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Carlisle JW, Wolner Z, Pannu S, Mitchell C, Hsu M, Aijaz A, Johnson M, Naqash AR. Bispecific Antibodies in Non-Small Cell Lung Cancer: From Targeted Innovation to Real-World Integration. Am Soc Clin Oncol Educ Book 2025; 45:e472792. [PMID: 40397846 DOI: 10.1200/edbk-25-472792] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2025]
Abstract
Bispecific antibodies have ushered in a transformative era in treating non-small cell lung cancer (NSCLC), enabling dual-pathway targeting with promising clinical outcomes in previously refractory disease subsets. Recent US Food and Drug Administration approvals-including amivantamab, an epidermal growth factor receptor (EGFR)/mesenchymal-epithelial transition factor-targeting monoclonal antibody for EGFR exon 20 insertions and frontline EGFR-mutant (Exon 19 and 21) NSCLC, and zenocutuzumab for tumors harboring neuregulin 1 fusions-highlight their expanding therapeutic footprint. However, a new spectrum of on-target toxicities and implementation challenges are essential considerations as part of this innovation. This review dissects the evolving clinical data for bispecific antibodies in NSCLC, focusing on amivantamab, and provides a practical framework for managing dermatologic, infusion-related, and class-specific adverse events. We explore quality-of-life outcomes, financial toxicity, and the role of subcutaneous formulations in improving patient adherence and treatment experience. Furthermore, we highlight an emerging PD-1/vascular endothelial growth factor-A bispecific antibody (ivonescimab) and its potential to reshape frontline therapy paradigms in NSCLC. By integrating clinical trial evidence with real-world considerations, this review aims to equip oncologists with the tools to optimize the use of bispecific antibodies in NSCLC and guide future therapeutic integration.
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Affiliation(s)
- Jennifer W Carlisle
- Department of Hematology and Medical Oncology, Emory University, Atlanta, GA
- Winship Cancer Institute of Emory University, Atlanta, GA
| | - Zachary Wolner
- Winship Cancer Institute of Emory University, Atlanta, GA
| | - Sagal Pannu
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK
| | | | - Melinda Hsu
- Case Western Reserve University, Cleveland, OH
| | - Ayesha Aijaz
- Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK
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Guidi L, Etessami J, Valenza C, Valdivia A, Meric-Bernstam F, Felip E, Curigliano G. Bispecific Antibodies in Hematologic and Solid Tumors: Current Landscape and Therapeutic Advances. Am Soc Clin Oncol Educ Book 2025; 45:e473148. [PMID: 40198874 DOI: 10.1200/edbk-25-473148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/10/2025]
Abstract
Bispecific antibodies (bsAbs) have emerged as a novel class of therapeutics, offering a dual-targeting strategy to enhance the therapeutic efficacy of monoclonal antibodies, which is often limited by tumor heterogeneity and the occurrence of resistance mechanisms. By simultaneously engaging two distinct antigens or pathways, bsAbs disrupt multiple signaling cascades simultaneously, preventing escape mechanisms and offering a more durable response. Furthermore, they can optimize immune activation, improving immune cell recruitment strategies. In particular, T-cell engager bsAbs facilitate immune cell-mediated tumor destruction by linking T cells to tumor antigens. Instead, dual immune checkpoint inhibitors (CPIs) enhance immune activation by blocking inhibitory signals. Additionally, bsAbs targeting tumor growth factors or receptor tyrosine kinases offer solutions for overcoming drug resistance in solid tumors. Although bsAbs have shown remarkable success in hematologic malignancies, their expansion into solid tumors faces key challenges, including tumor heterogeneity, limited tumor penetration, and the risk of on-target, off-tumor toxicities. Addressing these challenges requires innovative engineering strategies, optimized delivery mechanisms, and careful patient selection to maximize therapeutic benefit while mitigating adverse effects. The efficacy of bsAbs in clinical trials has led to their approval for both hematologic and solid malignancies, with numerous agents in development. Combination strategies with chemotherapy, targeted agents, and immune CPIs could represent a promising strategy to further expand their potential. As research progresses, bsAbs are expected to play a role in reshaping the future of precision oncology, offering more effective and tailored treatment options.
