HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs—A Long Way to the Top
Non-small-cell lung cancer (NSCLC) can harbour different HER2 alterations: HER2 protein overexpression (2–35%), HER2 gene amplification (2–20%), and gene mutations (1–4%). The discovery of the HER2 gene in the 1980s raised great expectations for the treatment of several tumours. However, it was only...
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2025-06-01
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| author | Pamela Trillo Aliaga Gianluca Spitaleri Ilaria Attili Carla Corvaja Elena Battaiotto Panagiotis Agisilaos Angelopoulos Ester Del Signore Antonio Passaro Filippo de Marinis |
| author_facet | Pamela Trillo Aliaga Gianluca Spitaleri Ilaria Attili Carla Corvaja Elena Battaiotto Panagiotis Agisilaos Angelopoulos Ester Del Signore Antonio Passaro Filippo de Marinis |
| author_sort | Pamela Trillo Aliaga |
| collection | DOAJ |
| description | Non-small-cell lung cancer (NSCLC) can harbour different HER2 alterations: HER2 protein overexpression (2–35%), HER2 gene amplification (2–20%), and gene mutations (1–4%). The discovery of the HER2 gene in the 1980s raised great expectations for the treatment of several tumours. However, it was only in 2004 that HER2 mutations were identified, and they currently represent a key druggable target in NSCLC. Despite numerous strengths, there is only one FDA/EMA-approved targeted therapy, an antibody-drug conjugate (ADC) called trastuzumab deruxtecan for pretreated patients with HER2 mutant NSCLC. In the first-line treatment, the standard of care (SoC) remains chemotherapy with or without immunotherapy. In the past, pan-HER tyrosine kinase inhibitors (TKIs) were extensively studied with poor results. But, two newly developed HER2-specific TKIs with low EGFR WT inhibition (BAY2927088 and zongertinib) reported encouraging results and received the breakthrough therapy designation from the FDA. Ongoing clinical trials are investigating new agents. This review focuses on HER2 alterations. Additionally, the anti-HER2 therapies explored so far will be discussed in detail, including the following: HER2 inhibitors (pan-inhibitors and selective inhibitors), monoclonal antibodies (mAbs), and ADCs. A section of this paper is dedicated to the role of immunotherapy in HER2-altered NSCLC. The last section of this paper focuses on the drugs under development and their challenges. |
| format | Article |
| id | doaj-art-e8e96c6dce5d4173bcddead6de386636 |
| institution | OA Journals |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-e8e96c6dce5d4173bcddead6de3866362025-08-20T02:21:14ZengMDPI AGMolecules1420-30492025-06-013012264510.3390/molecules30122645HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs—A Long Way to the TopPamela Trillo Aliaga0Gianluca Spitaleri1Ilaria Attili2Carla Corvaja3Elena Battaiotto4Panagiotis Agisilaos Angelopoulos5Ester Del Signore6Antonio Passaro7Filippo de Marinis8Division of Thoracic Oncology, IEO—European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, ItalyDivision of Thoracic Oncology, IEO—European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, ItalyDivision of Thoracic Oncology, IEO—European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, ItalyDivision of Thoracic Oncology, IEO—European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, ItalyDivision of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, ItalyDivision of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, ItalyDivision of Thoracic Oncology, IEO—European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, ItalyDivision of Thoracic Oncology, IEO—European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, ItalyDivision of Thoracic Oncology, IEO—European Institute of Oncology, IRCCS, Via Ripamonti 435, 20141 Milan, ItalyNon-small-cell lung cancer (NSCLC) can harbour different HER2 alterations: HER2 protein overexpression (2–35%), HER2 gene amplification (2–20%), and gene mutations (1–4%). The discovery of the HER2 gene in the 1980s raised great expectations for the treatment of several tumours. However, it was only in 2004 that HER2 mutations were identified, and they currently represent a key druggable target in NSCLC. Despite numerous strengths, there is only one FDA/EMA-approved targeted therapy, an antibody-drug conjugate (ADC) called trastuzumab deruxtecan for pretreated patients with HER2 mutant NSCLC. In the first-line treatment, the standard of care (SoC) remains chemotherapy with or without immunotherapy. In the past, pan-HER tyrosine kinase inhibitors (TKIs) were extensively studied with poor results. But, two newly developed HER2-specific TKIs with low EGFR WT inhibition (BAY2927088 and zongertinib) reported encouraging results and received the breakthrough therapy designation from the FDA. Ongoing clinical trials are investigating new agents. This review focuses on HER2 alterations. Additionally, the anti-HER2 therapies explored so far will be discussed in detail, including the following: HER2 inhibitors (pan-inhibitors and selective inhibitors), monoclonal antibodies (mAbs), and ADCs. A section of this paper is dedicated to the role of immunotherapy in HER2-altered NSCLC. The last section of this paper focuses on the drugs under development and their challenges.https://www.mdpi.com/1420-3049/30/12/2645NSCLCadenocarcinomaHER2ERBB2targeted therapyantibody–drug conjugate |
| spellingShingle | Pamela Trillo Aliaga Gianluca Spitaleri Ilaria Attili Carla Corvaja Elena Battaiotto Panagiotis Agisilaos Angelopoulos Ester Del Signore Antonio Passaro Filippo de Marinis HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs—A Long Way to the Top Molecules NSCLC adenocarcinoma HER2 ERBB2 targeted therapy antibody–drug conjugate |
| title | HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs—A Long Way to the Top |
| title_full | HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs—A Long Way to the Top |
| title_fullStr | HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs—A Long Way to the Top |
| title_full_unstemmed | HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs—A Long Way to the Top |
| title_short | HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs—A Long Way to the Top |
| title_sort | her2 in non small cell lung cancer nsclc evolution of the therapeutic landscape and emerging drugs a long way to the top |
| topic | NSCLC adenocarcinoma HER2 ERBB2 targeted therapy antibody–drug conjugate |
| url | https://www.mdpi.com/1420-3049/30/12/2645 |
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