruited were analysed for toxicity, in order to decide on Xeloda dose escalation. Second interim analysis to confirm safety profiles included 204 patients. Secondary endpoints included PFS, ORR (RECIST criteria), toxic effects and QoL. 1. Sumpter et al. Br J Cancer 2005 2. Cunningham et al. N Eng J Med 2008 表柔比星 50mg/m2 第1天 顺铂 60mg/m2 vs 奥沙利铂 130mg/m2 第1天 5-FU 200mg/m2 每天静脉输注 vs 希罗达® 500–625mg/m2 bid 每天口服 24周：每3周一个疗程，共8个疗程 † 5-FU 通过中心静脉导管给药 Cunningham et al. N Engl J Med 2008

REAL-2: 治疗方案 E 表柔比星 50mg/m2 iv C 顺铂 60mg/m2 iv F 持续小剂量输注 5-FU 200mg/m2/d* E 表柔比星 50mg/m2 iv C 顺铂 60mg/m2 iv X 希罗达® 625mg/m2 bid E 表柔比星 50mg/m2 iv O 奥沙利铂 130mg/m2 iv F 持续小剂量输注 5-FU 200mg/m2/d E 表柔比星 50mg/m2 iv O 奥沙利铂 130mg/m2 iv X 希罗达® 625mg/m2 bid 所有药物每3周给药一次 预定的治疗时间为24周（8个疗程） 分别在基线、12周和24周时进行CT扫描 *通过中心静脉导管持续小剂量输注 5-FU Cunningham et al. N Engl J Med 2008

REAL-2: 主要终点 – 总体生存期 总体生存期的非劣效性 希罗达® vs 5-FU 奥沙利铂 vs 顺铂 四组方案总体生存期的比较 在ECF方案1年生存率35%的基础上, 1 000 例患者（每组250例）需证实具有非劣效性 (检验效能80% ,单侧 a=0.05) 试验组的危险度（HR）上限和标准治疗组相比需<1.23 四组方案总体生存期的比较 Non-inferiority to be demonstrated between the two platinum-containing regimens and between the two fluoropyrimidine-containing regimens [1]. Secondary analysis was for OS superiority in three test arms vs ECF control. The first 80 patients recruited were analysed for toxicity, in order to decide on Xeloda dose escalation. Second interim analysis to confirm safety profiles included 204 patients. 1. Cunningham D et al. Proc ASCO 2006 (Abst LBA4017) Cunningham et al. N Engl J Med 2008

REAL-2:次要终点 无进展生存（PFS） 总体缓解率（ORR） 毒性 (CTC 2.0版) 生活质量 (EORTC QLQ-C30) Cunningham et al. N Engl J Med 2008

入选标准 食管、胃食管交界或胃 转移性或局部晚期的腺癌、鳞癌或未分化癌 未接受过化疗（包括辅助治疗） 之前未接受过放疗，除了放疗区域外复发接受辅助治疗 单维量可测量病变 年龄18 岁 ECOG评分 0–2 血液和生化指标完整 心功能良好 签署书面知情同意书 Cunningham et al. N Engl J Med 2008

