西妥昔单抗/FOLFIRI可延长转移性结直肠癌生存

芝加哥——美国临床肿瘤学会(ASCO)2013年会上发布的FIRE-3Ⅲ期试验结果显示，与贝伐珠单抗联合FOLFIRI化疗相比，西妥昔单抗联合FOLFIRI化疗可使KRAS野生型转移性结直肠癌患者的总生存率显著延长大约4个月。

西妥昔单抗(爱必妥)组和贝伐珠单抗(阿瓦斯汀)组患者具有相似的至疾病进展时间，分别为10个月和10.3个月[危险比(HR)，1.06；P=0.54]，但西妥昔单抗组患者的生存期明显更长(28.7个月 vs. 25个月；HR，0.77；P=0.017)。

这项由德国AIO研究组开展的试验首次直接对比了西妥昔单抗和贝伐珠单抗这两种靶向药物与FOLFIRI(亚叶酸、氟尿嘧啶及伊立替康)化疗配伍的效果。研究者将592例野生型患者随机分组，给予FOLFIRI每2周1次+西妥昔单抗第1天400 mg/m²，之后每周250 mg/m²治疗，或者FOLFIRI每2周1次+贝伐珠单抗每2周5 mg/kg治疗。98%患者的美国东部肿瘤协作组(ECOG)体能状态为0~1，男性占66%，中位年龄为64岁。

该试验最初招募了735例患者而未限制KRAS状态，但在得知西妥昔单抗对这些患者无活性之后调整了试验方案，改为仅招募KRAS野生型患者。在2011年ASCO年会上，Heinemann博士报告称，这两种治疗方案在KRAS突变性肿瘤亚组患者中并未显示出疗效和生存率方面的差异。

在野生型肿瘤患者中，西妥昔单抗组患者的中位治疗持续时间更短(4.7 个月 vs. 5.3个月)，鉴于西妥昔单抗易引起皮肤问题，这一差异并不令人意外。但研究者表示，两组的毒性问题均在可控范围内。

主要研究者、德国慕尼黑大学的肿瘤内科学教授Volker Heinemann博士在ASCO年会期间的新闻发布会上指出：“基于上述发现，我们认为，对于KRAS野生型转移性结直肠癌患者，以西妥昔单抗联合FOLFIRI化疗作为一线治疗可获得明确的生存益处。”

然而，FIRE-3是一项阴性试验，针对所有592例患者的治疗意向分析显示，两组在主要终点(客观应答率)方面并无统计学差异[62% vs. 57%；比值比(OR)，1.18；P=0.18]。不过，在可评估疗效的526例患者中，西妥昔单抗组的应答率明显更高(72.2% vs. 63.1%；OR，1.52；P=0.17)。

ASCO发言人、美国俄亥俄州立大学综合癌症中心主任Richard Goldberg医生指出，这项研究的关键信息在于：转移性结直肠癌患者有一种以上治疗方案可供选择。不过并不一致的研究结果也带来了一个问题：后续治疗对总生存的影响是怎样的？“不可否认的是，各线治疗都会对结局产生影响，我希望AIO研究者回头再分析一下他们的数据，看看受试者接受的二线、三线和四线治疗都是什么，这或许有助于阐释该研究得出的颇有些奇怪的结果。”

Heinemann博士答复称，将在即将举行的巴塞罗那会议上公布这些数据，并且这些数据提示以西妥昔单抗为基础的治疗比贝伐珠单抗更有助于缩小肿瘤。他还补充道，大约60%的患者接受了二线治疗，大约40%的患者交叉到另一个研究组。

美国西北大学Robert Lurie综合癌症中心副主任Al B. Benson III医生在接受采访时表示，该研究观察到的生存获益令人印象深刻，将会巩固西妥昔单抗+ FOLFIRI的地位，不过不太可能明显改变临床医生对贝伐珠单抗+ FOLFOX(亚叶酸、5氟尿嘧啶及奥沙利铂)的处方习惯，后一方案目前在美国占据着主导地位。很多医生将会继续等待北美合作研究组的C80405Ⅲ期试验结果，该试验在部分接受FOLFIRI化疗的患者中比较了西妥昔单抗和贝伐珠单抗，但多数患者接受的是FOLFOX化疗。“使用西妥昔单抗时面临的一大问题在于，很多患者不愿承受皮疹风险。我们发现，一些野生型患者宁愿推迟接受西妥昔单抗治疗。”

Goldberg医生同意“FIRE-3难以改变美国临床实践”的看法，并表示80405试验的研究者已申请提前公布试验数据(原计划在明年公布)。“我们希望数据监测委员会能对此作出回应，假如没有对数据保密的强制性原因存在，不妨在今年发布数据以供公众监督。”

在近期发布的2013年美国国立综合癌症网络(NCCN)转移性结直肠癌指南中，FOLFOX和FOLFIRI均被列为推荐的一线化疗方案，并且可选择加用一种生物制剂。假如患者接受含贝伐珠单抗的一线治疗，指南建议在发生进展后继续使用贝伐珠单抗和另一种化疗支柱方案。曾参与该指南更新的80405试验研究者Benson医生表示，后续治疗以及降低剂量、治疗持续时间等因素，均会影响对FIRE-3生存数据的解读。

Heinemann博士承认获得了由研究赞助者默克公司提供的酬金和研究资金，并且从罗氏公司获得酬金。多位合作者报告称从默克公司获得酬金和研究资金。默克公司在美国以外地区销售西妥昔单抗。

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By: PATRICE WENDLING, Oncology Practice

CHICAGO – Pairing cetuximab with first-line FOLFIRI chemotherapy significantly extended overall survival by roughly 4 months over bevacizumab plus FOLFIRI among patients with KRAS wild-type metastatic colorectal cancer in the phase III FIRE-3 trial.

