低剂量放射治疗（LDRT）可能增强免疫治疗和立体定向放疗（SBRT）的协同抗肿瘤效应。本研究首次评估了这种新型三联合治疗作为转移性非小细胞肺癌（NSCLC）患者的一线治疗的安全性和疗效。该前瞻性1期研究纳入了29名患者，并包括剂量递增和剂量扩张阶段。患者同时接受了SBRT（30 Gy/3次）治疗小病变和LDRT（2 Gy/1次、4 Gy/2次或10 Gy/5次）治疗大病变，随后使用辛米替单（一种PD-1抑制剂）。主要终点是安全性和耐受性，次要终点包括客观缓解率（ORR）、无进展生存期（PFS）和总生存期（OS）。在剂量递增阶段未观察到剂量限制性毒性，4 Gy/2次被推荐为LDRT剂量。中位随访时间为15.6个月。与治疗相关的不良事件（TRAEs）在96.6%（28/29）的患者中发生（≥3级，20.7%（6/29））；两名患者（6.9%）因TRAEs停止治疗。七名患者出现肺炎（2级，n = 6；3级，n = 1）。约有58.6%（17/29）的患者出现免疫相关不良事件。在肿瘤评估的患者中（n = 28），ORR和确认的ORR分别为60.7%和57.1%。中位PFS为8.6个月（95%置信区间3.7-16.5），中位OS未达到。探索性分析表明，扩增和新出现的TCR克隆型与较好的PFS相关。研究结果表明，新型SBRT + LDRT + 辛米替单疗法在PD-L1阳性、驱动基因阴性的原发性转移性NSCLC患者中安全且具有良好前景。

Low-dose radiation therapy (LDRT) may enhance the synergistic anti-tumor effect of combined immunotherapy and stereotactic body radiation therapy (SBRT). The safety and efficacy of this novel triple-combination therapy were evaluated for the first time as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC).This prospective phase 1 study enrolled 29 patients and included a dose-escalation and dose-expansion phase. Patients received SBRT (30 Gy/3f) to small lesions and LDRT (2 Gy/1f, 4 Gy/2f, or 10 Gy/5f) to a large lesion concurrently, followed by sintilimab (a PD-1 inhibitor). The primary endpoint was safety and tolerability; secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).No dose-limiting toxicities were observed during the dose-escalation phase; 4 Gy/2f was the recommended LDRT dose. Median follow-up was 15.6 months. Treatment-related adverse events (TRAEs) occurred in 96.6% (28/29) of patients (grade ≥ 3, 20.7% [6/29]); two patients (6.9%) discontinued due to TRAEs. Seven patients experienced pneumonitis (grade 2, n = 6; grade 3, n = 1). Immune-related adverse events were noted in 58.6% (17/29) of patients. In patients with tumor assessment (n = 28), ORR and confirmed ORR were 60.7% and 57.1%, respectively. Median PFS was 8.6 months (95% confidence interval 3.7-16.5), and median OS was not reached. Exploratory analyses suggested both expanded and newly emerging TCR clonotypes were associated with better PFS.The findings indicate that the novel SBRT + LDRT + sintilimab therapy is safe and promising in patients with PD-L1-positive, driver gene-negative primary metastatic NSCLC.