Department of Medicine, Division of Oncology, Stanford Cancer Institute and Stanford University School of Medicine, Stanford University, 875 Blake Wilbur Drive, Stanford, CA 94305, USA.
Division of Hematology-Oncology, Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, 32 Fruit Street, Boston, MA 02114, USA.
Nat Rev Clin Oncol. 2015 Mar;12(3):135-46. doi: 10.1038/nrclinonc.2014.222. Epub 2014 Dec 23.
In cancer-drug development, a number of different end points have been used to establish efficacy and support regulatory approval, such as overall survival, progression-free survival (PFS), and radiographic response rate. However, these traditional end points have important limitations. For example, in lung cancer clinical trials, evaluating overall survival end points is a protracted process and these end points are most reliable when crossover to the investigational therapy is not permitted. Furthermore, although radiographic surrogate end points, such as PFS and response rate, generally correlate with clinical benefit in the setting of cytotoxic chemotherapy and molecular targeted therapies, novel immunotherapies might have atypical response kinetics, which confounds radiographic interpretation. In this Review, we discuss the need to develop alternative or surrogate end points for lung cancer clinical trials, and focus on several new biomarkers that could serve as surrogate end points, including functional imaging biomarkers, circulating factors (tumour proteins, DNA, and cells), and pharmacodynamic tumour markers. By enabling the size, duration, and complexity of cancer trials to be reduced, biomarker end points hold the promise to accelerate drug development and improve patient outcomes.
在癌症药物研发中，已经使用了许多不同的终点来建立疗效并支持监管批准，例如总生存期、无进展生存期 (PFS) 和影像学反应率。然而，这些传统的终点存在重要的局限性。例如，在肺癌临床试验中，评估总生存期终点是一个漫长的过程，并且当不允许交叉到研究性治疗时，这些终点是最可靠的。此外，尽管影像学替代终点，如 PFS 和反应率，通常与细胞毒性化疗和分子靶向治疗的临床获益相关，但新型免疫疗法可能具有非典型的反应动力学，这使得影像学解释变得复杂。在这篇综述中，我们讨论了为肺癌临床试验开发替代或替代终点的必要性，并重点介绍了几种新的生物标志物，它们可以作为替代终点，包括功能影像学生物标志物、循环因子（肿瘤蛋白、DNA 和细胞）和药效学肿瘤标志物。通过能够减少癌症试验的规模、持续时间和复杂性，生物标志物终点有望加速药物开发并改善患者的治疗结果。
