2012ASCO肠癌最新进展.docx

最新资讯echo1166加关注 Lancet Oncol：持续应用贝伐单抗治疗对转移性结直肠癌患者有益2012-11-21 09:11 来源：丁香园 作者：echo1166 总体生存期和无进展生存期贝伐单抗联合基于氟尿嘧啶的化疗方案是转移性结直肠癌患者的一线治疗方案，对既往没有应用过贝伐单抗的患者的二线治疗方案。本文的研究者评估了在接受过标准一线基于贝伐单抗治疗后仍出现疾病进展转移性结直肠癌患者中继续应用贝伐单抗联合二线化疗方案的有效性。Jaafar Bennouna等的研究结果发表在Lancet Oncol 11月最新的在线期刊上。本研究为开放标签、3期临床研究，研究在奥地利、比利时、捷克共和国、丹麦、爱沙尼亚、芬兰、法国、德国、荷兰、挪威、葡萄牙、沙特阿拉伯、西班牙、瑞典和瑞士等国中的220个中心中进行，患者的入组标准为年龄大于等于18岁、经组织学证实的不可手术切除的转移性结直肠癌、在停止了贝伐单抗联合一线化疗方案3个月内出现疾病进展。这些患者按照1:1的比例随机分为2组，一组治疗方案为二线化疗方案联合贝伐单抗（5mg/kg每2周或7.5 mg/kg 每3周，静脉给药），另一组治疗方案为二线化疗方案不联合贝伐单抗。根据患者第一次的治疗方案决定二线治疗方案以奥沙利铂或伊立替康为基础。采用排列区组设计结合Pocock and Simon最小随机化法对患者进行随机化分组。本研究的主要终点为采用意向治疗分析患者的总体生存情况。研究在ClinicalT注册。在2006年2月1日至2010年6月9日期间，有409名患者被纳入贝伐单抗联合化疗组，411名患者被纳入化疗组，两组的中位随访时间分别为11.1月和9.6月。贝伐单抗联合化疗组患者的总体生存期为11.2月，化疗组的总体生存期为9.6月。3-5级的出血在联合组为8人，在单化疗组为1人，胃肠道穿孔在联合组为7人，在单化疗组为3人，静脉栓塞在联合组为19人，在单化疗组为12人，总之，贝伐单抗联合化疗组的患者较单独化疗组的患者而言，3-5级的不良反应发生更多。最常见的不良反应包括3-5级的中性粒细胞减少（65人/52人）、腹泻（40人/34人）和无力（23人/17人）。贝伐单抗联合化疗组的与治疗相关死亡数为4人，单化疗组为3人。研究结果提示持续应用VEGF抑制剂贝伐单抗联合标准二线化疗能给疾病出现进展的转移性结直肠癌患者带来治疗获益。目前在转移性乳腺癌和非小细胞肺癌患者中也在进行相似的治疗方案的疗效研究。最新资讯ESMO2012：辅助化疗加入西妥昔单抗对术后期结直肠癌患者无益2012-10-14 08:26 来源：丁香园 作者：sensenmam ESMO2012年会上，法国巴黎Georges Pompidou欧洲医院的Julien Taieb博士报告了III期随机化临床试验欧洲内部的PETACC8试验的初步分析结果，该结果显示，西妥昔单抗加入FOLFOX4标准辅助化疗方案中，对KRAS野生型（WT）的术后III期结直肠癌无益。研究这项辅导治疗的理论基础是前期的研究结果，即FOLFOX方案中加入西妥昔单抗治疗转移的KRAS野生型结直肠癌有益。然而，PETACC8试验是第二个测试辅助治疗方案中的西妥昔单抗的临床试验，同时，在美国开展的N0147试验（西妥昔单抗+ mFOLFOX6）也因未能显示临床获益而以失败告终。考察辅助治疗对消化系统癌症的是否能取得显著收益需要进行大规模的临床试验来验证，这几个小组以PETACC的名义（消化道肿瘤泛欧洲试验）合作，从而能入选大量患者。该合作组是由十几个欧洲国家和国际合作小组所组成。这个主要的泛欧洲协作组织的成立是为了研究西妥昔单抗联合以奥沙利铂为基础的化疗（FOLFOX4）是否会减少全切除术后期结直肠癌的复发和延长生存期。这项协作试验由来自Fdration Francophone de Cancrologie Digestive (FFCD) 的科学家们牵头，与欧洲肿瘤研究与治疗组织和PETACC架构内的国家小组合作研究。在PETACC8试验中，入选KRAS野生型的全切除术后III期结直肠癌患者1602例，术后2856天开始12疗程的化疗（每2周为一疗程），患者随机分配到A组或B组进行治疗。FOLFOX4化疗为第一天静脉团注给予奥沙利铂85 mg/m2和甲酰四氢叶酸200 mg/m2及5-FU 400 mg/ m2，第12天以5-FU 600 mg/m2静注22小时，A组不给予西妥昔单抗，B组则每周一次使用西妥昔单抗或（负荷剂量为400 mg/m2）。主要疗效指标是无病生存期（DFS），次要疗效指标包括总生存期，治疗依从性，安全性，以及对预测复发和/或治疗效果的标记物评价的生物学研究。中期分析时，中位随访期约为3.3年。对于KRAS野生型患者，两组间无病生存期或总生存期无明显差异，DFS（HR = 1.047，95CI：0.853-1.286，P = 0.6562）总生存期（OS，HR 1.092; 95CI：0.813-1.466，P = 0.5583）（N = 1602）。对于KRAS / BRAF野生型患者，两组间的无病生存期或总生存期无明显差异，DFS（HR = 0.985，95CI：0.755-1.284，P = 0.9117）或OS（HR = 0.981，95CI：0.669-1.438，P = 0.9236）（N = 984）。西妥昔单抗治疗患者中DFS较差的是：年龄 70岁的（n = 149，HR 1.97，95CI：0.99-3.93，p = 0.051），女性患者（n = 666，HR 1.45，95CI：1.03-2.02 ，p = 0.031），右侧结直肠癌患者（n = 570; HR 1.40，95CI：1.01-1.94，p = 0.043）。相反，在肿瘤预后不良的患者中有转归较好的趋势（即：肿瘤分级高的患者HR 0.76，95CI：0.49-1.16，T4疾病患者HR 0.71，95CI：0.50-1.02，或发生穿孔/梗阻的患者HR 0.79，95CI：0.53-1.18），在诊断为pT4N2的患者中有显著疗效（n = 146; HR 0.555; 95CI：0.348-0.885，p = 0.0122）。