HB0025联合化疗治疗晚期非小细胞肺癌：一项2期非随机临床试验。
完整摘要 · 中文译文
重要性：靶向血管内皮生长因子（VEGF）和程序性细胞死亡蛋白1（PD-1）/PD-1配体1（PD-L1）通路的双特异性抗体是晚期非小细胞肺癌（NSCLC）的一种有前景的治疗策略。HB0025是一种新型靶向PD-L1和VEGF的双特异性抗体融合蛋白。 目的：评估HB0025联合化疗在既往未经治疗的晚期、驱动基因变异阴性NSCLC中的疗效和安全性。 设计、设置和参与者：这项开放标签、多中心、2期非随机临床试验在中国13家医院入组了无致敏性EGFR、ALK或ROS1改变的IIIB/C期或IV期NSCLC患者。参与者包括非鳞状NSCLC和鳞状NSCLC患者。患者入组时间为2024年1月15日至2025年5月21日。数据截止日期为2026年4月20日。 干预措施：患者接受静脉注射10 mg/kg HB0025每3周一次或20 mg/kg HB0025每3周一次联合化疗：非鳞状NSCLC采用培美曲塞/卡铂，鳞状NSCLC采用紫杉醇/卡铂，最多6个周期，随后接受HB0025维持治疗（非鳞状NSCLC联合培美曲塞），直至疾病进展或出现不可接受的毒性反应。 主要结局和指标：主要终点为安全性和研究者根据实体瘤疗效评价标准第1.1版评估的客观缓解率（ORR）。次要终点包括疾病控制率、缓解持续时间、无进展生存期（PFS）和总生存期（OS）。 结果：169例入组患者的治疗效果可评估。 非鳞状细胞队列包括85例患者（中位[IQR]年龄，63.0[58.0-68.0]岁；女性26例[30.6%]，男性59例[69.4%]），鳞状细胞队列包括84例患者（中位[IQR]年龄，65.0[60.0-69.0]岁；女性6例[7.1%]，男性78例[92.9%]）。在非鳞状细胞队列中，10-mg/kg和20-mg/kg剂量组的确认ORR分别为36.4%（95% CI，17.2%-59.3%）和57.1%（95% CI，44.1%-69.5%）。在鳞状细胞队列中，相应剂量下的ORR分别达到68.2%（95% CI，45.1%-86.1%）和74.2%（95%，61.5%-84.5%）。非鳞状细胞队列的中位PFS为12.52个月（95% CI，10.15-16.56），鳞状细胞队列为14.78个月（95% CI，11.30至不可估计）。非鳞状细胞和鳞状细胞队列的12个月PFS率分别为54.3%（95% CI，41.6%-65.3%）和62.1%（95% CI，49.9%-72.1%），12个月OS率分别为75.8%（95% CI，65.0%-83.7%）和85.5%（95% CI，75.8%-91.5%）。非鳞状细胞队列85例患者中有56例（65.9%）发生3级或以上治疗相关不良事件，鳞状细胞队列84例中有51例（60.7%）发生，主要为血液学毒性效应。与非鳞状细胞队列中20例患者（23.5%）和鳞状细胞队列中21例患者（25%）发生了与HB0025相关的任何级别免疫相关不良事件。 结论：在这项2期非随机临床试验中，HB0025联合化疗在晚期、驱动基因变异阴性NSCLC的非鳞状细胞和鳞状细胞组织学类型患者中显示出有前景的抗肿瘤活性和可控的安全性，支持在随机3期临床试验中进一步评估。 试验。 试验注册：ClinicalTrials.gov 标识符：NCT06758557。
完整摘要 · 英文原文
IMPORTANCE: Bispecific antibodies targeting vascular endothelial growth factor (VEGF) and programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) pathways represent a promising therapeutic strategy for advanced non-small cell lung cancer (NSCLC). HB0025 is a novel bispecific antibody fusion targeting PD-L1 and VEGF. OBJECTIVE: To evaluate the efficacy and safety of HB0025 plus chemotherapy in previously untreated advanced, driver variant-negative NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This open-label, multicenter, phase 2 nonrandomized clinical trial enrolled patients with stage IIIB/C or IV NSCLC without sensitizing EGFR, ALK, or ROS1 alterations across 13 hospitals in China. Participants included those with nonsquamous NSCLC and squamous NSCLC. Patients were enrolled from January 15, 2024, to May 21, 2025. Data cutoff was April 20, 2026. INTERVENTIONS: Patients received intravenous 10-mg/kg HB0025 every 3 weeks or 20-mg/kg HB0025 every 3 weeks plus chemotherapy: pemetrexed/carboplatin for nonsquamous and paclitaxel/carboplatin for squamous for up to 6 cycles, followed by HB0025 maintenance (with pemetrexed for nonsquamous) until disease progression or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES: The primary end points were safety and investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1. The secondary end points included disease control rate, duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: Treatment efficacy was evaluable in 169 enrolled patients. The nonsquamous cohort included 85 patients (median [IQR] age, 63.0 [58.0-68.0] years; 26 [30.6%] female and 59 [69.4%] male patients), and the squamous cohort included 84 patients (median [IQR] age, 65.0 [60.0-69.0] years; 6 [7.1%] female and 78 [92.9%] male patients). In the nonsquamous cohort, confirmed ORR was 36.4% (95% CI, 17.2%-59.3%) and 57.1% (95% CI, 44.1%-69.5%) in the 10-mg/kg and 20-mg/kg dose groups, respectively. In the squamous cohort, ORR reached 68.2% (95% CI, 45.1%-86.1%) and 74.2% (95%, 61.5%-84.5%) at the respective doses. Median PFS was 12.52 months (95% CI, 10.15-16.56) in the nonsquamous cohort and 14.78 months (95% CI, 11.30 to not estimable) in the squamous cohort. The 12-month PFS rates were 54.3% (95% CI, 41.6%-65.3%) and 62.1% (95% CI, 49.9%-72.1%) in the nonsquamous and squamous cohorts, and the 12-month OS rates were 75.8% (95% CI, 65.0%-83.7%) and 85.5% (95% CI, 75.8%-91.5%) , respectively. Grade 3 or higher treatment-related adverse events occurred in 56 of 85 patients (65.9%) in the nonsquamous cohort and 51 of 84 (60.7%) in the squamous cohort, mainly as hematologic toxic effects. Any-grade immune-related adverse events related to HB0025 occurred in 20 patients (23.5%) in the nonsquamous cohort and 21 patients (25%) in the squamous cohort. CONCLUSIONS: In this phase 2 nonrandomized clinical trial, HB0025 plus chemotherapy showed promising antitumor activity and manageable safety in patients with advanced, driver variant-negative NSCLC in both nonsquamous and squamous histologic types, supporting further evaluation in randomized phase 3 clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06758557.