HERTHENA-Lung01，HER3-DXd用于EGFR-TKI联合铂类化疗后具有EGFR受体突变肺癌患者II期试验

SCI

17 September 2023

HERTHENA-Lung01, a Phase II Trial of Patritumab Deruxtecan (HER3-DXd) in Epidermal Growth Factor Receptor–Mutated Non–Small-Cell Lung Cancer After Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy and Platinum-Based Chemotherapy

(Journal of Clinical Oncology, IF: 45.3)

Helena A. Yu, Yasushi Goto, Hidetoshi Hayashi, Enriqueta Felip, James Chih-Hsin Yang, Martin Reck, Kiyotaka Yoh, Se-Hoon Lee, Luis Paz-Ares, Benjamin Besse, Paolo Bironzo, Dong-Wan Kim, Melissa L. Johnson, Yi-Long Wu, Thomas John, Steven Kao, Toshiyuki Kozuki, Erminia Massarelli, Jyoti Patel, Egbert Smit, Karen L. Reckamp, Qian Dong, Pomy Shrestha, Pang-Dian Fan, Parul Patel, Andrea Sporchia, David W. Sternberg, Dalila Sellami, and Pasi A. J¨anne

CORRESPONDENCE TO: YuH@mskcc.org

PURPOSE 目的

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).

Patritumab deruxtecan，或HER3-DXd，是一种抗体-药物偶联物，由人表皮生长因子受体3（HER3）的全人单克隆抗体组成，通过稳定的基于四肽的可裂解接头连接到拓扑异构酶I抑制剂有效载荷上。我们评估了HER3-DXd治疗表皮生长因子受体（EGFR）突变非小细胞肺癌（NSCLC）患者的疗效和安全性。

METHODS 方法

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.

这项II期研究（ClinicalTrials.gov标识符：NCT04619004）旨在评估HER3-DXd在既往接受EGFR酪氨酸激酶抑制剂（TKI）治疗和铂基化疗（PBC）治疗的晚期EGFR突变NSCLC患者中的作用。患者每3周静脉注射一次HER3 DXd 5.6 mg/kg，或接受一种药物递增方案（3.2→ 4.8→ 6.4mg/kg）。主要终点是通过盲法独立中心评审（BICR）确认的客观有效率（ORR；RECIST 1.1），根据历史数据，零假设为26.4%。

RESULTS 结果

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.

根据对I期U31402-A-U102试验数据的预先指定的获益-风险评估，较早地结束了药物递增组的入组。总共225名患者每3周接受一次HER3 DXd 5.6 mg/kg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14.9-27.5）。经BICR确认的ORR为29.8%（95%CI为23.9至36.2哥月）；中位反应持续时间，6.4个月；中位无进展生存期，5.5个月；中位总生存期11.9个月。既往有奥西替尼和PBC的患者亚组具有相似的结果。在广泛的具有肿瘤HER3膜表达水平和EGFR-TKI耐药性的不同机制中的预治疗试验中观察到疗效。在未经放射治疗的脑转移患者（n = 30）基线水平，根据BICR，CNS RECIST确认的CNS ORR为33.3%（95%CI，17.3至52.8）。安全性（美国癌症研究所不良事件通用术语标准v5.0）是可控制和可耐受的，与之前的观察结果一致。

CONCLUSION 结论

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).

EGFR突变的NSCLC患者在EGFR-TKI治疗和PBC治疗后发生肿瘤进展后，其中肿瘤进展包括存在中枢神经系统转移，进行每3周一次的HER3-DXd治疗显示出具有临床意义的疗效和持久的反应。EGFR TKI进展后EGFR突变NSCLC的III期试验正在进行中。

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