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作者：SCI天天读
SCI
27 May 2024
Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study
(Lancet Oncol, IF: 51.1)
Li BT, Meric-Bernstam F, Bardia A, et al: Trastuzumab deruxtecan in patients with solid tumours harbouring specific activating HER2 mutations (DESTINY-PanTumor01): an international, phase 2 study. Lancet Oncol S1470-2045(24)00140–2, 2024
Background 背景
Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate approved by the US Food and Drug Administration and the European Medicines Agency for HER2-mutant non-small-cell lung cancer. Few treatment options exist for patients with HER2-mutant solid tumours beyond lung cancers. We investigated trastuzumab deruxtecan in metastatic solid tumours with specific activating HER2 mutations.
曲妥珠单抗 deruxtecan 是美国FDA和EMA批准治疗HER2突变型非小细胞肺癌的 HER2导向抗体-药物偶联物。对于肺癌以外的 HER2突变型实体瘤患者，几乎没有治疗选择。我们研究了曲妥珠单抗 deruxtecan 在具有特异性激活 HER2突变的转移性实体瘤中的作用。
Methods 方法
In this open-label, phase 2, basket study done in 29 centres in Asia, Europe, and North America, we investigated trastuzumab deruxtecan (5·4 mg/kg every 3 weeks by intravenous infusion) in patients aged 18 years or older with unresectable or metastatic solid tumours with specific activating HER2 mutations, an Eastern Cooperative Oncology Group performance status of 0 or 1, and disease progression following previous treatment (previous HER2-targeted therapy was permitted) or with no satisfactory alternative treatment options. The primary endpoint was confirmed objective response rate by independent central review. Anti-tumour activity and safety were analysed in all patients who received at least one dose of trastuzumab deruxtecan. This trial is registered with ClinicalTrials.gov, NCT04639219, and is active but no longer recruiting.
在这项在亚洲、欧洲和北美的29个中心进行的开放性2期篮式研究中，我们对18岁以上不能切除或转移性实体瘤患者进行曲妥珠单抗 deruxtecan (5.4 mg/kg/3周，静脉注射) ，这些患者具有特异性激活 HER2突变，ECOG体力评分为0或1，以及既往治疗(允许既往HER2靶向治疗)后的疾病进展，或者没有满意的替代治疗选择。主要终点是通过独立的中央评价确认客观反应率。对所有接受至少一剂曲妥珠单抗的患者进行抗肿瘤活性和安全性分析。该试验已在 clinicaltrials.gov NCT04639219注册，正在进行中，但不再招募。
Findings 结果
Between Dec 30, 2020, and Jan 25, 2023, 102 patients (62 [61%] female and 40 [39%] male; median age 66·5 years [IQR 58-72]; 51 [50%] White, two [2%] Black or African American, 38 [37%] Asian, and 11 [11%] did not have race information reported) with solid tumours with activating HER2 mutations received trastuzumab deruxtecan and were included in the anti-tumour activity and safety analyses sets. Patients had a median of three (IQR 2-4) previous treatment regimens. The median duration of follow-up was 8·61 months (IQR 3·71-12·68). The objective response rate by independent central review was 29·4% (95% CI 20·8-39·3; 30 of 102 patients). 52 (51%) patients had a treatment-emergent adverse event of grade 3 or worse; the most common events (in ≥5% of patients) were anaemia (16 [16%]) and neutrophil count decreased (eight [8%]). Drug-related treatment-emergent serious adverse events occurred in ten (10%) patients. Adjudicated drug-related interstitial lung disease or pneumonitis of any grade occurred in 11 patients (11%; three grade 1, five grade 2, one grade 3, and two grade 5); there were two (2%) cases of fatal adjudicated drug-related interstitial lung disease or pneumonitis.
在2020年12月30日至2023年1月25日期间，102名患者(62名[61% ]女性和40名[39% ]男性; 中位年龄66.5岁[ IQR 58-72] ; 51名[50% ]白人，两名[2% ]黑人或非洲裔美国人，38名[37% ]亚洲人和11名[11% ]没有种族信息)与激活 HER2突变的实体瘤接受曲妥珠单抗 deruxtecan，并被纳入抗肿瘤活性和安全性分析集。患者之前的治疗方案中位数为3(IQR 2-4)。中位随访时间为8 · 61个月(IQR 3 · 71-12 · 68)。独立中心评估的客观缓解率为29.4% (95% CI 20.8-39.3; 102例患者中有30例)。52例(51%)患者出现3级或更严重的治疗紧急不良事件; 最常见的事件(≥5% 的患者)是贫血(16例[16% ])和嗜中性粒细胞计数下降(8例[8% ])。10例(10%)患者发生与药物相关的紧急严重不良事件。判定与药物有关的间质性肺病或任何级别的肺炎发生在11名患者(11% ; 1级3名、2级5名、3级1名和5级2名) ，有2名(2%)死亡病例判定为与药物有关的间质性肺病或肺炎。
Interpretation 意义
Trastuzumab deruxtecan showed anti-tumour activity and durable responses in heavily pretreated patients across multiple tumour types with activating HER2 mutations, with no new safety signals. Prespecified HER2 mutations might be targeted by HER2-directed antibody-drug conjugates and our findings support further investigation of trastuzumab deruxtecan in the pan-tumour setting.
曲妥珠单抗 deruxtecan 在多种肿瘤类型的重度预处理患者中显示出抗肿瘤活性和持久的反应，并且激活 HER2突变，没有新的安全信号。预先指定的 HER2突变可能被 HER2定向的抗体-药物偶联物靶向，我们的研究结果支持进一步研究曲妥珠单抗 deruxtecan 在泛肿瘤环境中的作用。
Funding 资金来源
AstraZeneca and Daiichi Sankyo.
阿斯利康和第一三共。
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