阿伯西普联合以氟尿嘧啶为基础的化疗治疗晚期大肠癌的研究课件

读书报告,汇报人：罗娜,1,BACKGROUND,2,PATIENTS AND METHODS,3,RESULTS,4,CONCLUSIONS,Background,Patients with metastatic colorectal cancer (mCRC) previously-treated with oxaliplatin benefit significantly from the addition of aflibercept to FOLFIRI in relation to overall survival, progression-free survival and response rate.,1,01,typically regimen,02,FOLFOX+bevacizumab,03,FOLFIRI+aflibercept,04,Aflibercept,Background,typically regimen,Treatment of metastatic colorectal cancer (mCRC) typically involves a fluoropyrimidine-based hemotherapy regimen, combining infusional fluorouracil (5-FU) and leucovorin with oxaliplatin (FOLFOX regimen) or rinotecan (FOLFIRI regimen).,1 Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22(1):2330. 2 Saltz LB, Cox JV, Blanke C, et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000;343(13):90514. 3 Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22(2):22937.,FOLFOX+bevacizumab,In the E3200 study, it was shown that the addition of bevacizumab to FOLFOX improves survival duration for patients with previously treated mCRC who had not received first-line treatment with oxaliplatin or bev-acizumab.,Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007;25(12):153944.,FOLFIRI+aflibercept,VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen (VELOUR) was the first randomised, placebo-controlled, phase III trial to show a statistically significant improvement in OS, progression-free survival (PFS) and response rate (RR) for an anti-angiogenic in combination with FOLFIRI compared with FOLFIRI alone in a prior oxaliplatin-treated population.,Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30(28):3499506.,FOLFIRI+aflibercept,Patients receiving FOLFIRI plus aflibercept had a median OS of 13.5 months versus 12.0 months for patients receiving FOLFIRI plus placebo, representing a relative reduction in the risk of death of 18.3% for the aflibercept arm compared with the placebo arm.,Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30(28):3499506.,编译自：Aflibercept Approved for Colorectal Cancer in the US.Medscape.2012.8.3,阿柏西普是一种血管生成抑制剂，一种重组人融合蛋白，与循环VEGF紧密结合，使其不能与细胞表面受体相互作用，从而抑制血管内皮生长，比目前可用的抗血管生成药物如贝伐珠单抗有更广泛的作用机制。 2012年8月3日，FDA批准阿柏西普（Zaltrap，Regeneron/赛诺菲）治疗转移性结直肠癌。 3期VELOUR（阿柏西普vs安慰剂治疗奥沙利铂方案失败的转移性结直肠癌病人）试验的结果。在1226名病人中，阿柏西普添加到FOLFIRI方案中可显著改善总生存期和无进展生存期。 VELOUR临床试验的结果首次公布是在2011年的世界胃肠肿瘤大会上。阿柏西普的添加使反应率翻倍，从10%上升到20%。无进展生存期提高了23个月，最重要的是，总生存期从12.0个月上升到13.5个月。后续FDA发布的新闻稿中又增加了临床试验的细节：FOLFIRI方案单独治疗中位无进展生存期为4.7个月，添加阿柏西普上升到了6.9个月。,Aflibercept,Patients and Methods,The results for efficacy and safety over the time course of the VEGF Trap (aflibercept) with irinotecan in colorectal cancer after failure of oxaliplatin regimen trial were analysed based on data from 1226 patients randomised to receive FOLFIRI plus either aflibercept (n = 612) or placebo (n = 614). Hazard ratios (HR) by 6-month time period were estimated using a piecewise Cox proportional hazard model. Severity of adverse events (AEs) was graded using National Cancer Institute Common Terminology Criteria, version 3.0.,2,Fig. 1. CONSORT chart.,Results,The estimated probabilities of survival were 38.5% versus 30.9% at 18 months, 28.0% versus 18.7% at 24 months and 22.3% versus 12.0% at 30 months, for the aflibercept-and placebo-treated arms, respectively. The proportional improvement in the HR over time was consistent with the survival probability results; survival at 24 months was improved by 50% and almost doubled at 30 months.,一、,3,1,Fig.2,Efficacy,Efficacy,Results,The majority of worst-grade AEs occurred within the first four cycles of treatment and in a small percent of treatment cycles and were mostly reversible. Common chemotherapy and anti-vascular epithelial growth factor (VEGF)associated AEs occurred rarely and in a small proportion of cycles with the majority being of single occurrence.,3,2,Safety,Fig.3 Occurrence of selected anti-vascular epithelial growth factor (VEGF) and chemotherapy-related grade 34 adverse events (AEs) over the course of VELOUR. AFLI, aflibercept; PBO, placebo.,Safety,Safety,Fig.4,Fig.4,Safety,Cycle of Worst Occurrence of Anti-VEGF- related and chemotherapy-related AEs，Grade 3/4,Fig.4,Safety,Fig.4,Safety,Conclusion,4,1,2,The addition of aflibercept