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Affiliation(s)
- Lorenzo Guidi
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Julian Etessami
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Carmine Valenza
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
- Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA
| | - Augusto Valdivia
- Department of Medical Oncology, Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Funda Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Enriqueta Felip
- Department of Medical Oncology, Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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Le X, Eisert A, Hsia TC, Raut NV, Ahmad A, Chan OSH, De Bondt C, Farrugia D, Froesch P, González-Cao M, Hendriks L, Hochmair MJ, Mazieres J, O'Sullivan H, Popat S, Samol J, van der Wekken AJ, Yang TY, Tho LM, Himpe U, Lam WS, Lee KWC, Petrini I, Berghoff K, Karachaliou N, Joshi K, Vlassak S, Chang GC. Tepotinib Plus an EGFR Tyrosine Kinase Inhibitor in Patients With EGFR-Mutant MET-Altered NSCLC: A Case Series. Clin Lung Cancer 2025; 26:338-346.e1. [PMID: 40140342 DOI: 10.1016/j.cllc.2025.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 02/18/2025] [Accepted: 02/18/2025] [Indexed: 03/28/2025]
Affiliation(s)
- Xiuning Le
- Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
| | - Anna Eisert
- Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, University Hospital of Cologne, Cologne, Germany
| | - Te-Chun Hsia
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | | | | | - Oscar Siu Hong Chan
- Department of Clinical Oncology, Hong Kong Integrated Oncology Centre, Hong Kong
| | - Charlotte De Bondt
- Department of Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium
| | - David Farrugia
- Gloucestershire Oncology Centre, Cheltenham General Hospital, Cheltenham, United Kingdom
| | - Patrizia Froesch
- Oncology Institute of Southern Switzerland (IOSI), Ente Ospedaliero Cantonale (EOC), Bellinzona, Switzerland
| | - Maria González-Cao
- Translational Cancer Research Unit, Instituto Oncológico Dr Rosell, Quirón Dexeus University Hospital, Barcelona, Spain
| | - Lizza Hendriks
- Department of Respiratory Medicine, Maastricht University Medical Centre, GROW School for Oncology and Reproduction, Maastricht, Netherlands
| | - Maximillian J Hochmair
- Department of Respiratory & Critical Care Medicine, Karl Landsteiner Institute of Lung Research & Pulmonary Oncology, Klinik Floridsdorf, Vienna, Austria
| | - Julien Mazieres
- Toulouse University Hospital, Pneumology Department, Université Paul Sabatier, Toulouse, France
| | - Hazel O'Sullivan
- Department of Medical Oncology, Cork University Hospital, Cork, Ireland
| | - Sanjay Popat
- Lung Unit, Royal Marsden NHS Foundation Trust, London, United Kingdom
| | - Jens Samol
- Department of Medical Oncology, Tan Tock Seng Hospital, Singapore; Lee Kong Chian School of Medicine, Singapore; School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Anthonie J van der Wekken
- Department of Pulmonary Medicine, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
| | - Tsung-Ying Yang
- Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Lye Mun Tho
- Department of Oncology, Pantai Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
| | - Ulrike Himpe
- Department of Pulmonary Diseases, AZ Delta, Roeselare, Belgium
| | - Wei-Sen Lam
- Western Haematology and Oncology Clinics, West Perth, Australia
| | | | - Iacopo Petrini
- Department of Translational Research and New Technologies, University of Pisa, Pisa, Italy
| | - Karin Berghoff
- Global Patient Safety, the healthcare business of Merck KGaA, Darmstadt, Germany
| | - Niki Karachaliou
- Global Clinical Development, the healthcare business of Merck KGaA, Darmstadt, Germany
| | - Kirti Joshi
- Global Development Operations, the healthcare business of Merck KGaA, Darmstadt, Germany; ICON plc, Dublin, Ireland
| | - Soetkin Vlassak
- Global Medical Affairs, Merck N.V.-S.A., Overijse, Belgium, an affiliate of Merck KGaA, Darmstadt, Germany
| | - Gee-Chen Chang
- School of Medicine and Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan; Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan; Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan
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Waissengrin B, Reckamp KL. An evaluation of patritumab deruxtecan for the treatment of EGFR-mutated non-small cell lung cancer. Expert Opin Biol Ther 2025:1-9. [PMID: 40374579 DOI: 10.1080/14712598.2025.2507833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/28/2025] [Accepted: 05/14/2025] [Indexed: 05/17/2025]
Abstract
INTRODUCTION Epidermal growth factor receptor (EGFR) mutations represent targetable alterations in non-small cell lung cancer (NSCLC). The treatment landscape in the frontline setting for patients with advanced EGFR-mutated NSCLC is evolving with increasing treatment options. EGFR tyrosine kinase inhibitors (TKIs) have significantly improved outcomes, but resistance inevitably develops, necessitating alternative strategies. AREAS COVERED Patritumab deruxtecan is a novel antibody-drug conjugate targeted human epidermal growth factor receptor-3 (HER3), delivering a topoisomerase-I inhibitor payload to HER3-expressing cancer cells. Phase I and II studies have demonstrated efficacy in patients with EGFR-mutant NSCLC with disease progression after prior therapies, including third-generation EGFR TKIs and platinum-based chemotherapy. The phase-II trial reported an objective response rate of 39% and a median progression-free survival of 5.5 months. Patritumab deruxtecan is associated with notable toxicities, including grade 3 and higher hematologic adverse events, gastrointestinal toxicity, and interstitial lung disease (ILD). ILD occurred in 5.3% of patients in the Phase-II study. Early detection and management are crucial for minimizing the risk of complications. EXPERT OPINION Patients with advanced EGFR-mutant NSCLC who have received TKI therapy and chemotherapy have limited treatment options. Patritumab deruxtecan demonstrates clinical activity in this population with manageable side effects, addressing an unmet need for patients.
