CHICAGO (EGMN) – AMG 386, a vascular endothelial growth factor used to inhibit angiogenesis, has been found to be active against advanced ovarian cancer, based on the results of a multisite phase II study.
“While VEGF may be the master regulator required to initiate angiogenesis, it must work with other factors including the angiopoietins to establish a network of capillaries and to establish blood flow,” explained Dr. Beth Y. Karlan, lead author of a placebo-controlled phase II study that assessed two doses of the experimental peptibody in combination with paclitaxel.
AMG 386, a first-in-class recombinant peptide–Fc fusion protein, neutralizes the interaction between the Tie2 receptor and angiopoietin 1 and 2, the latter of which is upregulated in many ovarian cancers.
Researchers at 38 sites in five countries randomized 161 women with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer on a 1:1:1 basis to paclitaxel 80 mg/m2 for 3 weeks with 1 week off plus weekly IV AMG 386 at 10 mg/kg; or weekly IV AMG 386 at 3 mg/kg, or weekly IV placebo. Treatment was continued until disease progression or unacceptable toxicity developed.
More than half of the patients had failed a prior platinum-based regimen; 5% had received prior anti-VEGF therapy. Their median age was 60 years.
Progression-free survival was 7.2 months in the high-dose experimental arm, 5.7 months in the low-dose experimental arm, and 4.6 months in the placebo arm (hazard ratio, 0.76 for either AMG arm vs. placebo; P = .17), Dr. Kaplan said. A trend test looking for a dose response demonstrated a significant P value of .037, suggesting that the higher dose was superior.
A subgroup analysis stratified by prior treatment showed the “greatest benefit from AMG treatment appears to be in those patients who are our most challenging group, those with refractory and resistant disease,” said Dr. Karlan, director of the Women’s Cancer Research Institute at Cedars-Sinai Medical Center, Los Angeles.
The objective response rate per RECIST criteria, including complete and partial responses, was 37% in the high-dose arm A, 19% in the low-dose arm B, and 27% in the placebo arm C, she said at the meeting.
Confirmed CA-125 response rates by Gynecologic Oncology Group criteria were 71% vs. 58% vs. 28%, respectively. All of the women in the high-dose arm had a reduction in their CA 125 levels from baseline, 84% did in the low-dose arm and 63% did in the placebo arm.
“If one looks back in the field of similar experiments in similar populations, the signal is a very good one and a very promising one that needs to be pursued,” said Dr. George Coukos, director of the ovarian cancer research center at the University of Pennsylvania, Philadelphia, who was invited to discuss the findings.
He said he could find no particular weaknesses in the design of the study, except that there were no translational studies.
Dr. Kaplan described the therapy as being very well tolerated, with the most notable adverse event being peripheral edema of any grade reported in more than half of patients. Grade 3 hypokalemia occurred in all three arms, but the study did not control for the use of diuretics.
She noted that the adverse event profile of AMG 386 is distinct from that of VEGF axis inhibitors. In particular, there were no bowel perforations and no increased incidences of hypertension, thromboembolic events, proteinuria, or hemorrhagic events associated with AMG administration.
Exposure-response analysis suggests that the maximum effective dose of AMG 386 may not have been reached at 10 mg/kg. Further investigation using higher doses of AMG 386 is warranted in women with ovarian cancer, Dr. Kaplan concluded.
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芝加哥(EGMN)——基于一项多中心II 期临床研究的结果，研究者发现AMG 386(用于抑制血管生成的一种血管内皮生长因子)对晚期卵巢癌患者有效。
据一项安慰剂对照II 期临床研究的主要作者Beth Y. Karlan 博士解释说：“尽管血管内皮生长因子(VEGF)是机体赖以启动血管生成的最重要调控因子，但该因子必须与包括促血管生成素在内的其他因子共同发挥作用才能构建毛细血管网并确保血供”。该研究就联用2种不同剂量的试验药肽体(peptibody)与紫杉醇的疗效进行了评估。
AMG 386是首个获批的重组Fc-肽融合蛋白类药物，该药可以中和Tie2受体与促血管生成素1和2之间的相互作用，从而上调了卵巢癌患者体内的促血管生成素水平。
来自5个国家的38个医学中心的研究者们将161例患有复发性卵巢上皮癌、输卵管癌或原发性腹膜癌的女性患者按1:1:1的比例分配至服用80 mg/m2紫杉醇3周(之后停药1周)+每周静脉注射1次AMG 386 10 mg/kg；或每周静脉注射1次AMG 386 3 mg/kg或安慰剂。治疗一直持续到患者发生疾病进展或产生无法接受的毒性效应为止。
有超出半数的患者在之前采用以铂类药物为主的治疗方案时疗效不佳；有5%的患者之前曾接受过抗VEGF治疗。患者的中位年龄为60岁。
Kaplan博士说，高剂量试验药物组患者的无进展生存期为7.2个月，其在低剂量试验药物组患者为5.7个月，安慰剂组患者则为4.6个月(任意AMG药物组对安慰剂组的危险比0.76；P=0.17)。一项旨在探明该药物的剂量反应关系的趋势检验证明其P值=0.037(具有显著性)，这表明高剂量疗效更佳。
洛杉矶市Cedars-Sinai 医学中心妇女癌症研究所的主任Karlan博士说，一项以先前接受的治疗为分层依据的亚组分析表明：“从AMG药物治疗中获益最多的患者似乎均来自于我们最富挑战性的患者组，这些患者均患有难治性或耐药性疾病。”
她在会议上发言说，当按照RECIST标准(实体瘤疗效评价标准)对该药的客观有效率(包括完全有效和部分有效)进行评价时，A组(高剂量)、B组(低剂量)和C组(安慰剂)的有效率分别为37%、19%和27%。
经妇科肿瘤学组标准证实，3组患者在CA-125这一指标上的有效率分别为71%对58%对28%。高剂量组的所有女性的CA 125水平均较基线时下降，而低剂量组和安慰剂组分别有84%和63%的患者达成了这一目标。
应邀参与对该结果进行讨论的费城宾夕法尼亚大学卵巢癌研究中心主任George Coukos 博士说：“如果你回顾该领域在类似人群中完成的类似试验，你会发现该研究所传达的这一信号是极好和极富希望的，应该对其进行进一步研究”。
他说，除了尚未进行转化研究外，他并未发现该研究在试验设计方面存在任何特别的缺陷。
Kaplan博士称患者对该疗法的耐受性极佳，最显著的不良事件是有超过半数患者报告说发生各种级别的外周水肿。所有3组患者均存在3级低钾血症，但该研究并未对利尿剂的使用情况进行校对。
她指出，AMG 386的不良事件谱有别于VEGF轴抑制剂类药物的不良事件谱。尤其是，患者不会出现肠穿孔，且使用AMG类药物也不会导致高血压、血栓栓塞事件、蛋白尿或出血性事件的发病率升高。
Kaplan博士总结说，剂量-效应分析显示，AMG 386的最大有效剂量可能尚未达到10 mg/kg。在进一步研究中理应对卵巢癌女性患者使用更高剂量的AMG 386。
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