CHICAGO (EGMN) – The highly anticipated, targeted-therapy AVAGAST trial failed to demonstrate a significant survival advantage for bevacizumab plus chemotherapy in the first-line treatment of advanced gastric cancer, but it leaves the door open for further investigation.
Patients who were given capecitabine and cisplatin plus bevacizumab survived a median of 12.1 months, compared with 10.1 months for the same chemotherapy plus placebo (hazard ratio, 0.87; P = .10). A subgroup analysis revealed no significant advantage for any patient population.
The targeted agent did, however, significantly improve the study’s secondary efficacy end points, indicating clinical activity for bevacizumab plus chemotherapy in advanced gastric cancers, said Dr. Yoon-Koo Kang of the Asan Medical Center in Seoul, South Korea, who presented the findings at the annual meeting of the American Society of Clinical Oncology.
The overall response rate for chemotherapy plus bevacizumab was significantly higher at 46% vs. 37% for chemotherapy and placebo (P = .031). Median progression-free survival also significantly favored the bevacizumab combination, at 6.7 months vs. 5.3 months for chemotherapy and placebo (HR, .80; P = .0037), he said.
“Despite these extremely provocative results from AVAGAST, the findings do not support routine use of bevacizumab in advanced esophagogastric adenocarcinoma,” said Dr. Charles Fuchs, director of the center for gastrointestinal cancer at the Dana-Farber Cancer Institute in Boston, who was invited to discuss the study.
Differences in the use of second-line therapy between arms may account for the lack of overall survival benefit, but he suggested that another culprit may be regional differences.
The investigators reported that the overall survival benefit with bevacizumab was greatest among patients who were enrolled in the Americas (HR, 0.63), was somewhat less in Europe (HR, 0.85), and was virtually absent in Asia (HR, 0.97).
Progression-free survival followed a similar trend: Americas (HR, 0.65), Europe (HR, 0.71), Asia (HR, 0.92), said Dr. Kang, who called the findings “hypothesis generating.”
“This East vs. West disparity raises the possibility that regional differences in patient selection, clinical practice, population genetics, or tumor biology could have modified the effect of bevacizumab in the trial,” Dr. Fuchs said. Nonetheless, no significant differences were observed in treatment effect across intestinal vs. diffuse histologies, or across primary tumor sites of gastroesophageal junction vs. stomach.
“Without question, there remains a critical need for novel, more effective therapies for patients with gastric and esophageal cancer,” he said. “In my opinion, given the apparent trends observed in AVAGAST, further investigation of bevacizumab and other targeted agents in this pathway are indeed warranted.”
Bevacizumab was considered a promising candidate because it has been shown to improve survival in several solid tumors when combined with chemotherapy. This humanized monoclonal antibody targets VEGF (vascular endothelial growth factor), which is overexpressed in many human tumors including gastric cancer, and it has demonstrated promising phase II results in advanced gastric cancer (J. Clin. Oncol. 2006;24:5201-6).
AVAGAST evenly randomized 774 patients with metastatic or inoperable locally advanced adenocarcinoma of the stomach or gastroesophageal junction to oral capecitabine 1,000 mg/m2 twice daily on days 1-14 and cisplatin 80 mg/m2 on day 1 for a maximum of six cycles, with or without bevacizumab 7.5 mg/kg on day 1. Capecitabine and bevacizumab/placebo were given until disease progression.
Roughly 95% of patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 0-1 and metastatic disease. Two-thirds were male; their median age was about 58 years.
No new safety signals with bevacizumab were observed.
Some audience members questioned the trial’s rapid enrollment, which occurred at 93 centers in just 15 months, and forced the team to miss an event-triggered interim analysis because it occurred too close to the final analysis. Dr. Kang said the fast pace reflects the investigators’ hope and enthusiasm for new targeted agents.
Further analysis is ongoing, including preplanned biomarker analysis, to explain these “disappointing but challenging results,” he said.
Genentech Inc. sponsored the trial in collaboration with Roche Pharma AG and Chugai Pharmaceutical Co. The investigators reported employment or leadership roles with Roche, acting in a consultancy or advisory role for and receiving honoraria from Roche, Jeil Pharmaceutical Co., and Sanofi-Aventis, and research funding from Roche and Genentech. Dr. Fuchs reported acting in a consultancy or advisory role for 10 companies, including Genentech and Roche, which comarket bevacizumab.
