Axitinib对转移性肾细胞瘤具有活性


  October 30, 2007 — 一种正在研究中的药物axitinib(由辉瑞药厂研发中),在第二期临床研究中显示对于转移性肾细胞瘤具有活性,这项研究发表于10月22日的Lacent肿瘤学期刊上;研究者表示,某些反应是可以持续很久的,但是该研究结果需要在后续研究中获得证实,这些研究目前正在进行中。
  
  Axitinib是一种口服效价高,且对于血管内皮生长因子受体第一、二、三型具有活性的选择性抑制剂,且已经被证实可以有效对抗甲状腺与胰脏癌;这两个具有潜力的适应症目前正在一项由厂商赞助的第三期临床试验中进行研究。
  
  这项由制造商赞助、针对肾细胞癌的研究,是由法国巴黎Pitie-Salpetriere医院Olivier Rixe医师执行,研究收纳52位已经转移,且对于至少一种细胞激素为基础的治疗(干扰素阿法、间白素2或是两者)无效的病患,这些病患都接受axitinib,一开始以5 mg每天两次的剂量投予;然而,8位病患因为发生第三级的不良反应(2位病患发生腹泻,2位病患严重疲倦;另1位病患发生肠胃道不适、脱水、肌肉酸痛、与痛风),另外7位病患因为第二级高血压而调降剂量。
  
  由研究者评估的整体反应是44.2%,其中有2位病患表现出完全反应,而有21位病患有部份反应;研究者评论,某些反应在很短的时间内就看得到(12位病患在治疗第30天与第65天就有反应),但是仍有些病患的反应较慢,有9位病患的反应发生在第90与403天,另外2位病患的完全反应发生在第246天与第362天。然而,研究者表示,23位病患中有12位一开始有反应,但之后疾病恶化;反应的时间长短从4.2到26.5个月,平均为23个月。
  
  Rixe医师与其同事表示,对过去使用细胞激素为主疗法但反应不佳的肾细胞瘤病患,疾病恶化所需要的时间平均为15.7个月,且这项结果连同44.2%的反应率是显著的;他们附带表示,使用该药物的疾病恶化所需时间,相较于其它药物来说是较长的;该团队表示,22位病患使用该药物后,疾病稳定时间达8周,包括其中13位病患的疾病稳定时间长达24周以上,这些结果显示,该药物具有临床上的好处,即使对肿瘤并未显著缩小的病患也是如此;他们的结论是,虽然需要随机分派临床研究来确认这些结果,但Axitinib对于罹患转移性肾细胞瘤病患而言,可能是具有潜力的药物治疗。
  
  Rixe医师与其同事表示,该药物所产生的毒性反应是可以处理的,且没有血液毒性;最常被报导的不良反应是腹泻、高血压、疲倦、恶心与声音沙哑,且这些不良反应都可以剂量调整以及支持性疗法,或者是两者并用来治疗;他们指出,高血压是这类药物中一个可以预期的不良反应,以及同类药物,例如bevacizumab(Avastin,基因技术公司制造);在这项研究中,当病患正在使用axitinib治疗时,可以使用降血压药物来控制血压,且停止使用axitinib后,血压会恢复正常。
  
  在随后的主编评论中,马里兰班塞斯达国家癌症机构的Marston Linehan医师对这些不良反应提出评论,他表示这些不良反应比使用其它多重磷酸酶抑制剂药物少,例如sunitinib(Sutent,辉瑞药厂制造)与sorafenib(Nevaxar,拜耳药厂制造),这两个药物都已经被核准在美国使用于治疗进展性肾脏癌症。除了毒性较低的潜力之外,axitinib所针对的单一生长因子受体提供了对抗复杂分子途径中单一精确标的机会,他表示,很难知道针对哪里一种生张因子受体是最有效的。
  
  Linehan医师的结论是,虽然需要更多的研究,这项研究的发现显示这样的药物,例如axitinib,是有潜力作为对细胞激素疗法无效肾细胞恶性肿瘤的第二线疗法,且可能具有作为与其它药物并用的第一线疗法。
  