基线特征 ECF (n=249) ECX (n=241) EOF (n=235) EOX (n=239) 中位年龄, 岁 (范围) 65 (22–83) 64 (25–82) 61 (33–78) 62 (25–80) 男性 (%) 81.1 80.5 81.3 82.8 食管 (%) 胃食管交界处 (%) 胃 (%) 34.9 28.9 36.1 29.5 28.2 42.3 39.6 23.4 37.0 34.3 22.2 43.5 PS† (0/1 vs 2, %) 88.4/11.6 87.6/12.4 91.5/8.5 90/10 转移 (%) 局部晚期病变(%) 79.5 20.5 76.8 23.2 77.0 23.0 75.7 24.3 腺癌 (%) 鳞癌 (%) 其他/未分化 (%) 90.0 7.6 2.4 89.6 9.5 0.8 86.0 12.8 1.3 87.4 12.1 0.4 转移部位 (0/1 vs ≥2, %) 63.5/36.5 59.3/40.7 60.9/39.1 64.4/35.6 之前接受过手术 (%) 7.6 7.5 7.7 8.8 The baseline demographic and clinical characteristics were well balanced across all treatment groups [1]. The majority of patients in all trials were male; the median age was 61–65 years and PS scores were predominantly 0–1. The median number of cycles administered was six in each study group. Median actual dose intensities of the epirubucin, platinum and fluoropyrimidine drugs were similar in all treatment groups, as was the percentage of patients undergoing at least one dose reduction. The median follow-up was 17.5 months in the ECF group, 17.6 months in the ECX group, 19.3 months in the EOF group and 18.9 months in the EOX group. 1. Cunningham et al. N Engl J Med 2008 † PS=体力状况 Cunningham et al. N Engl J Med 2008

REAL-2:总体生存期希罗达®非劣于5-FU 估计概率 1.0 希罗达® (n=480) 5-FU (n=484) 0.8 0.6 HR=0.86 (95% 可信限: 0.80–0.99) 和HR上限1.23相比, p<0.0001 0.4 The primary endpoint of the REAL-2 study was met, as the OS of patients receiving Xeloda-based regimens (EOX or ECX) was non-inferior to that of patients receiving 5-FU-based regimens (EOF or ECF) [1]. The HR comparing Xeloda triplets with 5-FU triplets was 0.86 (95% CI: 0.80–0.99). The upper limit of the HR was 0.99, significantly below the 1.23 predefined margin for non-inferiority (p<0.0001; per protocol analysis). 1. Cunningham D et al. Proc ASCO 2006 (Abst LBA4017) 0.2 9.6 10.9 0.0 12 24 36 48 60 72 月 完成治疗分析 Cunningham et al. N Engl J Med 2008

EOX vs ECF: 总体生存更高 EOX (n=244) ECF (n=263) 估计概率 1.0 0.8 0.6 HR=0.80 (95% 可信限: 0.66–0.97) p=0.020 0.4 Non-inferiority in OS was demonstrated for the EOX arm vs the reference arm (ECF) [1]. The ITT analysis showed that substituting 5-FU with Xeloda and cisplatin with oxaliplatin resulted in an HR value of 0.80 (95% CI: 0.66–0.97), translating into a significant 20% reduction in risk of disease recurrence in patients receiving EOX (p=0.020). The response rates for ECX and EOX were 46% and 48%, respectively, with disease stabilisation in 32% and 28% of the patients. Response rates for ECF and EOF were 41% and 42%, with 31% and 15% of the patients achieving disease stabilisation, respectively. Overall these data indicate that Xeloda and oxaliplatin can effectively replace 5-FU and cisplatin, respectively, for the treatment of oesophagogastric cancer. 1. Cunningham D et al. Proc ASCO 2006 (Abst LBA4017) 0.2 9.9 11.2 0.0 6 12 18 24 30 36 月 治疗意向分析 Cunningham et al. N Engl J Med 2008

REAL-2: 以希罗达®为基础的治疗方案有效 患者 (%) ECX (n=241) ECF (n=249) EOX (n=239) EOF (n=235) Cunningham et al. N Engl J Med 2008

