Lim-Fat Mary Jane, Roberto Katrina, Wen Patrick Y
Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
Center For Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
J Neurooncol. 2025 Jan;171(1):21-33. doi: 10.1007/s11060-024-04846-5. Epub 2024 Oct 8.
Biomarker-based clinical trials investigating targeted treatments for brain tumors have surged due to better access to biomarker testing and a deeper grasp of the molecular basis of tumor development. The design of clinical trials is crucial for evaluating safety, confirming effectiveness, and affirming the clinical advantage of novel agents, with the goal of approval by regulatory authorities to expand patient treatment options. Given some challenges unique to brain tumors, early-stage clinical trials for novel targeted agents must integrate pharmacokinetics and tissue-based pharmacodynamic assessments to establish timely go-no-go decisions for larger studies. Surgical window-of-opportunity trials can allow for the comparison of treated and untreated tumor samples, verifying target engagement and its modulatory effects for evidence of biological activity. Due to the challenges of achieving the required sample sizes to power efficacy analyses, later-stage trials of targeted therapies can include basket trials which test one drug on multiple tumor types, while umbrella trials evaluate several biomarkers within a single histology. Platform trials can also be leveraged to investigate multiple biomarker-driven hypotheses within a unified protocol and can incorporate Bayesian algorithms for adaptive randomization. Selecting appropriate endpoints, such as progression-free survival or overall response rate, is crucial and novel response assessment criteria need to be considered in the context of the tumor and therapy being investigated. Lastly, inclusivity in trials is essential to address health disparities and engage diverse patient populations to ensure real-world impact. Future trials should build upon the knowledge gained from both initial achievements and past setbacks in the field.
由于生物标志物检测的可及性提高以及对肿瘤发生分子基础的更深入理解，基于生物标志物的脑肿瘤靶向治疗临床试验激增。临床试验的设计对于评估安全性、确认有效性以及肯定新型药物的临床优势至关重要，目标是获得监管机构的批准以扩大患者的治疗选择。鉴于脑肿瘤存在一些独特的挑战，新型靶向药物的早期临床试验必须整合药代动力学和基于组织的药效学评估，以便为更大规模的研究及时做出继续或终止的决策。手术机会窗试验可以对治疗和未治疗的肿瘤样本进行比较，验证靶点结合及其调节作用以证明生物学活性。由于难以达到进行疗效分析所需的样本量，靶向治疗的后期试验可以包括在多种肿瘤类型上测试一种药物的篮子试验，而伞形试验则在单一组织学类型内评估多种生物标志物。平台试验也可用于在统一方案内研究多个生物标志物驱动的假设，并可纳入贝叶斯算法进行适应性随机化。选择合适的终点，如无进展生存期或总体缓解率，至关重要，并且需要在正在研究的肿瘤和治疗背景下考虑新的反应评估标准。最后，试验的包容性对于解决健康差异和吸引不同患者群体以确保产生实际影响至关重要。未来的试验应基于该领域初期成果和过去挫折所获得的知识。
