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.
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.
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DOI：
10.1200/jco.23.00059
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发表时间：
2023-10-10
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这项首次人体剂量递增和剂量扩展研究评价了Datopotamab deruxtecan（Dato-DXd）的安全性、耐受性和抗肿瘤活性，Datopotamab deruxtecan是一种新型滋养层细胞表面抗原2（TR 0 P2）导向的抗体药物偶联物，用于治疗实体瘤，包括晚期非小细胞肺癌（NSCLC）。局部晚期/转移性NSCLC成人患者在递增期接受0.27-10 mg/kg Dato-DXd，每3周一次，或在扩展期接受4、6或8 mg/kg Dato-DXd，每3周一次。主要终点是安全性和耐受性。次要终点包括客观缓解率（ORR）、生存率和药代动力学。210例患者接受了Dato-DXd，包括4-8 mg/kg剂量扩展队列中的180例患者。该人群既往接受过三线治疗的中位数。最大耐受剂量为8 mg/kg，每3周一次;进一步开发的推荐剂量为6 mg/kg，每3周一次。在接受6 mg/kg的患者（n = 50）中，研究中位持续时间（包括随访）和中位暴露分别为13.3和3.5个月。最常见的任何级别治疗后出现的不良事件（TEAE）为恶心（64%）、口腔炎（60%）和脱发（42%）。分别有54%和26%的患者发生≥3级TEAE和治疗相关AE。50例患者中有3例（6%）发生了裁定为药物相关的间质性肺病（2例2级和1例4级）。ORR为26%（95% CI，14.6 - 40.3），中位缓解持续时间为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TROP 2表达如何，均发生反应。Dato-DXd在接受过大量预治疗的晚期NSCLC患者中观察到有希望的抗肿瘤活性和可管理的安全性特征。正在进一步研究作为晚期NSCLC的一线联合治疗以及作为二线及二线以上环境的单药治疗。
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). 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. 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 (n = 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. 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.