CHICAGO (EGMN) – Another phase II study has picked up a signal for cetuximab in metastatic esophageal cancer, but more data are needed to clearly define the role of epidermal growth factor receptor therapy in this setting.
Therapies that target EGFR, such as the monoclonal antibody cetuximab, are of interest because EGFR is expressed in three-fourths of patients with esophageal cancer, and overexpression correlates with prognosis. In contrast, KRAS gene mutations occur in only about 2% of esophageal cancers, making it a far less relevant target than in colorectal cancer, explained the lead author, Dr. Peter Enzinger, clinical director of the gastrointestinal cancer center at the Dana-Farber Cancer Institute in Boston.
Dr. Enzinger presented a phase II study that compared cetuximab in combination with the following three standard chemotherapy regimens. All three arms met the primary end point of at least a 40% response rate, he reported at the annual meeting of the American Society of Clinical Oncology.
– Oxaliplatin, leucovorin, and fluorouracil chemotherapy plus cetuximab (FOLFOX-C) demonstrated good response and survival outcomes and was the best tolerated, suggesting it is the best regimen for phase III development, he said.
– Cisplatin and irinotecan (plus cetuximab [IC-C]) had the lowest response and survival rates and the most adverse events.
– Epirubicin, cisplatin and fluorouracil plus cetuximab (ECF-C) elicited the highest response, but the regimen had the highest treatment-related mortality and treatment-related modifications.
Although the results favor the FOLFOX-C regimen, they were made in the context of an underpowered phase II study that was not designed to make such formal comparisons, said invited discussant Dr. Charles Fuchs, director of the gastrointestinal cancer center at Dana-Farber. Additionally, potential imbalances in patient characteristics cannot be excluded. As such, the results should be examined in multivariate analyses that adjust for relevant patient and disease characteristics.
“Without a no-cetuximab control arm, this trial does not address the relative benefit of cetuximab in this setting,” he said.
The ECF-C and FOLFOX-C arms, however, appeared to do better when they were compared with historical controls, with a 15% improvement in response rate and a 2.5-month improvement in overall survival, Dr. Enzinger said. Patients in the IC-C arm did worse than in previous single-institution, phase II studies.
More robust data exist in squamous cell carcinoma, where a randomized, phase II trial suggested a benefit for first-line cetuximab in combination with cisplatin and infusional 5-FU (Ann. Oncol. 2009;20:1667-73), he said.
Ultimately, both Dr. Fuchs and Dr. Enzinger agreed that the ongoing EXPAND and REAL-3 trials, which are assessing the addition of cetuximab or panitumumab to standard chemotherapy regimens, should define the role of anti-EGFR therapy in esophagogastric adenocarcinoma.
In the current trial, all patients received a chemotherapy regimen and a loading dose of cetuximab at 400 mg/m2, and subsequently 250 mg/m2 weekly.
Of the 210 evaluable patients, 55% had esophageal cancer and 42% had GI junction cancer, with the rest unknown. Nearly half (48%) had an ECOG performance status of 0 and 49% a performance status of 1. None had locally advanced disease; only seven cases were post esophagectomy. Their median age was about 60 years. The analysis was powered for adenocarcinoma, although a small number of patients with squamous cell carcinoma were enrolled.
The objective response rate according to RECIST (Response Evaluation Criteria in Solid Tumors) was 57.8% for ECF-C, 45.6% for IC-C and 53.6% for FOLFOX-C (P less than .0001 for all three), Dr. Enzinger said. The median duration of response was 6.1 months, 5.3 months, and 5.7 months, respectively.
The median overall survival time was 11.5 months for the ECF-C regimen, 8.9 months for IC-C and 12.4 months for FOLFOX-C. Corresponding median progression-free survival was 5.9 months, 5.0 months, and 6.7 months, he said.
Grade 3/4 hematologic toxicity occurred in 49% of patients on ECF-C, in 58% on IC-C, and in 46% on FOLFOX-C. There were no significant differences between arms, and no grade 5 events.
Two-thirds of all patients had nonhematologic toxicities, with significantly more gastrointestinal and metabolic events occurring in the IC-C arm and a trend toward more neurologic events in the FOLFOX-C arm. There was also a significantly higher rate of death in the ECF-C arm at 6%, compared with none in the other arms (P = .01), Dr. Enzinger said.
Treatment modifications occurred in 90% of patients in the ECF-C arm, 86% in the IC-C arm, and 72% in the FOLFOX-C arm, with the ECF-C and FOLFOX-C arms significantly different (P = .03), he said.
The National Cancer Institute, Bristol-Myers Squibb Co., Pfizer Inc., and Sanofi-Aventis supported the trial. The researchers disclosed relationships with Bristol-Myers Squibb, ImClone Systems Inc., Pfizer, Roche, and Sanofi-Aventis. Dr. Fuchs reported acting as an advisor or consultant for 10 companies including Merck and Co., which markets cetuximab.
Copyright (c) 2009 Elsevier Global Medical News. All rights reserved. This material may not be published, broadcast, rewritten, or redistributed.
