帕替单抗-德鲁鲁襻神经胶质瘤素（Patritumab deruxtecan，简称HER3-DXd）是一种抗体-药物偶联物，由一种全人源单克隆抗体与人表皮生长因子受体3（HER3）结合，并通过稳定的四肽基可裂解连接剂与拓扑异构酶I抑制剂负荷物相连。我们评估了HER3-DXd在表皮生长因子受体（EGFR）突变性非小细胞肺癌（NSCLC）患者中的疗效和安全性。该II期研究（ClinicalTrials.gov识别号：NCT04619004）旨在评估已接受EGFR酪氨酸激酶抑制剂（TKI）治疗和铂类化疗（PBC）的晚期EGFR突变NSCLC患者中的HER3-DXd。患者每3周一次静脉注射HER3-DXd 5.6 mg/kg，或按逐步加量方案（3.2 → 4.8 → 6.4 mg/kg）给予。主要终点是经盲目独立中央评审（BICR）确认的客观缓解率（ORR；RECIST 1.1），基于历史数据的零假设为26.4%。逐渐加量组的招募提前停止，依据的是一项对U31402-A-U102试验资料进行的预先规定的利益风险评估。总共225名患者每3周一次接受HER3-DXd 5.6 mg/kg。截至2023年5月18日，研究的中位持续时间为18.9个月（范围为14.9-27.5个月）。BICR确认的ORR为29.8%（95% CI，23.9%至36.2%）；缓解持续时间的中位数为6.4个月；无进展生存期的中位数为5.5个月；总生存期的中位数为11.9个月。先前接受奥西美坦和PBC治疗的患者亦有类似结果。HER3-DXd的疗效在各种不同的EGFR TKI耐药机制和前治疗肿瘤HER3膜表达水平广泛范围内观察到。在有非放射性脑转移的基线患者（n = 30）中，经CNS RECIST盲目独立中央评审确认的CNS ORR为33.3%（95% CI，17.3%至52.8%）。安全性概况（根据国家癌症研究所不良事件共同术语（CTCAE）第5版）可管理且可耐受，与以前观察到的结果一致。在EGFR突变NSCLC患者中，在EGFR TKI治疗失败后的PBC中，每3周一次的HER3-DXd显示出具有持久缓解效果的临床意义疗效，包括对中枢神经系统转移的缓解。在EGFR TKI进展后的EGFR突变NSCLC患者中，正在进行第III期试验（HERTHENA-Lung02；ClinicalTrials.gov识别号：NCT05338970）。

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 (EGFR)-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 EGFR-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 EGFR-mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR-mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).