Patients in the cetuximab (Erbitux) and bevacizumab (Avastin) arms had similar times to disease progression of 10 and 10.3 months, respectively (Hazard ratio, 1.06; P = .54), but those given cetuximab lived for 28.7 months vs. 25 months with bevacizumab (HR, 0.77; P = .017).

The German AIO (Arbeitsgemeinschaft In-ternistische Onkologie) study group trial is the first to directly compare the two approved targeted agents with FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy.

"Based on our findings, we believe that a substantial gain in survival can be achieved when doctors offer cetuximab-based treatment as first-line to their patients with KRAS wild-type metastatic colorectal cancer," lead author Dr. Volker Heinemann said in a press briefing at the annual meeting of the American Society of Clinical Oncology (ASCO), where the data were presented.

FIRE-3 was a negative trial, however, as the primary end point of objective response rate was statistically similar between the cetuximab and bevacizumab arms at 62% and 57% in an intent-to-treat analysis of all 592 patients (odds ratio, 1.18; P = .18). Response was significantly greater with cetuximab though among the 526 patients assessable for efficacy (72.2% vs. 63.1%; OR, 1.52; P = .17), said Dr. Heinemann, professor of medical oncology at the University of Munich.

The take-home message is that patients with metastatic colorectal cancer have options, but the mixed results also raise questions about the influence of subsequent therapies on overall survival, Dr. Richard Goldberg, physician-in-chief at The Ohio State University’s Comprehensive Cancer Center and an ASCO spokesperson, said at the briefing.

"Really all of the different lines of therapy contributed to this outcome and I would challenge the investigators from the AIO to go back and study their data -- study the second, third and fourth-line treatments that their patients had and help explain this finding, which does seem a bit anomalous," he said.

Dr. Heinemann responded that these data will be presented at a forthcoming meeting in Barcelona, and that data suggest cetuximab-based therapy causes deeper tumor shrinkage than bevacizumab. About 60% of all patients received second-line therapy and about 40% crossed over to the other study arm, he added.

The survival benefit is impressive and will reinforce cetuximab and FOLFIRI in those already using the combination, but is unlikely to result in a profound shift in prescribing habits away from bevacizumab and FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) chemotherapy, the dominant combination in the United States, Dr. Al B. Benson III, said in an interview. Instead, many clinicians are awaiting results from the North American intergroup phase III C80405 trial comparing cetuximab with bevacizumab in some patients on FOLFIRI, but the majority on FOLFOX.

"One of the problems in the U.S. with cetuximab is that many patients really do not want to be exposed to the risk of rash; so, what we’ve found, is that people would rather postpone that decision to receive cetuximab if they’re wild-type," said Dr. Benson, professor of hematology/oncology and associate director for clinical investigations at the Robert Lurie Comprehensive Cancer Center of Northwestern University in Chicago.

Dr. Goldberg agreed that it’s doubtful FIRE-3 will change U.S. practice, and said the 80405 trial investigators have petitioned to have the data released ahead of its expected timeline of next year.

"We’re hoping that the data monitoring committee will respond to the uncertainty that this presentation raises and if there is no compelling reason to keep the data blinded, release the data for public scrutiny sometime this year," he said in an interview.

FOLFOX and FOLFIRI are each recommended first-line treatments in the recently updated 2013 National Comprehensive Cancer Network (NCCN) guidelines for metastatic colon cancer, with the addition of a biologic agent optional. If patients receive a bevacizumab-containing regimen first line, the guidelines now recommend that bevacizumab continuation with a different chemotherapy backbone after progression.

Dr. Benson, who helped pen the 2013 NCCN update and is an 80405 trial investigator, said that subsequent therapies, as well as dose reductions and treatment duration, will influence interpretation of the FIRE-3 survival data.

FIRE-3 randomized 592 patients with wild-type tumors to FOLFIRI every 2 weeks plus cetuximab 400 mg/m2 on day 1, followed by 250 mg/m2 weekly, or bevacizumab 5 mg/kg every 2 weeks. An ECOG performance status of 0-1 was present in 98% of patients, 66% were male, and their median age was 64 years.

The trial initially recruited 735 patients independent of KRAS status, but was amended to include only KRAS wild-type tumors after it became known that cetuximab was not active in these patients. At the ASCO 2011 meeting, Dr. Heinemann reported no difference in efficacy or survival between the two strategies in the subgroup of patients with KRAS-mutated tumors.

Among patients with wild-type tumors, the median treatment duration was shorter with cetuximab at 4.7 months vs. 5.3 months with bevacizumab. This is not surprising given the potential for skin issues with cetuximab, but that the toxicity profiles were manageable for both combinations, he said in an interview.

Dr. Heinemann reported honoraria, other remuneration and research funding from the study sponsor, Merck, and honoraria and other remuneration from Roche. Several of his coauthors reported honoraria, other remuneration, and research funding from Merck. Merck distributes cetuximab outside of the United States.

Heinemann, V., et al. "Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRIE plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0303 (FIRE-3)." LBA3506.