Cancer Research and Treatment

Original Articles

Lung and Thoracic cancer

Tumor Microenvironment Modulation by Neoadjuvant Erlotinib Therapy and Its Clinical Impact on Operable EGFR-Mutant Non–Small Cell Lung Cancer: Beung-Chul Ahn, Charny Park, Moon Soo Kim, Jong Mog Lee, Jin Ho Choi, Hyae Young Kim, Geon Kook Lee, Namhee Yu, Youngjoo Lee, Ji-Youn Han; Cancer Res Treat. 2024;56(1):70-80. Published online June 21, 2023; DOI: https://doi.org/10.4143/crt.2023.482

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Purpose
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in EGFR-mutant (EGFRm) non–small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC.
Materials and Methods
This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (EGFR exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling.
Results
A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor β, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS.
Conclusion
NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.

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Dual Inhibition of SYK and EGFR Overcomes Chemoresistance by Inhibiting CDC6 and Blocking DNA Replication
Jayaprakash Mandal, Tiffany Nicole Jones, Juliane Marie Liberto, Stephanie Gaillard, Tian-Li Wang, Ie-Ming Shih
Cancer Research.2024; 84(22): 3881. CrossRef

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Real World Characteristics and Clinical Outcomes of HER2-Mutant Non–Small Cell Lung Cancer Patients Detected by Next-Generation Sequencing: Beung-Chul Ahn, Ye-Jeong Han, Hye Ryun Kim, Min Hee Hong, Byoung Chul Cho, Sun Min Lim; Cancer Res Treat. 2023;55(2):488-497. Published online November 9, 2022; DOI: https://doi.org/10.4143/crt.2022.359

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Purpose
This study was conducted to investigate the clinical characteristics of patients with advanced non–small cell lung cancer (NSCLC) harboring human epidermal growth factor receptor 2 (HER2) mutations and to evaluate response to standard treatment and HER2-targeted agents.
Materials and Methods
Using tissue and/or blood next-generation sequencing, we identified 44 patients with NSCLC harboring HER2 mutations who were treated at Severance Hospital between December 2016 and February 2021. Clinical data, including patient characteristics, mutation status, incidence of metastasis for distant lesions, and response to chemotherapy, were retrospectively analyzed.
Results
The median age was 58 years, and 61% of the patients were female. Most patients (64%) were never-smokers. Adenocarcinoma was the most predominant subtype (98%). A total of 66% of the patients had extrathoracic metastatic lesions, and 32% had intracranial lesions at initial presentation. The median time to the development of brain metastasis was 15.6 months (range, 2.4 to 43.7). The most common type of HER2 mutation was 12 base pair in-frame insertion in exon 20, A775_G776insYVMA. Of the 44 patients, two had concomitant driver mutations, one with epidermal growth factor receptor (EGFR) mutation (V769M), and one with BRAF mutation (V600E). Patients treated with pemetrexed-based chemotherapy (75%) had an overall response rate (ORR) and progression-free survival (PFS) of 30% and 8.3 months (95% confidence interval [CI], 3.9 to 12.7), respectively. The ORR and PFS of HER2-targeted agent treated patients (14%) were 0.0% and 1.9 months (95% CI, 0.1 to 2.8), respectively.
Conclusion
Given its distinct characteristics and treatment responses, novel treatment strategies for HER2-mutant NSCLC should be developed promptly to improve survival outcomes of patients.

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Targeted therapy for older patients with an oncogene driven non-small cell lung cancer: Recommendations from a SIOG expert group
L. Decoster, D.R. Camidge, J.A. Fletcher, A. Addeo, A. Greystoke, K. Kantilal, L.Bigay Game, R. Kanesvaran, F. Gomes
Lung Cancer.2025; 200: 108087. CrossRef
HER2-Selective Tyrosine Kinase Inhibitor, Zongertinib (BI 1810631), in Patients With Advanced/Metastatic Solid Tumors With HER2 Alterations: A Phase Ia Dose-Escalation Study
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Targeting HER2 in lung cancers: Evolving treatment landscape and drug development strategies
Daniel Reinhorn, Mor Moskovitz, William D. Tap, Bob T. Li
Cancer.2025;[Epub] CrossRef
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Yating Hou, Xingyang Xue, Zhuoyun Zhang, Dahai Mai, Wei Luo, Mingyu Zhou, Zichuan Liu, Yisheng Huang
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HER2 in Non-Small Cell Lung Cancer (NSCLC): Evolution of the Therapeutic Landscape and Emerging Drugs—A Long Way to the Top
Pamela Trillo Aliaga, Gianluca Spitaleri, Ilaria Attili, Carla Corvaja, Elena Battaiotto, Panagiotis Agisilaos Angelopoulos, Ester Del Signore, Antonio Passaro, Filippo de Marinis
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Stefan Wölke, Behbood Sadrolhefazi, Habib Esmaeili, Sven Wind, Simone M. Blattner, Guanfa Gan, Dongmei Qiang, Andrea Schirmer, Fabian Müller
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Relative Bioavailability of Zongertinib, an Orally Administered HER2-Selective Tyrosine Kinase Inhibitor, under Fed and Fasted Conditions in Healthy Male Participants: Results from Two Randomized, Open-Label, Crossover Studies
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Real-World Characteristics, Treatment Patterns, and Outcomes in Advanced HER2 (ERBB2)-Mutant Non-Small Cell Lung Cancer: A Retrospective Study of Single Centers in France and Germany
Petros Christopoulos, Christin Assmann, Lirong Zhang, Kyle Dunton, Ahmed Ali, Mehmet Berktas, Lisa Delmastro, Alessandria Strübing, Yan Xiong, Sarah Lay-Flurrie, Pooja Hindocha, Tarana Mehdikhanova, Nicolas Girard
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Trastuzumab Deruxtecan for ERBB2-Mutant Metastatic Non–Small Cell Lung Cancer With or Without Brain Metastases
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Clinicopathologic and Molecular Characteristics of HER2 (ERBB2)-Altered Non–Small Cell Lung Cancer: Implications for Precision Medicine
Yurimi Lee, Boram Lee, Yoon-La Choi, Dong-Wook Kang, Joungho Han
Modern Pathology.2024; 37(6): 100490. CrossRef
Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations
Meng Hu, Congying Zhong, Jiabing Wang, JinQin Chen, Tao Zhou
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Real-World Clinical Outcomes for Patients with EGFR and HER2 Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer
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