西妥昔单抗不胜任胃癌一线治疗

维也纳——德国莱比锡大学癌症中心的Florian Lordick博士在欧洲肿瘤内科学会(ESMO)年会上报告的EXPAND试验结果表明，胃癌患者在接受一线化疗药物的基础上添加西妥昔单抗，收益-风险比反而不佳。

在这项开放、随机对照的西妥昔单抗(爱必妥)Ⅲ期试验中，870例未行切除术的晚期胃腺癌或胃食管交界处腺癌患者随机接受顺铂(第1天80 mg/m2)+卡培他滨(1,000 mg/m2 ，2次/天，第1天晚上至第15天早上)添加或不添加西妥昔单抗(初始剂量400 mg/m2 ，然后每周250 mg/m2)。患者平均年龄59~60岁，3/4为男性，1/3为胃癌，几乎所有患者都为转移性癌症。

结果显示，西妥昔单抗组与单纯接受2种化疗药物的患者相比，主要终点指标——无进展生存期呈非显著性下降，分别为4.4个月和5.6个月，风险比(HR)为1.09 (P=0.3158)。患者在总生存期或客观应答率方面也未见受益：总生存期分别为9.4个月和10.7个月 (HR=1.0，P=0.96)，最佳客观应答率分别为30%和 29%。患者分层分析结果仍然如此。

但值得注意的是，西妥昔单抗组血液系统不良事件率略低。西妥昔单抗组和单纯化疗组3/4级中性粒细胞减少症发生率分别为22%和32%，3/4级贫血发生率分别为9%和11%。该结果与其他有关西妥昔单抗联合化疗药物治疗结直肠癌、头颈癌和肺癌的研究结果相反。但西妥昔单抗组非血液系统不良事件比单纯化疗组更为多见，包括3/4级皮肤反应(13% vs. 0%)、腹泻(8% vs. 4%)、手足综合征(7% vs. 2%)、低镁血症(11% vs. 1%)和低钾血症(13% vs. 9%)。西妥昔单抗组3/4级心脏不良事件发生率也略高(6.7% vs. 4.1 %)。

Lordick博士称：“包括卡培他滨和顺铂的一线化疗方案中添加西妥昔单抗未能使晚期胃癌患者受益，令人遗憾。”FDA已批准西妥昔单抗联合包含伊立替康治疗方案，用于表皮生长因子受体(EGFR)表达的转移性结直肠癌的治疗。

这已经不是首个有关EGFR抑制剂用于胃癌治疗的失望结果。在最近报告的有关REAL-3 试验的结果中，标准化疗方案添加帕尼单抗(维克替比)也未能使食管胃癌患者受益。PETACC8试验的结果也表明，包含奥沙利铂的辅助化疗方案添加西妥昔单抗也未使晚期转移性结直肠癌症患者获益。

日内瓦大学医院的Arnaud Roth博士认为，该项研究在一定程度上证实了 ASCO年会上报告的REAL-3试验结果。他指出，尽管未达到终点指标，但这是一项设计和实施均十分优秀的研究，为转化研究提供了绝佳机会。然而，Roth博士不同意该项研究是更多了解EGFR抑制剂与胃癌的最佳试验。尽管如此，考虑到患者同意参加这项研究，能够得到相关数据和生物标本非常重要，也是“一种道义责任”。Roth博士没有参与该项研究。

Lordick博士在Roth博士指出：“好消息是，已经得到了97%的患者组织，有关标志物的分析研究正在进行中。”

该研究得到默克公司资助。Lordick博士曾接受默克、葛兰素史克和费森尤斯生物技术公司的经费和酬金以及安进、Ganymed、Ribological和罗氏公司的咨询费。Roth博士曾担任默克公司顾问。

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By: SARA FREEMAN, Oncology Practice

VIENNA – Adding cetuximab to first-line chemotherapy for gastric cancer was associated with a worse benefit-to-risk ratio in the open-label, randomized, controlled, phase III EXPAND trial.

Investigators reported that progression-free survival was nonsignificantly decreased in patients who had received cetuximab (Erbitux) in addition to capecitabine (Xeloda) and cisplatin treatment versus those just receiving the chemotherapy doublet. Progression-free survival, which was the primary end point, was 4.4 months versus 5.6 months, respectively, with a hazard ratio (HR) of 1.09 (P = .3158).

There was also no benefit in overall survival or objective response rates. Overall survival was 9.4 months vs. 10.7 months (HR, = 1.0; P = .96). The best objective response rates were 30% and 29%, respectively.

"Unfortunately there was no benefit from adding cetuximab to chemotherapy [consisting of] capecitabine and cisplatin as first-line treatment for advanced gastric cancer," said Dr. Florian Lordick, who presented the findings at the European Society for Medical Oncology Congress.

"The results are consistent across subgroups," added Dr. Lordick, of the University Cancer Center Leipzig in Germany.

This is not the first disappointment seen with the use of an epidermal growth factor receptor inhibitor (EGFR) in gastric cancer. Recently reported results of the REAL-3 trial showed that panitumumab (Vectibix) was also not of benefit when added to standard chemotherapy for esophagogastric cancer.

Cetuximab also failed to show a benefit in patients when added to adjuvant oxaliplatin-containing chemotherapy for advanced metastatic colorectal cancer in the PETACC8 trial.

It is approved by the Food and Drug Administration in combination with irinotecan-containing regimens against EGFR-expressing metastatic colorectal cancer.

In the EXPAND study, 870 patients with unresected, advanced adenocarcinoma of the stomach gastric or gastroesophageal junction were randomized to receive cisplatin (80 mg/m2 on day 1) and capecitabine (1,000 mg/m2 twice daily, starting the evening of day 1 until the morning of day 15) with or without additional cetuximab (400 mg/m2 initial dose, then 250 mg/m2 per week).

The median age of enrolled patients was 59-60 years. Three quarters of participants were men and the main tumor site was the stomach in about a third of the cases with almost all patients having metastatic disease.

"Interestingly, the rate of hematologic adverse events was somewhat lower in the chemotherapy plus cetuximab arm," Dr. Lordick said. Compared with chemotherapy only, the rates of grade 3/4 neutropenia were 22% with cetuximab and 32% without. Grades 3/4 anemia occurred in 9% vs. 11% of patients, respectively.

"This is in contrast to other studies that have been performed in colorectal cancer, head and neck cancer, and lung cancer, where usually an increase of hematologic toxicity is seen with the administration of cetuximab in combination with chemotherapy," Dr. Lordick observed.

Nonhematologic adverse events, however, were more common in the cetuximab-containing vs. cetuximab-free arm, including grade 3 or 4 skin reactions (13% vs. 0%), diarrhea (8% vs. 4%), hand-foot syndrome (7% vs. 2%), hypomagnesemia (11% vs. 1%), and hypokalemia (13% vs. 9%).

Patients given the cetuximab-containing regimen also had a slightly higher rate of grade 3/4 cardiac adverse events (6.7% vs. 4.1 %).

"This study confirms a little bit what we heard at ASCO in the REAL-3 trial," said Dr. Arnaud Roth of Geneva University Hospital. Dr. Roth, who was not involved in the EXPAND study, noted that it was a well designed and conducted study and although negative, provided an excellent opportunity to conduct translational research.

However, Dr. Roth disagreed that this was the right setting to learn much more about anti-EGFRs and gastric cancer. Nevertheless, gaining access to the data and biospecimens was important and "a moral obligation" considering the patients who had given their consent for their participation in the trial.