Taieb博士总结说，“对于KRAS wt 或KRAS及 BRAF wt的术后期结直肠癌患者而言，FOLFOX4治疗加入西妥昔单抗后DFS或OS未见获益”。他说，“与在四期疾病中的作用相比，西妥昔单抗对于微转移疾病可能有不同活性形式”，这可能可解释为什么西妥昔单抗在这种设定的治疗方案中没有取得额外的收益。 最新资讯雪道人加关注 ASCO2012：3期临床试验发现regorafenib能够提高结直肠癌患者的生存期2012-02-06 14:22 来源：丁香园 作者：雪道人 一个国际性的三期临床试验发现：一种名为regorafenib的研究性药物在治疗转移性结肠癌患者时，能够减缓肿瘤的进展和延长患者生命。该研究结果由三藩市MayoClinic肿瘤科的AxelGrothey博士发表在美国临床肿瘤协会的胃肠道癌症研究论文集上。试验的主要研究者在美国。“多年来，标准化疗未能阻止肿瘤生长，并且医生已经黔驴技穷无法为患者提供有效的药物，故而转移性结肠癌患者面临灾难性的困境，”Grothey博士说道，“八年来，对于无法用药的结肠癌患者，这是第一种显示出提高整体生存率的新型药物。”研究人员在美国、欧洲、澳大利亚和中国对regorafenib同时进行了随机、安慰剂对照的三期临床试验。他们评判了760例行标准化疗的患者的生存结果。Regorafenib是一种多激酶抑制剂，该制剂起到抑制肿瘤血管生成、肿瘤细胞增殖以及灭活被各种生物途径激活的肿瘤。研究人员发现，治疗转移性结肠癌的结果表明，以该药治疗组比安慰剂组增加了29%的总体生存率。以该药物进行治疗的患者平均生存时间增加了56.5个月，具有显著意义性的增长。总体而言，regorafenib可将病人死于癌症的风险下降23%左右。该实验中最大的研究组是美国的MayoClinic，在计划进度上提前了一年多的时间。“所有被认可的标准疗法对转移性结肠癌患者预后均较差，”Grothey说，“目前来说，这是第一种也是唯一一种在整体生存率方面有着显著统计意义的药物。” Cetuximab in Combination with Folfiri / TherascreenOn July 6, 2012 , the U. S. Food and Drug Administration granted approval to cetuximab (Erbitux, ImClone LLC, a wholly owned subsidiary of Eli Lilly and Co) for use in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFR-expressing metastatic colorectal cancer (mCRC) as determined by FDA-approved tests for this use.FDA also approved the Therascreen KRAS RGQ PCR Kit (QIAGEN Manchester, Ltd) concurrent with this cetuximab approval.This approval was based on retrospective analyses in the patient subsets according to K-ras mutation status in tumor samples from patients enrolled in the CRYSTAL trial and in two supportive studies, CA225025 and EMR 62 202-047 (OPUS).The addition of cetuximab to chemotherapy or best supportive care (BSC) resulted in improved survival (OS), progression-free survival (PFS), and overall responses rates (ORR) in the subset with K-ras wild-type tumors; whereas, there was no benefit or potential harm in patients with K-ras mutant tumors.The approval of the companion diagnostic, the QIAGEN Therascreen KRAS RGQ PCR Kit, provides a reliable way to identify these subsets of patients with colon cancer.This QIAGEN test, a genetic assay, is a real-time polymerase chain reaction assay detecting 7 different mutations of the K-ras gene in a tumor specimen. Tumors that are K-ras mutation-negative in this assay are commonly referred to as K-ras wild-type.CRYSTAL was an open-label, randomized, controlled trial in patients with EGFR-expressing mCRC who had not received prior chemotherapy for metastatic disease. A total of 1217 patients, irrespective of K-ras mutation status, were randomized (1:1) to receive either cetuximab in combination with FOLFIRI or FOLFIRI alone. PFS was