  Rixe医师其它作者们担任辉瑞药厂的顾问,且接受该公司的报酬。Linehan医师表示无相关资金上的往来。

Axitinib Active in Metastatic<

By Zosia Chustecka
Medscape Medical News

October 30, 2007 — The investigational drug axitinib (under development by Pfizer) has shown activity against metastatic renal cell carcinoma in a phase 2 clinical trial reported online October 22 in Lancet Oncology. Some of the responses were long lasting, but the results need to be confirmed in further studies, which are currently under way, say the researchers

Axitinib is an oral potent and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 that has shown promising activity against thyroid and pancreatic cancers. These 2 potential indications are now being explored in company-sponsored phase 3 clinical trials.

The trial in renal cell cancer was also sponsored by the manufacturer and was conducted by Olivier Rixe, MD, from Pitié-Salpêtrière Hospital in Paris, France. It involved 52 patients with metastases who had failed at least 1 cytokine-based treatment (interferon-alpha, interleukin-2, or both). All of the patients received axitinib, beginning with a dose of 5 mg twice daily. However, the dose was reduced in 8 patients because of grade 3 adverse events (diarrhea in 2 patients; fatigue in 2 patients; and gastrointestinal upset, dehydration, myalgia, and gout in 1 patient each) and in 7 patients because of grade 2 hypertension.

The overall response, assessed by the investigators, was 44.2%, with 2 patients showing a complete response and 21 showing partial responses. Some of the responses were seen quickly (12 patients had responses between days 30 and 65), but there was also a more gradual time course, the researchers comment, with 9 patients showing responses between days 90 and 403 and the 2 complete responses reported on days 246 and 362. However, 12 of the 23 patients who initially responded have progressed, the researchers comment. The duration of the response ranged from 4.2 to 26.5 months, with a median response duration of 23 months.

The median time to progression was 15.7 months, and this result, as well as the 44.2% response rate, is "notable" in a patient population with cytokine-refractory renal cell cancer, Dr. Rixe and colleagues comment. The time to progression compares favorably with data reported for other drugs, they add. Together with the finding that 22 patients showed stable disease for more than 8 weeks — including 13 patients with stable disease for 24 weeks or longer — these results suggest that the drug had a clinical benefit, even for patients without significant tumor shrinkage, the team says. "Axitinib might be a promising drug in the treatment of patients with metastatic renal cell cancer, although a randomized controlled trial is needed to confirm this finding," they conclude.

The toxic effects were manageable, and there was no hematological toxicity, Dr. Rixe and colleagues comment. The most commonly reported adverse events were diarrhea, hypertension, fatigue, nausea, and hoarseness, and they were controlled with dose modification, supportive care, or both. Hypertension is an expected adverse effect of this class of drugs and has also been reported with bevacizumab (Avastin, Genentech), they point out. In this study, it was managed with standard antihypertensives drugs while the patients were on axitinib therapy, and it resolved on discontinuation of axitinib.

In an accompanying editorial, Marston Linehan, MD, from the National Cancer Institute, in Bethesda, Maryland, comments that these adverse events "were probably less severe than those reported by patients receiving multikinase targeted drugs," such as sunitinib (Sutent, Pfizer) and sorafenib (Nevaxar, Bayer), both of which are already approved in the United States for use in advanced kidney cancer. As well as having the potential to decrease toxicity, the selective targeting by axitinib of a single growth factor receptor offers an opportunity to target 1 precise point on the complex pathways involved. With the multikinase inhibitors, it is difficult to know which of the growth factor receptors is most effective, he says.

Although further studies are needed, the findings from this trial suggest that a drug such as axitinib has promise as a second-line treatment in cytokine-refractory metastatic renal cell carcinoma and might have potential as a first-line treatment or in combination with other agents (or both), Dr. Linehan concludes.

Dr. Rixe and another of the authors have acted as consultants to Pfizer and have received honoraria from Pfizer. Dr. Linehan declared no relevant financial relationships.

Lancet Oncology 2007; 8:975-984 Abstract, 956-957.

    
相关报导
新的甲状腺癌试验指出治疗思维改变已经不远了
2008/7/8 下午 03:06:00

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