以希罗达®为基础的治疗方案耐受性良好 不良反应分级3 / 4 ECX (n=234) ECF (n=234) EOX (n=227) EOF (n=225) 患者 (安全性人群, %) * 不良反应分级3 / 4 * * * * * * * Xeloda-containing regimens were characterised by a favourable safety profile [1]. In particular, compared with the reference arm, patients in the EOX arm experienced less grade 3/4 neutropenia (p<0.05), febrile neutropenia and hand-foot syndrome, but more diarrhoea (p<0.05). The 60-day all-cause mortality was similar between arms (ECF: 7.2%, EOF: 5.7%, ECX: 5.6%, EOX: 6.1%). Thromboembolism, a common complication of oesophagogastric cancer, is associated with morbidity and mortality and may be increased by chemotherapy. The AE sections of the trial database were searched for thromboembolic events (TEs) in the treated (per protocol) population (n=964) [2]. TEs were classified as venous (VTE) and arterial (ATE). The overall incidence of TEs was 117/964 (12.1%). VTEs occurred in 98/964 patients (10.2%) and ATEs in 19/964 (1.97%). TEs (%) ECX ECF EOX EOF VTEs 10.0 16.1 6.7 7.7 ATEs 4.1 1.6 1.3 0.9 Total 14.1 17.7 7.9* 8.5* *p<0.01 QoL at baseline was balanced between the arms. No differences in QoL scores (p>0.01) between arms for any change from baseline to 12 weeks [1,3]. 1. Cunningham et al. N Eng J Med 2008 2. Starling et al. ASCO GI 2007 3. Cunningham et al. ASCO 2006 HFS 口腔炎 腹泻 白细胞减少 粒细胞减少性发热 恶心/呕吐 血栓栓塞性事件 * 和ECF组相比，p<0.05 Cunningham et al. N Engl J Med 2008

REAL-2: 结论 达到主要终点 和5-FU相比，希罗达®具有非劣效性 在这些三联治疗方案中 希罗达®可以取代5-氟尿嘧啶 奥沙利铂可以取代顺铂 和ECF方案相比，EOX方案可提高治疗有效性 希罗达®联合治疗减少输注时间 治疗实施时间减少 患者舒适度提高 Cunningham et al. N Engl J Med 2008

简明处方 完整处方资料详见产品说明书 www.roche.com.cn 修改日期：2012 年8 月24 日 【警告】 对于同时服用卡培他滨和香豆素类衍生物抗凝药如华法令和苯丙香豆素的患者，应该频繁监测抗凝反应指标，如INR或凝血酶原时间，以调整抗凝剂的用量。在合并用药期间，曾有凝血参数改变和/或出血，包括死亡的报告。 发生时间：在开始卡培他滨治疗后几天到几个月时间内，也可能在停止使用卡培他滨后1个月内观察到。 易感因素：年龄〉60，诊断为癌症。 【药品名称】 通用名称：卡培他滨片 商品名称：希罗达® 英文名称：Capecitabine Tablets 【适应症】 胃癌：卡培他滨适用于不能手术的晚期或者转移性胃癌的一线治疗。 【用法用量】 卡培他滨的推荐剂量为1250mg/m2，每日2次口服（早晚各1次；等于每日总剂量2500mg/m2），治疗2周后停药1周，3周为一个疗程。卡培他滨片剂应在餐后30分钟内用水吞服。在与多西紫杉醇联合使用时，卡培他滨的推荐剂量为1250 mg/m2，每日2次，治疗2周后停药1周。与奥沙利铂联合使用时，在对患者给予奥沙利铂后的当天即可开始卡培他滨的治疗，剂量为1000 mg/m2，每日2次，治疗2周后停药1周。 【不良反应】 厌食、腹泻、呕吐、恶心、口腔炎、腹痛、手-足综合征、皮炎、疲劳、昏睡等 【禁忌】 已知对卡培他滨或其任何成份过敏者禁用。既往对氟尿嘧啶有严重、非预期的反应或已知对氟嘧啶过敏患者禁用卡培他滨。二氢嘧啶脱氢酶（DPD）缺陷的患者禁用卡培他滨。不应与索立夫定或其类似物（如溴夫定）同时给药。卡培他滨禁用于严重肾功能损伤患者（肌酐清除率低于30 mL/分）。联合化疗时，如存在任一联合药物相关的禁忌症，则应避免使用该药物。 【批准文号】 0.15g:国药准字 H20073023 0.5g :国药准字 H20073024

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