Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR -mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR -mutated non–small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0–52.4], and median progression-free survival was 8.2 (95% CI, 4.4–8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI–resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. Significance: In metastatic EGFR -mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism. See related commentary by Lim et al., [p. 16][1] . This article is highlighted in the In This Issue feature, [p. 1][2] [1]: /lookup/volpage/12/16?iss=1 [2]: /lookup/volpage/12/1?iss=1

中文翻译：

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Patritumab Deruxtecan (HER3-DXd) 在 EGFR 抑制剂耐药、EGFR 突变的非小细胞肺癌中的疗效和安全性

受体酪氨酸蛋白激酶 ERBB3 (HER3) 在大多数 EGFR 突变的肺癌中表达，但不是已知的 EGFR 抑制剂耐药机制。HER3-DXd 是一种抗体-药物偶联物，由通过基于四肽的可裂解接头连接到拓扑异构酶 I 抑制剂有效载荷的 HER3 抗体组成。该 I 期剂量递增/扩展研究包括既往接受过 EGFR 酪氨酸激酶抑制剂 (TKI) 治疗的局部晚期或转移性 EGFR 突变非小细胞肺癌 (NSCLC) 患者。在每 3 周一次静脉注射 HER3-DXd 5.6 mg/kg 的 57 名患者中，通过盲法独立中央审查（实体瘤反应评估标准 v1.1）确认的客观反应率为 39% [95% 置信区间 (CI)， 26.0–52.4]，中位无进展生存期为 8.2（95% CI，4.4–8.3）个月。在具有已知和未知 EGFR TKI 耐药机制的患者中观察到反应。在广泛的 HER3 膜表达范围内观察到临床活性。最常见的 ≥ 3 级治疗中出现的不良事件是血液学毒性。HER3-DXd 在 EGFR TKI 耐药癌症中具有独立于耐药机制的临床活性，提供了一种治疗广泛耐药癌症的方法。意义：在转移性 EGFR 突变的 NSCLC 中，在使用 EGFR TKI 疗法治疗疾病进展后，治疗方法包括针对已知耐药机制的基因型定向疗法或化学疗法。HER3-DXd 证明了跨越已知和未知的 EGFR TKI 耐药机制的临床活性。HER3-DXd 可以提供与 EGFR TKI 耐药机制无关的未来治疗选择。参见 Lim 等人的相关评论，[p. 16][1]。这篇文章在本期专题中突出显示，[p。1][2] [1]: /lookup/volpage/12/16?iss=1 [2]: /lookup/volpage/12/1?iss=1