the primary efficacy endpoint.A statistically significant improvement in PFS was observed with cetuximab plus FOLFIRI arm compared to the FOLFIRI alone median PFS 8.9 vs. 8.1 months, HR 0.85, (95% CI: 0.74, 0.99), p-value=0.036 in the overall population.OS, a secondary endpoint, was not significant in the planned analysis HR 0.93, (95% CI: 0.82, 1.07), p-value 0.327, 838 events.In an updated analysis with an additional 162 events, the median OS was 19.6 compared to 18.5 months for cetuximab-containing arm and FOLFIRI alone arm HR 0.88 (95% CI: 0.78, 1.00).Retrospective efficacy analyses in patient subsets with K-ras wild-type and mutant tumors, demonstrated that in the wild-type subgroup, the addition of cetuximab to FOLFIRI resulted in a favorable effect on OS, PFS and ORR.Tumor tissue was evaluable for K-ras mutation status assessment in 89% of the patients (N=1079/1217); 676 (63%) had wild-type and 403 (37%) had mutant tumors.The median OS for the wild-type subgroup was 23.5 versus 19.5 months for the cetuximab plus FOLFIRI and FOLFIRI alone, respectively HR 0.80 (95% CI: 0.67, 0.94).PFS and ORR findings in the K-ras wild-type subgroup supported the efficacy of cetuximab in combination with FOLFIRI; the median PFS was 9.5 versus 8.1 months for cetuximab plus FOLFIRI and FOLFIRI alone, respectively HR 0.70 (95% CI: 0.57, 0.86).ORR was 57% with cetuximab plus FOLFIRI compared to 39% with FOLFIRI alone. In the mutant subgroup, improvements in OS, PFS or ORR were not observed with the addition of cetuximab to FOLFIRI compared to FOLFIRI alone.Retrospective analyses of two supportive studies, CA225025 and OPUS by tumor K-ras mutation status supported cetuximabs efficacy in the wild-type subgroup:CA225025 was an open-label, randomized, trial comparing cetuximab plus best supportive care (BSC) with BSC alone in patients with previously treated EGFR-expressing mCRC.CA225025 demonstrated a statistically significant improvement in OS in the cetuximab plus BSC arm compared to BSC alone.The planned efficacy results served as the basis for the full approval of cetuximab in October 2007 as a single agent for EGFR-expressing mCRC after failure of both irinotecan- and oxaliplatin-based regimens or in patients intolerant to irinotecan-based regimens.Tumor tissue was evaluable for K-ras mutation status in 79% of patients (N=453/572).In the wild-type subgroup, cetuximab plus BSC resulted in an improvement in OS compared to those receiving BSC alone HR 0.63 (95% CI: 0.47, 0.84).The median OS was 8.6 versus 5.0 months in the cetuximab plus BSC and BSC arms, respectively.The median PFS was 3.8 and 