National Cancer Center Hospital, Tokyo, Japan.
Wakayama Medical University Hospital, Wakayama, Japan.
J Clin Oncol. 2023 Oct 10;41(29):4678-4687. doi: 10.1200/JCO.23.00059. Epub 2023 Jun 16.
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.
这是一项首次人体、剂量递增和剂量扩展研究，评估了新型滋养细胞表面抗原 2（TROP2）靶向抗体药物偶联物 datopotamab deruxtecan（Dato-DXd）在包括晚期非小细胞肺癌（NSCLC）在内的实体瘤中的安全性、耐受性和抗肿瘤活性。
局部晚期/转移性 NSCLC 成人患者接受 0.27-10mg/kg 的 Dato-DXd，每 3 周一次，在递增阶段；或 4、6 或 8mg/kg 的 Dato-DXd，每 3 周一次，在扩展阶段。主要终点为安全性和耐受性。次要终点包括客观缓解率（ORR）、生存和药代动力学。
210 例患者接受了 Dato-DXd 治疗，其中 180 例患者在 4-8mg/kg 剂量扩展队列中。该人群的中位治疗线数为三线。最大耐受剂量为 8mg/kg，每 3 周一次；进一步开发的推荐剂量为 6mg/kg，每 3 周一次。在接受 6mg/kg（n=50）的患者中，中位研究持续时间（包括随访）和中位暴露时间分别为 13.3 个月和 3.5 个月。最常见的任何级别治疗相关不良事件（TEAEs）为恶心（64%）、黏膜炎（60%）和脱发（42%）。54%的患者发生了≥3 级 TEAEs，26%的患者发生了治疗相关的 AEs。有 3 例（6%）患者发生了间质性肺病，被判定为与药物相关（2 级 2 例，4 级 1 例）。ORR 为 26%（95%CI，14.6%至 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 至 8.8 个月）和 11.4 个月（95%CI，7.1 至 20.6 个月）。无论 TROP2 表达情况如何，均观察到有缓解。
在既往大量治疗的晚期 NSCLC 患者中，Dato-DXd 显示出有前景的抗肿瘤活性和可管理的安全性特征。目前正在进行 Dato-DXd 作为晚期 NSCLC 一线联合治疗和二线及以上二线治疗的研究。
