NSCLC一线免疫治疗后的抗血管生成药物：基本原理，最新进展和未来前景

SCI 26 March 2023

Anti-angiogenic agents for NSCLC following first-line immunotherapy: rationale, recent updates, and future perspectives

(Lung Cancer, IF: 6.08)

Martin Reck, Sanjay Popat, Christian Grohé, Jesus Corral, Silvia Novello, Maya Gottfried, Wolfgang Brueckl, Dejan Radonjic, Rolf Kaiser, John Heymach

CORRESPONDENCE TO: dr.martin.reck@web.de

Abstract 摘要

The implementation of immune checkpoint inhibitors (ICIs), with or without chemotherapy, as first-line treatment for patients who do not have actionable mutations has proved to be a major paradigm shift in the management of advanced non-small cell lung cancer (NSCLC). However, the transition of ICIs, such as pembrolizumab and nivolumab, to a first-line setting has left an unmet need for effective second-line treatment options, which is an area of intense research. In 2020, we reviewed the biological and mechanistic rationale for antiangiogenic agents in combination with, or following, immunotherapy with the aim of eliciting a so called ‘angio-immunogenic’ switch in the tumor microenvironment. Here, we review the latest clinical evidence of the benefits of incorporating anti-angiogenic agents into treatment regimens. While there is a paucity of prospective data, several recent observational studies indicate that the marketed anti-angiogenic drugs, nintedanib or ramucirumab, are effective in combination with docetaxel following immuno-chemotherapy. Addition of anti-angiogenics, like bevacizumab, have also demonstrated clinical benefit when combined with first-line immuno-chemotherapy regimens. Ongoing clinical trials are assessing these agents in combination with ICIs, with encouraging early results (e.g., ramucirumab plus pembrolizumab in LUNG-MAP S1800A). Also, several emerging anti-angiogenic agents combined with ICIs are currently being assessed in phase III trials following immunotherapy, including lenvatinib (LEAP-008), and sitravatinib (SAPPHIRE) It is hoped that these trials will help expand second-line treatment options in patients with NSCLC. Areas of focus in the future will include further molecular dissection of the mechanisms of resistance to immunotherapy and the various response–progression profiles to immunotherapy observed in the clinic and the monitoring of the dynamics of immunomodulation over the course of treatment. Improved understanding of these phenomena may help identify clinical biomarkers and inform the optimal use anti-angiogenics in the treatment of individual patients.

免疫检查点抑制剂（ICIs）有无联合化疗，作为无可行突变的患者的一线治疗，已被证明是晚期非小细胞肺癌（NSCLC）患者治疗的主要范式转变。然而，ICI（如帕博利珠单抗和纳武利尤单抗）向一线治疗的转变使得目前暂无有效的二线治疗方案，即使这是一个深入研究的领域。在2020年，我们回顾了抗血管生成药物联合或随后进行免疫治疗的生物学和机械学原理，目的是在肿瘤微环境中引发所谓的“血管免疫原性”转换。在这里，我们回顾了将抗血管生成剂纳入治疗方案的益处的最新临床证据。虽然缺乏前瞻性数据，但最近的一些观察性研究表明，市售的抗血管生成药物nintedanib或ramucirumab在免疫化疗后与多西紫杉醇联合使用是有效的。当与一线免疫化疗方案联合使用时，添加抗血管生成药物如贝伐单抗也显示出临床益处。目前临床试验正在评估这些药物与ICI的组合，这些临床试验具有令人鼓舞的早期结果（例如，ramucirumab加pembrolizumab在LUNG-MAP S1800A中）。此外，目前II期临床试验正在评估免疫治疗后的应用几种新兴的抗血管生成药物联合ICI的效果，包括lenvatinib（LEAP-008）和sitravatinib（SAPPHIRE）。希望这些试验将有助于扩大NSCLC患者二线治疗方案。未来的重点领域将包括对免疫疗法抗性机制的进一步分子作用层面进行剖析，以及在临床中观察到的对免疫疗法的各种反应-进展概况，以及在治疗过程中监测免疫调节的动态。更好地理解这些现象可能有助于确定临床生物标志物，并为个体患者的治疗提供最佳使用抗血管生成药物。