Reinhorn Daniel, Moskovitz Mor, Tap William D, Li Bob T
Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva, Israel.
Cancer. 2025 Mar 15;131 Suppl 1:e35780. doi: 10.1002/cncr.35780.
ERBB2 (HER2) alterations, including mutations, amplifications, and overexpression are emerging therapeutic targets in non-small cell lung cancer (NSCLC). Despite recent advancements, standard first-line therapy remains chemotherapy with or without immunotherapy. Several therapies targeting HER2 are under development and have been evaluated in clinical trials with inconsistent efficacy, including monoclonal antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates. A major landmark was recently reached when trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate, became the first Food and Drug Administration (FDA)-approved therapy for pretreated HER2-mutant NSCLC, following the promising efficacy demonstrated in the DESTINY-Lung trials. Furthermore, T-DXd has shown efficacy across various tumor types harboring HER2 alterations in the DESTINY-PanTumor trials, leading to its recent pan-tumor FDA approval for HER2-positive solid tumors, highlighting the potential of tumor-agnostic drug development strategies. In this review, the authors describe the different HER2 alterations and their clinical consequences, including their impact on prognosis and response to standard therapies. They provide an up-to-date overview of the current treatment landscape and add a comprehensive review of pivotal and ongoing clinical trials of HER2-targeted therapies, including tumor-agnostic drug development strategies.
ERBB2（HER2）改变，包括突变、扩增和过表达，正在成为非小细胞肺癌（NSCLC）新的治疗靶点。尽管最近取得了进展，但标准一线治疗仍然是化疗，可联合或不联合免疫治疗。几种靶向HER2的疗法正在研发中，并已在临床试验中进行评估，但其疗效并不一致，这些疗法包括单克隆抗体、酪氨酸激酶抑制剂和抗体药物偶联物。近期取得了一个重要的里程碑，抗体药物偶联物曲妥珠单抗德卢替康（T-DXd）在DESTINY-Lung试验中显示出了令人鼓舞的疗效，成为首个获得美国食品药品监督管理局（FDA）批准用于治疗经治HER2突变型NSCLC的疗法。此外，T-DXd在DESTINY-PanTumor试验中对各种存在HER2改变的肿瘤类型均显示出疗效，这使其最近获得FDA的泛肿瘤批准，用于治疗HER2阳性实体瘤，凸显了不考虑肿瘤类型的药物开发策略的潜力。在这篇综述中，作者描述了不同的HER2改变及其临床后果，包括它们对预后的影响以及对标准疗法的反应。他们提供了当前治疗格局的最新概述，并对HER2靶向疗法的关键和正在进行的临床试验，包括不考虑肿瘤类型的药物开发策略进行了全面综述。
