Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.
National Cancer Center Hospital, Tokyo, Japan.
J Clin Oncol. 2023 Dec 10;41(35):5363-5375. doi: 10.1200/JCO.23.01476. Epub 2023 Sep 10.
Patritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor ()-mutated non-small-cell lung cancer (NSCLC).
This phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data.
Enrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations.
After tumor progression with EGFR TKI therapy and PBC in patients with -mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).
帕妥珠单抗 deruxtecan（HER3-DXd）是一种抗体药物偶联物，由与人表皮生长因子受体 3（HER3）完全人源化单克隆抗体通过稳定的四肽连接子与拓扑异构酶 I 抑制剂有效载荷连接而成。我们评估了 HER3-DXd 在表皮生长因子受体（EGFR）-突变型非小细胞肺癌（NSCLC）患者中的疗效和安全性。
这项 II 期研究（ClinicalTrials.gov 标识符：NCT04619004）旨在评估先前接受过 EGFR 酪氨酸激酶抑制剂（TKI）治疗和铂类化疗（PBC）的晚期突变型 NSCLC 患者中使用 HER3-DXd 的效果。患者接受静脉注射 5.6 mg/kg 的 HER3-DXd，每 3 周一次，或进行滴定方案（3.2→4.8→6.4 mg/kg）。主要终点是由盲法独立中心审查（BICR）确认的客观缓解率（ORR；RECIST 1.1），根据历史数据，假设值为 26.4%。
基于 I 期 U31402-A-U102 试验数据的预设获益风险评估，在滴定臂入组提前关闭。总共 225 名患者接受了每 3 周一次的 5.6 mg/kg HER3-DXd 治疗。截至 2023 年 5 月 18 日，中位研究持续时间为 18.9 个月（范围为 14.9-27.5）。BICR 确认的 ORR 为 29.8%（95%CI，23.9 至 36.2）；中位缓解持续时间为 6.4 个月；中位无进展生存期为 5.5 个月；中位总生存期为 11.9 个月。先前接受过奥希替尼和 PBC 的患者亚组具有相似的结果。在广泛的预处理肿瘤 HER3 膜表达水平和各种 EGFR TKI 耐药机制中均观察到疗效。在基线时有未经放疗的脑转移的患者（n=30）中，BICR 按中枢神经系统 RECIST 确认的中枢神经系统 ORR 为 33.3%（95%CI，17.3 至 52.8）。安全性特征（美国国家癌症研究所不良事件通用术语标准 v5.0）是可控和可耐受的，与之前的观察结果一致。
在接受 EGFR TKI 治疗和 PBC 后肿瘤进展的 -突变型 NSCLC 患者中，每 3 周一次的 HER3-DXd 显示出具有临床意义的疗效，包括持久缓解，包括中枢神经系统转移。一项针对 EGFR TKI 进展后的突变型 NSCLC 的 III 期试验正在进行中（HERTHENA-Lung02；ClinicalTrials.gov 标识符：NCT05338970）。