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芝加哥(EGMN)——备受期待的靶向治疗AVAGAST试验显示，贝伐单抗联合化疗用于晚期胃癌的一线治疗并不具有显著改善生存时间的优势，但该试验并未因此关闭进一步研究的大门。
卡培他滨/顺铂+贝伐单抗组患者的中位生存时间为12.1个月，而相同化疗+安慰剂组患者的中位生存时间为10.1个月(危险比HR，0.87；P = 0.10)。 亚组分析显示，贝伐单抗在任何患者人群中均无显著优势。
韩国首尔峨山医学中心的Yoon-Koo Kang博士在美国临床肿瘤学会年会上对该研究结果进行报告时指出，但这一靶向药物确实能够显著改善该研究的次要疗效终点，这表明贝伐单抗+化疗对晚期胃癌具有临床活性。
他表示，化疗+贝伐单抗组总有效率显著高于化疗+安慰剂组(46%对37%，P = 0.031)。此外，化疗+贝伐单抗组中位无进展生存期也显著长于化疗+安慰剂组(6.7个月对5.3个月；HR，0.80；P = 0.0037)。
波士顿Dana-Farber癌症研究所胃肠癌中心负责人Charles Fuchs博士说：“尽管这些AVAGAST试验结果非常令人兴奋，但它们并不支持将贝伐单抗用于晚期食管胃腺癌的常规治疗。”
二线治疗使用方面的组间差异可能是导致缺乏总生存益处的原因，但他表示，另一个原因可能是地区差异。
研究者指出，美国入组患者从贝伐单抗获得的总生存益处最大(HR，0.63)，其次为欧洲入组患者(HR，0.85)，在亚洲入组患者中则几乎未观察到这种益处(HR，0.97)。
在无进展生存方面也观察到相似趋势：美国(HR，0.65)、欧洲(HR，0.71)、亚洲 (HR，0.92)。Kang博士称这些结果可能“产生假说”。
Fuchs博士说：“这种东西方差异使我们更加相信，病例选择、临床实践、群体遗传学或肿瘤生物学方面的地区差异可能影响了该试验中贝伐单抗的效果。” 然而，未观察到以下方面的治疗效果存在显著差异：肠道病变对弥漫性病变、胃食管交界处原发性肿瘤对胃原发性肿瘤。
他说：“毫无疑问，对于胃食管癌患者，迫切需要更有效的新型疗法。我认为，鉴于在AVAGAST试验中已观察到明显趋势，确实有必要沿着这一方向对贝伐单抗和其他靶向药物继续进行进一步研究。”
贝伐单抗被认为是一种前景广阔的候选药物，因其与化疗联合时可改善几种实体瘤患者的生存。这种人源化单克隆抗体靶向于胃癌等许多人癌组织中过度表达的血管内皮生长因子(VEGF)。II期研究显示，贝伐单抗治疗晚期胃癌的结果喜人(J. Clin. Oncol. 2006;24:5201-6)。
在AVAGAST试验中，774例罹患转移性或不可手术的胃或胃食管交界处局部晚期腺癌的患者被随机平均分成两组，在口服卡培他滨(1,000 mg/m2，2次/d，第1~14天)/顺铂(80 mg/m2，第1天)(最多6个周期)基础上加服或不加服贝伐单抗(7.5 mg/kg，第1天)。给予卡培他滨和贝伐单抗/安慰剂直至出现疾病进展。
约95%的患者为转移癌患者，并且东部肿瘤协作组(ECOG)体能状态评分为0~1分。2/3为男性，中位年龄约为58岁。
未观察到与贝伐单抗相关的新安全性问题。
该试验在93个中心进行了为期仅15个月的快速招募工作，并且试验小组被迫放弃进行事件触发中期分析(event-triggered interim analysis)，因该分析的时间与最终分析过于接近。一些与会者对此提出了质疑。Kang博士回应称，快速的研究步伐反映了研究者对新型靶向药物进行研究的迫切希望和热情。
他表示，进一步分析(包括原先计划的生物标志物分析)正在进行中，以对这些“令人失望但具有挑战性的结果”作出解释。
该试验由基因泰克公司、罗氏制药公司和中外制药株式会社共同申办。研究者声明是罗氏的员工或领导，并担任罗氏、Jeil Pharmaceutical公司和赛诺菲-安万特公司的顾问和从这些公司获得酬金，同时还从罗氏和基因泰克公司获得研究资金。Fuchs博士声明是贝伐单抗联合营销商基因泰克和罗氏等10家公司的顾问。
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