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Affiliation(s)
- Barliz Waissengrin
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Karen L Reckamp
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Zhang W, Xiong J, Li Y, Nie J, Zhao W, Guo Z, Liu X, Zhang Q, Chen X, Ye L, Chen Z, Wang H, Xu K, Zhao L, Liu Y, Huang L, Li Y, He Y. Efficacy and safety of distinct regimens for individuals with advanced EGFR-mutated non-small-cell lung cancer who progressed on EGFR tyrosine-kinase inhibitors: a systematic review and network meta-analysis. Ther Adv Med Oncol 2025; 17:17588359251338046. [PMID: 40396122 PMCID: PMC12089717 DOI: 10.1177/17588359251338046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 04/08/2025] [Indexed: 05/22/2025] Open
Abstract
Background Targeted therapy with EGFR tyrosine-kinase inhibitors (TKIs) is the preferred first-line treatment for EGFR-mutated advanced non-small-cell lung cancer (NSCLC), but acquired resistance inevitably occurs in almost all responding individuals. Objectives We aimed to comprehensively review the literature to investigate the efficacy and safety of distinct regimens in the subsequent-line setting, thereby identifying the optimal regimen for these TKI-resistant NSCLC patients. Design A systematic review and network meta-analysis (NMA) using a Bayesian framework. Data sources and methods The PubMed, Embase, Cochrane Library databases, and abstracts of ASCO, ESMO, and WCLC were searched from database inception to November 3, 2024, to identify eligible randomized controlled trials (RCTs) that assessed distinct regimens for individuals with advanced EGFR-mutated NSCLC who progressed on TKIs. The outcomes of progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and grade 3 or higher adverse events (⩾3AEs) were compared and ranked in overall patients and various subgroups among eight regimens by NMA and the surface under the cumulative ranking curve, respectively. The protocol is registered with PROSPERO, CRD42024601619. Results In total, 14 RCTs, involving 3177 participants and 8 treatment regimens (chemotherapy plus ivonescimab (programmed cell death protein 1/vascular endothelial growth factor inhibitor; chemotherapy + ivonescimab (CT + IVO)); CT + amivantamab + lazertinib (CT + AMI + LAZ), CT + immunotherapy + bevacizumab (CT + IO + BEV), CT + AMI, CT + BEV, CT + IO, CT, and IO), were included. Overall, in patients, the most pronounced PFS benefit was observed with the "CT + IVO," followed by "CT + AMI + LAZ," "CT + IO + BEV," and "CT + AMI," ranked second, third, and fourth, respectively. In terms of OS, the regimen of "CT + AMI" ranked the best, followed by "CT + IVO." However, the comparisons of OS among different regimens did not reach statistical significance, possibly due to immature data. The results for ORR and DCR were similar to those for OS, with "CT + AMI" topping the rankings, followed by "CT + AMI + LAZ." In terms of safety, the incidence of ⩾3AEs was highest in "CT + AMI + LAZ," followed by "CT + AMI." In subgroup analysis, "CT + IVO" demonstrates stable PFS benefits across clinicopathological characteristics, ranking first in most subgroups. Due to the unavailability of OS subgroup data in most RCTs, many regimens were missing in the OS subgroup analysis. Conclusion Integrating the results of different clinical outcomes and subgroup analyses, we conclude that "CT + IVO" is the optimal treatment option with an acceptable safety profile for patients with advanced EGFR-mutated NSCLC who have progressed on TKIs. "CT + AMI + LAZ" and "CT + AMI" are alternative subsequent line options as well, with superior efficacy compared to immunotherapy-based or chemotherapy regimens, yet elevated toxicity profiles requiring vigilant management.
