Antibodies targeting the immune checkpoint molecules PD-1, PD-L1 and CTLA-4, administered alone or in combination with chemotherapy, are the standard of care in most patients with metastatic non-small-cell lung cancers. When given before curative surgery, tumor responses and improved event-free survival are achieved. New antibody combinations may be more efficacious and tolerable. In an ongoing, open-label phase 2 study, 60 biomarker-unselected, treatment-naive patients with resectable non-small-cell lung cancer were randomized to receive two preoperative doses of nivolumab (anti-PD-1) with or without relatlimab (anti-LAG-3) antibody therapy. The primary study endpoint was the feasibility of surgery within 43 days, which was met by all patients. Curative resection was achieved in 95% of patients. Secondary endpoints included pathological and radiographic response rates, pathologically complete resection rates, disease-free and overall survival rates, and safety. Major pathological (≤10% viable tumor cells) and objective radiographic responses were achieved in 27% and 10% (nivolumab) and in 30% and 27% (nivolumab and relatlimab) of patients, respectively. In 100% (nivolumab) and 90% (nivolumab and relatlimab) of patients, tumors and lymph nodes were pathologically completely resected. With 12 months median duration of follow-up, disease-free survival and overall survival rates at 12 months were 89% and 93% (nivolumab), and 93% and 100% (nivolumab and relatlimab). Both treatments were safe with grade ≥3 treatment-emergent adverse events reported in 10% and 13% of patients per study arm. Exploratory analyses provided insights into biological processes triggered by preoperative immunotherapy. This study establishes the feasibility and safety of dual targeting of PD-1 and LAG-3 before lung cancer surgery.

ClinicalTrials.gov Indentifier: NCT04205552.

针对免疫检查点分子 PD-1、PD-L1 和 CTLA-4 的抗体单独给药或与化疗联合给药，是大多数转移性非小细胞肺癌患者的标准治疗方法。当在治愈性手术前给予时，可以实现肿瘤反应并改善无事件生存期。新的抗体组合可能更有效且更耐受。在一项正在进行的开放标签 2 期研究中，60 名未选择生物标志物、未接受过治疗的可切除非小细胞肺癌患者被随机分配接受两剂术前纳武单抗（抗 PD-1）联合或不联合 relatlimab（抗-LAG-3)抗体治疗。主要研究终点是 43 天内手术的可行性，所有患者均达到了该终点。 95%的患者实现了根治性切除。次要终点包括病理和放射学反应率、病理完全切除率、无病生存率和总体生存率以及安全性。分别有 27% 和 10%（纳武单抗）以及 30% 和 27%（纳武单抗和 relatlimab）的患者实现了主要病理学（≤10% 活肿瘤细胞）和客观放射学缓解。在 100%（nivolumab）和 90%（nivolumab 和 relatlimab）的患者中，肿瘤和淋巴结在病理上被完全切除。中位随访时间为 12 个月，12 个月时的无病生存率和总生存率分别为 89% 和 93%（nivolumab），以及 93% 和 100%（nivolumab 和 relatlimab）。两种治疗都是安全的，每个研究组有 10% 和 13% 的患者报告了 ≥3 级治疗引起的不良事件。探索性分析提供了对术前免疫治疗触发的生物过程的见解。本研究确立了肺癌手术前双重靶向PD-1和LAG-3的可行性和安全性。

ClinicalTrials.gov 标识符：NCT04205552。