Purpose: Angiogenesis inhibitors are known to modify tumor immunity. Combination of angiogenesis inhibitors with immune checkpoint inhibitors (ICIs) has shown efficacy against many types of cancers, including non-small cell lung cancer (NSCLC). We investigated the feasibility of neoadjuvant therapy with pembrolizumab and ramucirumab, a vascular endothelial growth factor (VEGF) receptor-2 antagonist for patients with PD-L1-positive NSCLC and its influence on the tumor microenvironment (TME). Patients and Methods: Patients with pathologically proven NSCLC with PD-L1-positive, clinical stage IB-IIIA were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every three weeks. Surgery was scheduled 4 to 8 weeks after the last dose. The primary endpoint was the major pathologic response (MPR) rate by a blinded independent pathology review. The sample size was 24 patients. Exploratory endpoints were evaluated to elucidate the effects of neoadjuvant therapy on TME. Results: The 24 eligible patients were enrolled between July 2019 and April 2022. The MPR rate was 50.0% (90% confidence interval, 31.9-68.1%). Six patients showed pathological complete response. Grade 3 adverse events (AEs) occurred in 9 patients (37.5%), including 3 immune-related AEs (acute tubulointerstitial nephritis in 2 cases and polymyalgia rheumatica in one). There were no grade 4 or 5 AEs. The transcriptome and multiplexed immunohistochemistry results suggested that tumors with greater CD8+ T-cell infiltration and higher expression of effector molecules at the baseline could show better sensitivity to treatment. Conclusions:This new neoadjuvant combination of pembrolizumab plus ramucirumab was feasible and anti-VEGF agents may enhance the effects of ICIs.

中文翻译：

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新辅助 Pembrolizumab 联合雷莫芦单抗治疗 PD-L1 阳性 NSCLC 的疗效、安全性和对肿瘤微环境的影响：一项 2 期试验 （EAST ENERGY）


目的：已知血管生成抑制剂可以改变肿瘤免疫力。血管生成抑制剂与免疫检查点抑制剂 （ICI） 的组合已显示出对多种类型的癌症有效，包括非小细胞肺癌 （NSCLC）。我们研究了 pembrolizumab 和 ramucirumab（一种血管内皮生长因子 （VEGF） 受体-2 拮抗剂）对 PD-L1 阳性 NSCLC 患者进行新辅助治疗的可行性及其对肿瘤微环境 （TME） 的影响。患者和方法： 经病理证实的 PD-L1 阳性、临床 IB-IIIA 期 NSCLC 患者符合条件。患者每三周接受两个周期的 pembrolizumab （200 mg/body） 和 ramucirumab （10 mg/kg）。手术安排在最后一次给药后 4 至 8 周。主要终点是盲法独立病理学审查的主要病理反应 （MPR） 率。样本量为 24 名患者。评估探索性终点以阐明新辅助治疗对 TME 的影响。结果： 2019 年 7 月至 2022 年 4 月期间入组了 24 例符合条件的患者。MPR 率为 50.0% （90% 置信区间，31.9-68.1%）。6 例患者表现出病理完全缓解。9 例患者 （37.5%） 发生 3 级不良事件 （AEs），包括 3 例免疫相关 AE （2 例急性肾小管间质性肾炎和 1 例风湿性多肌痛）。没有 4 级或 5 级 AE。转录组和多重免疫组化结果表明，基线时 CD8+ T 细胞浸润程度更高和效应分子表达较高的肿瘤对治疗表现出更好的敏感性。结论： 这种 pembrolizumab 加雷莫芦单抗的新辅助组合是可行的，抗 VEGF 药物可能会增强 ICIs 的效果。