Burkhardt Brain Tumor Neuro-oncology Center, Cleveland, Ohio, USA.
Maimonides Medical Center, Brooklyn, New York, USA.
Oncologist. 2018 Oct;23(10):1199-1209. doi: 10.1634/theoncologist.2017-0572. Epub 2018 Apr 12.
Central nervous system (CNS) metastases are a common complication in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), resulting in a poor prognosis and limited treatment options. Treatment of CNS metastases requires a multidisciplinary approach, and the optimal treatment options and sequence of therapies are yet to be established. Many systemic therapies have poor efficacy in the CNS due to the challenges of crossing the blood-brain barrier (BBB), creating a major unmet need for the development of agents with good BBB-penetrating biopharmaceutical properties. Although the CNS penetration of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) is generally low, EGFR-TKI treatment has been shown to delay time to CNS progression in patients with CNS metastases from EGFR-mutated disease. However, a major challenge with EGFR-TKI treatment for patients with NSCLC is the development of acquired resistance, which occurs in most patients treated with a first-line EGFR-TKI. Novel EGFR-TKIs, such as osimertinib, have been specifically designed to address the challenges of acquired resistance and poor BBB permeability and have demonstrated efficacy in the CNS. A rational, iterative drug development process to design agents that could penetrate the BBB could prevent morbidity and mortality associated with CNS disease progression. To ensure a consistent approach to evaluating CNS efficacy, special consideration also needs to be given to clinical trial endpoints.
Historically, treatment options for patients who develop central nervous system (CNS) metastases have been limited and associated with poor outcomes. The development of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has improved outcomes for patients with EGFR-mutated disease, and emerging data have demonstrated the ability of these drugs to cross the blood-brain barrier and elicit significant intracranial responses. Recent studies have indicated a role for next-generation EGFR-TKIs, such as osimertinib, in the treatment of CNS metastases. In the context of an evolving treatment paradigm, treatment should be individualized to the patient and requires a multidisciplinary approach.
中枢神经系统（CNS）转移是表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者的常见并发症，导致预后不良且治疗选择有限。CNS 转移的治疗需要多学科方法，最佳治疗选择和治疗顺序尚未确定。由于血脑屏障（BBB）的挑战，许多全身治疗药物在 CNS 中的疗效不佳，这就需要开发具有良好 BBB 穿透性的生物制药特性的药物。尽管第一代和第二代 EGFR 酪氨酸激酶抑制剂（TKI）的 CNS 穿透率通常较低，但 EGFR-TKI 治疗已被证明可延迟 CNS 进展时间在 EGFR 突变疾病的 CNS 转移患者中。然而，EGFR-TKI 治疗 NSCLC 患者的主要挑战是获得性耐药的发生，大多数接受一线 EGFR-TKI 治疗的患者均发生了耐药。新型 EGFR-TKIs，如奥希替尼，专门设计用于解决获得性耐药和 BBB 通透性差的挑战，并在 CNS 中显示出疗效。一种合理的、迭代的药物开发过程，旨在设计能够穿透 BBB 的药物，可以预防与 CNS 疾病进展相关的发病率和死亡率。为了确保对 CNS 疗效评估采用一致的方法，还需要特别考虑临床试验终点。
从历史上看，开发中枢神经系统（CNS）转移患者的治疗选择有限，且预后不良。表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）的发展改善了 EGFR 突变疾病患者的预后，并且新出现的数据表明这些药物能够穿透血脑屏障并引起明显的颅内反应。最近的研究表明，新一代 EGFR-TKIs，如奥希替尼，在 CNS 转移的治疗中有一定作用。在不断发展的治疗范例的背景下，治疗应根据患者个体情况进行个体化，并需要多学科方法。
