DESTINY-Lung01：德曲妥珠单抗（Deruxtecan，DS-8201）治疗HER2突变非小细胞肺癌

Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer

(IF: NEJM, 91.245)

• Li BT, Smit EF, Goto Y, Nakagawa K, Udagawa H, Mazières J, Nagasaka M, Bazhenova L, Saltos AN, Felip E, Pacheco JM, Pérol M, Paz-Ares L, Saxena K, Shiga R, Cheng Y, Acharyya S, Vitazka P, Shahidi J, Planchard D, Jänne PA; DESTINY-Lung01 Trial Investigators. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022 Jan 20;386(3):241-251.
• Address reprint requests to Dr. Li at the Thoracic Oncology and Early Drug Development Service, Memorial Sloan Kettering Cancer Center, 530 E. 74th St., New York, NY 10021, or at lib1@ mskcc .org.
  
  

BACKGROUND 背景

Human epidermal growth factor receptor 2 (HER2)–targeted therapies have not been approved for patients with non–small-cell lung cancer (NSCLC). The efficacy and safety of trastuzumab deruxtecan (formerly DS-8201), a HER2 antibody–drug conjugate, in patients with HER2-mutant NSCLC have not been investigated extensively.

人类表皮生长因子受体2（HER2）靶向疗法尚未被批准用于非小细胞肺癌（NSCLC）患者。关于HER2抗体-药物结合物曲妥珠单抗（前DS-8201）治疗HER2突变型NSCLC患者的疗效和安全性，尚未进行广泛研究。

METHODS 方法

We conducted a multicenter, international, phase 2 study in which trastuzumab deruxtecan (6.4 mg per kilogram of body weight) was administered to patients who had metastatic HER2-mutant NSCLC that was refractory to standard treatment. The primary outcome was objective response as assessed by independent central review. Secondary outcomes included the duration of response, progression-free survival, overall survival, and safety. Biomarkers of HER2 alterations were assessed.

我们进行了一项多中心、国际性的2期研究，其中曲妥珠单抗deruxtecan（6.4 mg/kg 体重）用于对标准治疗无效的转移性HER2突变NSCLC患者。主要结果是独立中央审查评估的客观反应。次要结果包括持续缓解时间、无进展生存期、总生存期和安全性。同时评估了HER2改变的生物标志物。

RESULTS 结果

A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.

共有91名患者入组。中位随访时间为13.1个月（范围0.7-29.1）。55%的患者出现了集中确认的客观反应（95%置信区间[CI]，44-65）。中位持续缓解时间为9.3个月（95% CI, 5.7-14.7）。中位无进展生存期为8.2个月（95% CI，6.0-11.9），中位总生存期为17.8个月（95% CI，13.8-22.1）。安全性概况与之前的研究基本一致；46%的患者发生3级或更高级别的药物相关不良事件，最常见的事件是中性粒细胞减少（19%）。26%的患者发生与药物相关的间质性肺病，并导致2例患者死亡。在不同的HER2突变亚型，以及在未检测到HER2表达或HER2扩增的患者中观察到了药物响应。

CONCLUSIONS 结论

Trastuzumab deruxtecan showed durable anticancer activity in patients with previously treated HER2-mutant NSCLC. The safety profile included interstitial lung disease that was fatal in two cases. Observed toxic effects were generally consistent with those in previously reported studies.

曲妥珠单抗deruxtecan在先前经治的HER2突变NSCLC患者中显示出持久的抗癌活性。安全性分析包括两例致命的间质性肺病。观察到的毒性作用与之前报道的研究基本一致。