HER2 靶向抗体药物偶联物曲妥珠单抗rezetecan 治疗晚期 HER2 突变非小细胞肺癌 (HORIZON-lung)

Trastuzumab rezetecan (also known as SHR-A1811) is a novel antibody-drug conjugate consisting of a humanised HER2-directed monoclonal antibody, cleavable tetrapeptide-based linker, and DNA topoisomerase I inhibitor. In the phase 1 portion of this phase 1/2 study, trastuzumab rezetecan showed preliminary anti-tumour activity and a favourable safety profile in patients with HER2-mutant non-small-cell lung cancer (NSCLC). We present phase 2 results from the study, which aimed to further evaluate the activity and safety of trastuzumab rezetecan at the recommended dose.

Trastuzumab rezetecan（也称为SHR-A1811）是一种新型抗体偶联药物，由人源化 HER2 靶向单克隆抗体、可裂解的四肽连接子和 DNA 拓扑异构酶 I 抑制剂组成。在这项 I/II 期研究的 I 期部分，trastuzumab rezetecan在 HER2 突变的非小细胞肺癌 (NSCLC) 患者中显示出初步抗肿瘤活性和有利的安全性特征。我们提供了该研究的 II 期结果，旨在进一步评价曲妥珠单抗 rezetecan 在推荐剂量下的活性和安全性。

In this multicentre, single-arm, phase 2 trial, conducted in 35 hospitals in China, we recruited patients aged 18-75 years, with locally advanced or metastatic NSCLC with an activating HER2 mutation and an Eastern Cooperative Oncology Group performance status score of 0-1, who had disease progression after or were intolerant to platinum-based chemotherapy and anti-PD-1 treatment or anti-PD-L1 treatment. Trastuzumab rezetecan was administered at 4·8 mg/kg intravenously once every 3 weeks. The primary endpoint was objective response rate assessed by an independent review committee in patients who received at least one cycle of study treatment. All patients who received at least one cycle of study treatment were included in safety analyses. This study is registered with ClinicalTrials.gov, NCT04818333, and is ongoing but not recruiting.

在中国35家医院进行的这项多中心、单组、2期试验中，我们招募了年龄为18-75岁、HER2激活突变、美国东部肿瘤协作组体能状态评分为0-1分的局部晚期或转移性 NSCLC 患者，在铂类药物化疗和抗 PD-1 治疗或抗 PD-L1 治疗后发生疾病进展或不耐受。曲妥珠单抗 rezetecan 以4.8 mg/kg剂量静脉给药，每3周一次。主要终点是由独立审查委员会在接受至少一个周期研究治疗的患者中评估的客观缓解率。安全性分析包括至少接受1个周期研究治疗的所有患者。本研究在 ClinicalTrials 注册，NCT04818333，正在进行中，但未招募。

Between April 14, 2023, and Dec 14, 2023, 94 patients were enrolled and treated. 42 (45%) patients were male, 52 (55%) female, 92 (98%) were Han Chinese, and two (2%) were other ethnicity Chinese. At data cutoff (June 14, 2024), the median duration of follow-up was 8·7 months (IQR 7·0-10·4). 69 (73%; 95% CI 63·3-82·0) of 94 patients had a confirmed objective response, as assessed by independent review committee. The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (38 [40%] patients), decreased white blood cell count (25 [27%]), anaemia (22 [23%]), decreased platelet count (10 [11%]), and decreased lymphocyte count (seven [7%]). Treatment-related serious adverse events occurred in 22 (23%) patients, which were decreased platelet count (six [6%]), decreased neutrophil count (six [6%]), interstitial lung disease (five [5%]), decreased white blood cell count (four [4%]), anaemia (four [4%]), vomiting (three [3%]), pneumonia (three [3%]), hyponatraemia (two [2%]), and pyrexia (one [1%]), small intestinal obstruction (one [1%]), nausea (one [1%]), and chronic obstructive pulmonary disease (one [1%]). There were no treatment-related deaths.

在2023年04月14日至2023年12月14日期间，94例患者入组并接受治疗。42例 (45%) 患者为男性，52例 (55%) 为女性，92例 (98%) 为汉族，2例 (2%) 为其他种族中国人。在数据截止时（2024年06月14日），中位随访时间为8.7个月 (IQR 7.0-10.4)。根据独立审查委员会的评估，94例患者中有69例 (73%；95%CI 63.3-82.0) 达到经证实的客观缓解。最常见的3-4级治疗相关不良事件为中性粒细胞计数降低（38例 [40%] 患者）、白细胞计数降低（25例 [27%]）、贫血（22例 [23%]）、血小板计数降低（10例 [11%]）和淋巴细胞计数降低（7例 [7%]）。22例 (23%) 患者发生治疗相关严重不良事件，包括血小板计数降低（6例 [6%]）、中性粒细胞计数降低（6例 [6%]）、间质性肺疾病（5例 [5%]）、白细胞计数降低（4例 [4%]）、贫血（4例 [4%]）、呕吐（3例 [3%]）、感染性肺炎（3例 [3%]）、低钠血症（2例 [2%]）。发热（1例 [1%]）、小肠梗阻（1例 [1%]）、恶心（1例 [1%]）和慢性阻塞性肺疾病（1例 [1%]）。未发生给药相关死亡。