Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medicine, Cornell University, New York, NY, USA.
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lancet Oncol. 2024 Jun;25(6):707-719. doi: 10.1016/S1470-2045(24)00140-2. Epub 2024 May 3.
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.
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.
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.
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.
AstraZeneca and Daiichi Sankyo.
曲妥珠单抗 deruxtecan 是一种由美国食品和药物管理局以及欧洲药品管理局批准用于治疗 HER2 突变型非小细胞肺癌的 HER2 定向抗体药物偶联物。对于 HER2 突变型实体瘤患者，除了肺癌之外，治疗选择非常有限。我们在具有特定激活 HER2 突变的转移性实体瘤中研究了曲妥珠单抗 deruxtecan。
在这项在亚洲、欧洲和北美的 29 个中心进行的开放标签、2 期、篮子研究中，我们在 18 岁及以上患有不可切除或转移性实体瘤的患者中研究了曲妥珠单抗 deruxtecan（通过静脉输注每 3 周 5.4mg/kg），这些患者具有特定的激活 HER2 突变、东部合作肿瘤学组表现状态 0 或 1，并且在先前治疗（先前允许使用 HER2 靶向治疗）或没有满意的替代治疗选择后出现疾病进展。主要终点是独立中心审查确认的客观缓解率。在至少接受一剂曲妥珠单抗 deruxtecan 的所有患者中分析了抗肿瘤活性和安全性。该试验在 ClinicalTrials.gov 注册，NCT04639219，目前处于活跃状态但不再招募。
在 2020 年 12 月 30 日至 2023 年 1 月 25 日期间，共有 102 名（62%为女性，40%为男性；中位年龄 66.5 岁[IQR 58-72]；51%为白人，两名[2%]为黑人或非裔美国人，38%为亚洲人，11%[11%]未报告种族信息）患有具有激活 HER2 突变的实体瘤的患者接受了曲妥珠单抗 deruxtecan 治疗，并纳入了抗肿瘤活性和安全性分析集。患者接受了中位数为三（IQR 2-4）种先前的治疗方案。中位随访时间为 8.61 个月（IQR 3.71-12.68）。独立中心审查的客观缓解率为 29.4%（95%CI 20.8-39.3；30/102 名患者）。52 名（51%）患者出现了 3 级或更高级别的治疗相关不良事件；最常见的事件（≥5%的患者）是贫血（16[16%]）和中性粒细胞计数减少（8[8%]）。10 名（10%）患者发生了与药物相关的治疗紧急严重不良事件。11 名（11%）患者发生了任何级别的药物相关的间质性肺疾病或肺炎（3 级 1 例，2 级 5 例，3 级 1 例，5 级 2 例）；有 2 例（2%）致命的药物相关间质性肺疾病或肺炎的病例。
曲妥珠单抗 deruxtecan 在具有激活 HER2 突变的多种肿瘤类型的大量预处理患者中显示出抗肿瘤活性和持久的缓解，没有新的安全性信号。HER2 靶向抗体药物偶联物可能针对特定的 HER2 突变，我们的研究结果支持进一步研究曲妥珠单抗 deruxtecan 在泛肿瘤环境中的应用。
阿斯利康和第一三共。