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Affiliation(s)
- Wengang Zhang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jian Xiong
- Department of Pulmonary and Critical Care Medicine, Yueyang Central Hospital, Yueyang, China
| | - Yujie Li
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jing Nie
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wencheng Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhiyi Guo
- Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xinyue Liu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qianqian Zhang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xuyang Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Li Ye
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhimin Chen
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hao Wang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Kandi Xu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lishu Zhao
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yujin Liu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Lihua Huang
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yuhang Li
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yayi He
- Department of Medical Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China
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6
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Adou M, Guisier F. [Amivantamab with lazertinib - stage IV non-small cell lung cancer with EGFR exon 19 deletion or L858R mutation]. Bull Cancer 2025:S0007-4551(25)00200-0. [PMID: 40379500 DOI: 10.1016/j.bulcan.2025.02.024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 02/16/2025] [Indexed: 05/19/2025]
Affiliation(s)
- Marie Adou
- UFR de médecine, université Paris Cité, 75005 Paris, France.
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7
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Kawauchi D, Narita Y. The curse of blood-brain barrier and blood-tumor barrier in malignant brain tumor treatment. Int J Clin Oncol 2025:10.1007/s10147-025-02777-3. [PMID: 40338447 DOI: 10.1007/s10147-025-02777-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Accepted: 04/24/2025] [Indexed: 05/09/2025]
Abstract
The blood-brain barrier (BBB) is crucial for brain homeostasis but is a major obstacle in delivering anticancer drugs to brain tumors. However, this perspective requires re-evaluation, particularly for malignant brain tumors, such as gliomas and brain metastases. In these aggressive tumors, the BBB undergoes significant alterations, leading to the formation of a more permeable blood-tumor barrier. While this increased permeability allows better drug penetration, heterogeneity in blood-tumor barrier (BTB) integrity across different tumor regions remains a challenge. Additionally, the main challenge in treating brain tumors lies not in BBB penetration but in the lack of effective drugs. Conventional chemotherapies, including temozolomide and nitrosourea agents, have shown limited efficacy, and resistance mechanisms often reduce their long-term benefits. The "BBB curse" has often been blamed for the slow progress in drug development. However, emerging evidence suggests that even larger-molecule therapies, such as antibody-drug conjugates, can successfully target brain tumors. This review aims to critically reassess the roles of the BBB and BTB in brain tumor therapy, highlighting their impact on drug delivery and evaluating the current landscape of chemotherapeutic strategies. Furthermore, it explores new approaches to overcome treatment limitations, emphasizing the need for personalized and targeted therapeutic strategies.
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Affiliation(s)
- Daisuke Kawauchi
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Chuo City, Japan
| | - Yoshitaka Narita
- Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Chuo City, Japan.
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8
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Miyata M, Hayashi H. Current treatment landscape for patients with non-small cell lung cancer with common EGFR mutations. Respir Investig 2025; 63:576-584. [PMID: 40328075 DOI: 10.1016/j.resinv.2025.04.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/14/2025] [Accepted: 04/22/2025] [Indexed: 05/08/2025]
Abstract
Common EGFR mutations including exon-19 deletions and the L858R point mutation in exon 21 constitute predominant actionable genomic alterations in individuals with non-small cell lung cancer (NSCLC). The introduction of EGFR tyrosine kinase inhibitors (TKIs) has fundamentally changed the treatment landscape for such patients by improving both progression-free survival (PFS) and overall survival (OS). Among EGFR-TKIs, third-generation agents such as osimertinib have shown marked efficacy and favorable safety profiles and have become the standard of care in the first-line setting. The combination of osimertinib with platinum-based chemotherapy has recently been shown to improve PFS compared with osimertinib monotherapy in the FLAURA2 trial. Similarly, the MARIPOSA trial demonstrated clinical benefit of the combination of the EGFR-MET bispecific antibody, amivantamab, with the third-generation EGFR-TKI, lazertinib, further supporting the use of combination therapies as first-line treatment for EGFR-mutated NSCLC. Despite these advances, however, challenges such as brain metastases remain substantial barriers to successful treatment outcomes. Management of patients with such metastases often requires a multidisciplinary approach that integrates systemic treatment with local interventions such as radiation therapy. Finally, circulating tumor DNA has emerged as a promising biomarker for real-time monitoring of treatment response and evolution of drug resistance mechanisms. Analysis of such biomarkers can facilitate dynamic and personalized therapeutic adjustments, potentially improving outcomes. This review provides a comprehensive overview of the latest clinical evidence supporting therapeutic advances in the management of EGFR-mutated NSCLC, emphasizing the importance of tailoring treatment strategies based on tumor biology, patient-specific factors, and evolving therapeutic options.
