滋养层细胞表面抗原2导向抗体药物共轭物达托帕单抗Deruxtecan在非小细胞肺癌中的首次人体I期剂量递增和剂量扩大研究

SCI

14 July 2023

First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2–Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non–Small-Cell Lung Cancer: TROPION-PanTumor01

 (J Clin Oncol IF: 44.54)

Shimizu T, Sands J, Yoh K, et al. First-in-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2-Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non-Small-Cell Lung Cancer: TROPION-PanTumor01 [published online ahead of print, 2023 Jun 16]. J Clin Oncol. 2023;JCO2300059. doi:10.1200/JCO.23.00059 https://doi.org/10.1016/j.jtho.2023.06.018. 

PURPOSE 研究目的

This first-in-human, dose-escalation and dose-expansion study evaluated the safety, tolerability, and antitumor activity of datopotamab deruxtecan (Dato-DXd), a novel trophoblast cell-surface antigen 2 (TROP2)–directed antibody-drug conjugate in solid tumors, including advanced non–small-cell lung cancer (NSCLC).

这项首次人体试验、剂量递增和剂量扩大研究评估了新型滋养层细胞表面抗原2（TROP2）导向抗体-药物共轭物达托帕单抗德鲁司坦（Dato-DXd）在实体瘤（包括晚期非小细胞肺癌（NSCLC））中的安全性、耐受性和抗肿瘤活性。

PATIENTS AND METHODS 患者和方法  

Adults with locally advanced/metastatic NSCLC received 0.27-10 mg/kg Dato-DXd once every 3 weeks during escalation or 4, 6, or 8 mg/kg Dato-DXd once every 3 weeks during expansion. Primary end points were safety and tolerability. Secondary end points included objective response rate (ORR), survival, and pharmacokinetics.

局部晚期/转移性NSCLC成人患者在升级期接受0.27-10 mg/kg Dato-DXd，每3周1次；或在扩大期接受4、6或8 mg/kg Dato-DXd，每3周1次。主要终点为安全性和耐受性。次要终点包括客观反应率（ORR）、存活率和药代动力学。

RESULTS 研究结果  

Two hundred ten patients received Dato-DXd, including 180 in the 4-8 mg/kg dose-expansion cohorts. This population had a median of three prior lines of therapy. The maximum tolerated dose was 8 mg/kg once every 3 weeks; the recommended dose for further development was 6 mg/kg once every 3 weeks. In patients receiving 6 mg/kg (n5 50), median duration on study, including follow-up, and median exposure were 13.3 and 3.5 months, respectively. The most frequent any-grade treatment-emergent adverse events (TEAEs) were nausea (64%), stomatitis (60%), and alopecia (42%). Grade ≥3 TEAEs and treatment-related AEs occurred in 54% and 26% of patients, respectively. Interstitial lung disease adjudicated as drug-related (two grade 2 and one grade 4) occurred in three of 50 patients (6%). The ORR was 26% (95% CI, 14.6 to 40.3), and median duration of response was 10.5 months; median progression- free survival and overall survival were 6.9 months (95% CI, 2.7 to 8.8 months) and 11.4 months (95% CI, 7.1 to 20.6 months), respectively. Responses occurred regardless of TROP2 expression.

210例患者接受了Dato-DXd治疗，其中180例为4-8 mg/kg剂量扩增组。这些患者中位数曾接受过三线治疗。最大耐受剂量为8 mg/kg，每3周1次；进一步开发的推荐剂量为6 mg/kg，每3周1次。在接受6 mg/kg治疗的患者中（n5 50），包括随访在内的中位研究持续时间和中位暴露时间分别为13.3个月和3.5个月。最常见的任何等级治疗突发不良事件（TEAEs）为恶心（64%）、口腔炎（60%）和脱发（42%）。≥3级TEAE和治疗相关AEs分别发生在54%和26%的患者中。50例患者中有3例（6%）被判定为药物相关的间质性肺病（2例2级，1例4级）。ORR为26%（95% CI，14.6~40.3），中位应答持续时间为10.5个月；中位无进展生存期和总生存期分别为6.9个月（95% CI，2.7~8.8个月）和11.4个月（95% CI，7.1~20.6个月）。无论TROP2表达与否，均出现应答。

CONCLUSION 结论  

Promising antitumor activity and a manageable safety profile were seen with Dato-DXd in heavily pretreated patients with advanced NSCLC. Further investigation as first-line combination therapy in advanced NSCLC and as monotherapy in the second-line setting and beyond is ongoing.

在重度预处理的晚期NSCLC患者中，Dato-DXd具有良好的抗肿瘤活性和可控的安全性。作为晚期NSCLC一线联合治疗和二线及以后的单药治疗的进一步研究正在进行中。

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