Department of Medicine and Helen Diller Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
Department of Thoracic Surgery, University of Zurich (director Emeritus), Thoraxchirurgie, Klinik Bethanien, Zürich, Switzerland.
Lung Cancer. 2023 Mar;177:59-72. doi: 10.1016/j.lungcan.2023.01.002. Epub 2023 Jan 2.
While the discovery of oncogenic driver mutations has personalized the metastatic non-small cell lung cancer (NSCLC) treatment landscape with effective targeted therapies, implementation of new treatments in resectable NSCLC has been limited due to the long follow-up needed for overall survival (OS). Until recently, treatment for patients with early-stage resectable NSCLC has been limited to perioperative chemotherapy, which provides modest benefits. However, the regulatory acceptance of two surrogate endpoints for OS has allowed recent approval of both adjuvant osimertinib and atezolizumab, providing patients with new treatment options to improve outcomes. In phase 3 oncology trials, OS has historically been viewed as the gold-standard efficacy measure, but disease-free survival and event-free survival (EFS) are now validated surrogate endpoints for OS in clinical trials and should be considered when mature OS data is unavailable. Another potential surrogate endpoint in the adjuvant NSCLC setting is circulating tumor DNA (ctDNA)-based minimal residual disease (MRD), although prospective validation is needed. For neoadjuvant targeted therapies, EFS, major pathologic response and ctDNA-based MRD are potential surrogate endpoints. To fully translate the success of the personalized treatment advances in the metastatic setting to earlier-stage disease, prospective validation studies of these potential surrogate endpoints that can accelerate the evaluation of drug efficacy are needed. A collaborative effort is also needed from all clinical and regulatory parties to collate surrogate endpoint data for large-scale validation. In this review we discuss the trends in surrogate endpoints used in oncology trials, with a focus on considerations for selecting appropriate primary endpoints in early-stage resectable EGFR-mutant NSCLC, an area of unmet need for novel treatment options.
虽然致癌驱动基因突变的发现通过有效的靶向治疗使转移性非小细胞肺癌（NSCLC）的治疗个体化，但由于总生存（OS）需要长期随访，新治疗方法在可切除 NSCLC 中的应用受到限制。直到最近，早期可切除 NSCLC 患者的治疗还局限于围手术期化疗，该方法提供适度的益处。然而，两种 OS 替代终点的监管批准允许最近批准辅助奥希替尼和阿替利珠单抗，为患者提供了改善预后的新治疗选择。在 3 期肿瘤学试验中，OS 一直被视为金标准疗效指标，但无病生存（DFS）和无事件生存（EFS）现在已被验证为临床试验中的 OS 替代终点，在无法获得成熟的 OS 数据时应考虑这些替代终点。在辅助 NSCLC 环境中另一个潜在的替代终点是基于循环肿瘤 DNA（ctDNA）的微小残留病灶（MRD），尽管需要前瞻性验证。对于新辅助靶向治疗，EFS、主要病理缓解和基于 ctDNA 的 MRD 是潜在的替代终点。为了将转移性疾病治疗中个性化治疗进展的成功完全转化，需要对这些可能的替代终点进行前瞻性验证研究，这些研究可以加速药物疗效的评估。所有临床和监管方还需要共同努力，整理替代终点数据，进行大规模验证。在这篇综述中，我们讨论了肿瘤学试验中使用的替代终点的趋势，重点讨论了在早期可切除 EGFR 突变 NSCLC 中选择合适的主要终点的注意事项，这是新治疗选择的一个未满足需求领域。
