Aokage Keiju, Koyama Shohei, Kumagai Shogo, Nomura Kotaro, Shimada Yoshihisa, Yoh Kiyotaka, Wakabayashi Masashi, Fukutani Miki, Furuya Hideki, Miyoshi Tomohiro, Tane Kenta, Samejima Joji, Taki Tetsuro, Hayashi Takuo, Matsubayashi Jun, Ishii Genichiro, Nishikawa Hiroyoshi, Ikeda Norihiko, Tsuboi Masahiro
Department of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.
Division of Cancer Immunology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
Clin Cancer Res. 2024 Dec 16;30(24):5584-5592. doi: 10.1158/1078-0432.CCR-24-1561.
Angiogenesis inhibitors are known to modify tumor immunity. Combination of angiogenesis inhibitors with immune checkpoint inhibitors 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 VEGFR-2 antagonist for patients with PD-L1-positive NSCLC, and its influence on the tumor microenvironment.
Patients with pathologically proven, PD-L1-positive, clinical stage IB to IIIA NSCLC were eligible. Patients received two cycles of pembrolizumab (200 mg/body) and ramucirumab (10 mg/kg) every 3 weeks. Surgery was scheduled 4 to 8 weeks after the last dose. The primary endpoint was the major pathologic response rate by a blinded independent pathologic review. The sample size was 24 patients. Exploratory endpoints were evaluated to elucidate the effects of neoadjuvant therapy on the tumor microenvironment.
The 24 eligible patients were enrolled between July 2019 and April 2022. The major pathologic response rate was 50.0% (90% confidence interval, 31.9%-68.1%). Six patients showed pathologic complete response. Grade 3 adverse events (AE) occurred in nine patients (37.5%), including three immune-related AEs (acute tubulointerstitial nephritis in two cases and polymyalgia rheumatica in one case). There were no grade 4 or 5 AEs. The transcriptome and multiplex IHC 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.
This new neoadjuvant combination of pembrolizumab plus ramucirumab was feasible, and anti-VEGF agents may enhance the effects of immune checkpoint inhibitors.
已知血管生成抑制剂可改变肿瘤免疫。血管生成抑制剂与免疫检查点抑制剂联合应用已显示出对多种癌症有效，包括非小细胞肺癌（NSCLC）。我们研究了帕博利珠单抗和雷莫西尤单抗（一种VEGFR - 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的影响。
病理证实为PD - L1阳性、临床分期为IB至IIIA期NSCLC的患者符合条件。患者每3周接受两个周期的帕博利珠单抗（200mg/体）和雷莫西尤单抗（10mg/kg）治疗。在最后一剂后4至8周安排手术。主要终点是由盲法独立病理评估得出的主要病理缓解率。样本量为24例患者。评估探索性终点以阐明新辅助治疗对肿瘤微环境的影响。
24例符合条件的患者于2019年7月至2022年4月入组。主要病理缓解率为50.0%（90%置信区间，31.9% - 68.1%）。6例患者显示病理完全缓解。9例患者（37.5%）发生3级不良事件（AE），包括3例免疫相关AE（2例急性肾小管间质性肾炎和1例多肌痛）。无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细胞浸润更多且效应分子表达更高的肿瘤对治疗可能表现出更好的敏感性。
帕博利珠单抗联合雷莫西尤单抗这种新辅助联合治疗是可行的，抗VEGF药物可能增强免疫检查点抑制剂的效果。