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Affiliation(s)
- Masayuki Miyata
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan
| | - Hidetoshi Hayashi
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Osaka, 589-8511, Japan.
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9
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Kannan K, Mohan S. Targeting exon mutations in NSCLC: clinical insights into LAG-3, TIM-3 pathways, and advances in fourth-generation EGFR-TKIs. Med Oncol 2025; 42:196. [PMID: 40325239 DOI: 10.1007/s12032-025-02755-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Accepted: 04/28/2025] [Indexed: 05/07/2025]
Abstract
Lung cancer remains the second leading cause of cancer-related morbidity and mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have become the standard first-line therapy for advanced NSCLC with EGFR mutations, offering significant improvements in progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) compared to chemotherapy alone. Recent studies suggest that their effectiveness decreased with the emergence of acquired resistance, such as C797S and T790M. Immunotherapy alone also shows enhanced PFS and OS over chemotherapy; however, its applicability can be limited in cases with low programmed cell death ligand 1 (PD-L1) expression and result in immune-related adverse effects like those observed in retrospective, non-randomized studies. Emerging fourth-generation EGFR-TKIs, currently under clinical trials, show promising potential to address these resistance mechanisms. Advanced inhibitors, including BBT-176, BLU-945, and BLU-701, have effectively targeted resistant mutations and reduced disease progression. Studies have suggested that combining fourth-generation EGFR-TKIs with immunotherapies targeting novel pathways like LAG-3 and TIM-3 may enhance patient outcomes. Such combination regimens aim to optimize PFS, OS, and ORR while minimizing adverse effects and addressing the limitations of current therapies. This study explores the landscape of EGFR mutations, their clinical significance, and the integration of innovative fourth-generation EGFR-TKIs with immunotherapies, emphasizing the potential of precision medicine in advancing the management of EGFR-mutated NSCLC.
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Affiliation(s)
- Koteeswaran Kannan
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, 603 203, India
| | - Sumithra Mohan
- Department of Pharmacology, SRM College of Pharmacy, SRM Institute of Science and Technology, Kattankulathur, Chengalpattu, Tamil Nadu, 603 203, India.
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10
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Gomez-Randulfe I, Monaca F, Planchard D, Bria E, Califano R. Evolving treatment for advanced non-small cell lung cancer harbouring common EGFR activating mutations. Crit Rev Oncol Hematol 2025; 212:104762. [PMID: 40324662 DOI: 10.1016/j.critrevonc.2025.104762] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Revised: 04/26/2025] [Accepted: 05/01/2025] [Indexed: 05/07/2025] Open
Abstract
A clinically important subgroup of non-small cell lung cancer (NSCLC) is driven by common mutations in the epidermal growth factor receptor (EGFR). Over the past decade, first-, second-, and third-generation EGFR tyrosine kinase inhibitors (TKIs) have substantially improved clinical outcomes, although acquired resistance inevitably emerges. In particular, the third-generation TKI osimertinib has demonstrated superior progression-free survival (PFS) and overall survival (OS) compared to earlier-generation TKIs in the frontline setting, yet median OS remains approximately three years in pivotal trials. Efforts to extend disease control have led to various upfront intensification strategies, including combining EGFR TKIs with antiangiogenics or chemotherapy (e.g., the FLAURA-2 trial), and pairing novel bispecific antibodies such as amivantamab with third-generation TKIs. Upon progression on third-generation EGFR TKIs, platinum-based chemotherapy remains the standard second-line treatment, albeit with modest response rates. Emerging therapies targeting MET amplification (e.g., savolitinib plus osimertinib), leveraging antibody-drug conjugates (e.g., patritumab deruxtecan), or adding immunotherapy and antiangiogenics have shown preliminary promise in overcoming resistance. Ongoing trials are assessing optimal treatment sequencing and the use of circulating tumor DNA (ctDNA) to guide therapy escalation or de-escalation. Ultimately, the evolving landscape of EGFR-mutant NSCLC underscores the need for refined biomarker-driven approaches and personalized regimens to achieve further gains in survival. In this review, we discuss these strategies in detail, highlighting current evidence and future directions for EGFR-mutant NSCLC treatment.
