New challenges in endpoints for drug development in advanced melanoma.
New challenges in endpoints for drug development in advanced melanoma.
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DOI：
10.1158/1078-0432.ccr-11-2323
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发表时间：
2012-01-15
期刊：
影响因子：
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通讯作者：
Kirkwood JM
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文献类型：
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作者：
Ribas A;Hersey P;Middleton MR;Gogas H;Flaherty KT;Sondak VK;Kirkwood JM
在过去的三十年中，晚期黑色素瘤治疗的临床研究领域缺乏重大进展。现有药物的抗肿瘤活性较低，且未证实对总体生存有益处。最近，基于对这种疾病生物学的深入了解而开发的新药已显示出显着的益处，伊匹单抗和维莫非尼最近显示出对转移性黑色素瘤患者总生存期的积极影响，导致美国食品和药物管理局 (FDA) 批准该适应症。新活性药物的快速引入可能会挑战当前关于如何开发未来药物治疗黑色素瘤的观念。调节免疫调节检查点或靶向驱动癌基因的初始药物的益处的有力证据激发了人们对开发其他类似作用药物的极大兴趣。然而，这将为未来最终临床试验的终点选择带来问题，并且考虑到比较药物的相似活性或挽救治疗的竞争药物的可用性，实现这些终点的障碍将会更高。这一新的现实可能需要根据早期临床测试中证明的患者利益来调整注册临床试验终点。在本报告中，我们阐述了转移性黑色素瘤注册试验终点选择的挑战，并且随着对正在开发的药物的进一步了解，注册计划的设计可以通过早期的机制研究来确定最终临床测试的假设。
During the past three decades, the field of clinical research for the treatment of advanced melanoma lacked significant advances. Available drugs had low antitumor activity and no proven benefit in overall survival. Recently, new drugs developed based on an in-depth understanding of the biology of this disease have demonstrated significant benefit, with ipilimumab and vemurafenib having recently shown a positive impact in overall survival in patients with metastatic melanoma leading to approval in this indication by the US Food and Drug Administration (FDA). This rapid introduction of new active agents is likely to challenge current notions on how to develop future agents for the treatment of melanoma. The strong evidence of benefit for initial agents that modulate immune regulatory checkpoints or target driver oncogenes has spurred great interest in developing other similarly acting agents. However, this will pose problems in the choice of endpoints for the future definitive clinical trials, and the hurdles for achieving these endpoints will be higher given the similar activity for comparator agents or the availability of competing agents for salvage therapy. This new reality will likely require tailoring the registrational clinical trial endpoints to the patient benefits demonstrated in early clinical testing. In this report we illustrate the challenges in the choice of endpoints for registrational trials in metastatic melanoma and that, with an improved understanding of the agent being developed, the design of the registrational programs can be informed by earlier mechanistic studies to define the assumptions for definitive clinical testing.