1.9 months for the cetuximab plus BSC and the BSC alone, respectively HR 0.42 (95% CI: 0.32, 0.56).In the mutant subgroup, no improvements in OS, PFS or ORR were observed with the addition of cetuximab to BSC compared to BSC alone.OPUS was a randomized, open-label, phase 2 study comparing cetuximab in combination with 5-flourouracil, folinic acid, and oxaliplatin (FOLFOX-4) to FOLFOX-4 alone as first-line treatment of EGFR-expressing mCRC.Tumor tissue was evaluable for retrospective K-ras mutation status analysis in 93% of patients (N=315/337).ORR was the trials primary endpoint.In the wild-type subgroup (N=179/315, 57%), ORR was 57% (95% CI: 46, 68) in the cetuximab plus FOLFOX-4 arm compared to 34% (95% CI: 25, 44) with FOLFOX-4.A numerical improvement in PFS was noted in the wild-type subgroup HR 0.57 (95% CI: 0.38, 0.86). The median PFS was 8.3 compared to 7.2 months favoring the cetuximab-containing arm.A numerical OS improvement was also observed in the wild-type subgroup HR 0.86 (95% CI: 0.60, 1.22). The median OS for the cetuximab-containing arm was 22.8 versus 18.5 months in the control arm.In the K-ras mutant subgroup (N=136/315, 43%), improvement in OS, PFS or ORR were not observed with cetuximab plus FOLFOX-4 compared to FOLFOX-4 alone.Safety data were evaluated in 317 patients in the wild-type subgroup who received cetuximab in combination with FOLFIRI in the CRYSTAL study and in 118 patients with wild-type tumors who received cetuximab monotherapy in CA225025.The frequency and nature of the adverse events, including adverse events associated with cetuximab (acne-like rash, infusion reactions, cardiac events, and hypomagnesemia) observed in CRYSTAL, CA225025, and OPUS in the wild-type population were consistent with the known adverse drug reaction profiles of either cetuximab, chemotherapy agents, or the underlying disease.No significant differences between the wild-type, mutant and the overall safety populations have been noted.The recommended dose and schedule for cetuximab is 400 mg/m2 administered intravenously as a 120-minute infusion as an initial dose, followed by 250 mg/m2 infused over 30 minutes weekly in combination with FOLFIRI.Cetuximab administration should be completed 1 hour prior to FOLFIRI.Product labeling for cetuximab provides “Limitation of Use” information specifying that cetuximab is not indicated for treatment of K-ras mutation-positive colorectal cancer.Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at:/drugsatfda_docs/label/2012/125084s225lbl.pdf1Healthcare professionals should report all serious adverse events suspected to be assoc