芝加哥(EGMN)——一项最新的Ⅱ期研究提供了有关西妥昔单抗对转移性食管癌治疗效果的初步结果，但要明确这种表皮生长因子受体(EGFR)疗法对此类患者的治疗作用，仍需进一步研究。
如今，靶向EGFR的治疗方法受到广泛关注，如单克隆抗体西妥昔单抗，这是因为3/4的食管癌患者表达EGFR，且其过表达与患者预后相关。波士顿Dana-Farber癌症研究所胃肠癌症中心临床主任Peter Enzinger博士解释说，相比之下，仅2%的食管癌患者发生KRAS基因突变，这使得其与食管癌的相关性远不及其与结直肠癌的相关性那么密切。
Enzinger博士在美国临床肿瘤学会年会上报告了一项比较西妥昔单抗分别联合以下3种标准化疗方案对食管癌治疗效果的Ⅱ期研究的结果。3组患者均达到研究主要终点，即至少40%的有效率。
—奥沙利铂、亚叶酸和氟尿嘧啶+西妥昔单抗(FOLFOX-C)治疗组有效率和生存结果均较好，并且患者对其耐受性最佳，这提示这一方案是用于III期临床开发的最佳方案。
—顺铂和依立替康[+西妥昔单抗(IC-C)]治疗组的有效率和生存率最低，且不良事件最多。
—表柔比星、顺铂和氟尿嘧啶+西妥昔单抗(ECF-C)治疗组的有效率最高，但这种方案的治疗相关病死率和中转率最高。
该研究的特邀评论员、Dana-Farber癌症研究所胃肠癌症中心主任Charles Fuchs博士说，虽然这一结果中FOLFOX-C方案的效果更佳，但这只是一项检验效能不足的Ⅱ期研究的结果，并且该研究并非旨在对以上方案进行正式比较。另外，也不能排除患者临床特征方面潜在的不均衡性。因此，此结果应在对相关的患者和疾病特征进行校正后的多因素分析中加以验证。
Fuchs博士说：“由于未设不含西妥昔单抗的对照组，该研究未能阐明西妥昔单抗对此类患者的相对益处。”
Enzinger博士说，然而，与历史对照相比，ECF-C和FOLFOX-C治疗组似乎效果更好，其有效率提高了15%，总体生存期也延长了2.5个月。与以往单中心Ⅱ期研究相比，IC-C治疗组的效果不佳。
Enzinger博士说，有关西妥昔单抗对鳞状细胞癌治疗效果的数据更为强大，一项随机Ⅱ期临床研究发现，此类患者可从西妥昔单抗联合顺铂、静脉输注氟尿嘧啶的一线治疗中获益。
最后，Fuchs博士和Enzinger博士均认为，正在进行的EXPAND和REAL-3研究将明确抗EGFR治疗对胃食管腺癌的治疗效果，这两项研究均正在评价标准化疗方案联合西妥昔单抗或帕尼单抗的效果。
本项研究中，所有患者均接受某一种方案化疗和西妥昔单抗(初始剂量400 mg/m2，之后每周250 mg/m2)治疗。
在210例可供评价的患者中，55%的患者患有食管癌，42%有胃肠交界癌，其他患者情况不明。近半数(48%)患者的ECOG体能状况评分为0，49%的患者评分为1。无局部晚期肿瘤患者，仅7例为食管切除术后。患者中位年龄为60岁。，尽管其其也纳入了少数鳞状细胞癌患者，但该研究针对的是腺癌。
Enzinger博士表示，据实体瘤疗效评价标准(Response Evaluation Criteria in Solid Tumors，RECIST)，ECF-C治疗组的客观有效率为57.8%，IC-C治疗组为45.6%，FOLFOX-C治疗组为53.6%(3组P值均小于0.0001)。3组的中位有效持续时间分别为6.1、5.3和5.7个月。
ECF-C治疗组的中位总体生存时间为11.5个月，IC-C治疗组为8.9个月，FOLFOX-C治疗组为12.4个月。而3组相应的中位无进展生存期分别为5.9、5.0和6.7个月。
ECF-C治疗组3/4级血液毒性的发生率为49%，IC-C治疗组为58%，而FOLFOX-C治疗组为46%；3组两者之间均无显著差异，亦无5级血液毒性事件发生。
2/3的患者发生了非血液学毒性事件，IC-C治疗组明显发生更多的胃肠和代谢性不良事件，而FOLFOX-C治疗组更易发生神经系统不良事件。Enzinger博士说，ECF-C治疗组病死率(6%)显著高于其他两组(均为0)(P=0.01)。
ECF-C治疗组中，90%的患者改变了治疗方案，IC-C治疗组有86%，而FOLFOX-C治疗组有72%，ECF-C组与FOLFOX-C组之间差异显著(P=0.03)。
该研究获得了美国国立癌症研究所、百时美施贵宝制药公司、辉瑞制药公司、赛诺菲-安万特制药公司的资助。研究者声明与百时美施贵宝、ImClone系统、辉瑞、罗氏及赛诺菲-安万特公司之间存在关系。Fuchs博士表示其为10家公司(包括西妥昔单抗制造商默克公司)的咨询师或顾问。
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