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Affiliation(s)
- Igor Gomez-Randulfe
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Federico Monaca
- Department of Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - David Planchard
- Department of Medical Oncology, Thoracic Group, Gustave Roussy, Villejuif, France
| | - Emilio Bria
- Università Cattolica del Sacro Cuore, Rome, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy
| | - Raffaele Califano
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Division of Cancer Sciences, The University of Manchester, Manchester, UK.
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11
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Han L, Wang K, Jiang Z, Guo X, Yu J. Recent development in bispecific antibody immunotherapy for hematological malignancies. Crit Rev Oncol Hematol 2025; 212:104752. [PMID: 40320222 DOI: 10.1016/j.critrevonc.2025.104752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/24/2025] [Accepted: 04/26/2025] [Indexed: 05/08/2025] Open
Abstract
While monoclonal antibody (mAb)-based therapies have revolutionized cancer treatment, challenges such as resistance mechanisms and tumor progression via alternative pathways underscore the need for novel therapeutic strategies. Bispecific antibodies (BsAbs), which target two distinct antigens simultaneously, represent a promising next-generation solution, improving therapeutic precision, efficacy, and safety. BsAbs also redirect cytotoxic effector cells to tumor sites, providing additional therapeutic mechanisms. Recent advancements in BsAb design, such as enhancements in pharmacokinetics and modular multi-specific formats, are expanding their use in hematological malignancies. Combining BsAbs with immune checkpoint inhibitors and other therapies may overcome resistance and improve clinical outcomes. Leading BsAbs, including mosunetuzumab, glofitamab, and blinatumomab, have demonstrated promising efficacy in clinical trials for leukemia and lymphoma subtypes. Despite remaining challenges, particularly in acute myeloid leukemia (AML), ongoing research into new targets and combination therapies is expected to enhance the efficacy of BsAbs in relapsed or refractory (R/R) disease. This review explores the structural and functional innovations of BsAbs, the challenges in current therapies, and their transformative potential in hematological malignancy immunotherapy.
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Affiliation(s)
- Lijie Han
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ke Wang
- Department of Hematology/Oncology, Puyang Oilfield General Hospital Affiliated with Xinxiang Medical College, Puyang, China
| | - Zhongxing Jiang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xuejun Guo
- Department of Hematology/Oncology, Puyang Oilfield General Hospital Affiliated with Xinxiang Medical College, Puyang, China.
| | - Jifeng Yu
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
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12
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Chen MF, Jeng MY, Ma J, Agrawal P, Dunne E, Boe LA, Kris MG, Huang J, Veeraraghavan H, Gomez D, Yu HA. Outcomes After Radiation for Oligoprogressive Disease Sites in Patients With EGFR-Mutant Lung Cancer Treated With Osimertinib. JCO Precis Oncol 2025; 9:e2500047. [PMID: 40373257 DOI: 10.1200/po-25-00047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/21/2025] [Accepted: 04/07/2025] [Indexed: 05/17/2025] Open
Abstract
PURPOSE Oligoprogressive disease (OPD) commonly occurs in patients with advanced EGFR mutation-positive non-small cell lung cancer (EGFR+ LC) on systemic therapy. While radiation therapy (XRT) to treat OPD can improve outcomes, the clinical and genomic predictors of benefit from local therapy for oligoprogression on osimertinib are unclear. METHODS We conducted a single-center retrospective analysis of 81 patients with EGFR+ LC on osimertinib who received XRT for OPD (defined as progression in ≤5 lesions) between January 2014 and December 2022. Progression patterns were identified. Times from local therapy to progression, next therapy, and death were measured. RESULTS The median duration of osimertinib treatment before XRT was 16.9 months. After XRT, time on osimertinib was extended for a median of 9.7 months, with a median progression-free survival (PFS) and overall survival of 6.9 and 24.4 months, respectively. Post-XRT recurrence was most common in the lung (43%), viscera (35%), and bone (35%), with only 15% of patients experiencing in-field recurrence. Patients receiving XRT to lymph nodes or visceral metastases exhibited shorter PFS compared with other sites. EGFR mutation type, concurrent TP53/RB1 mutations, and mechanisms of resistance did not significantly predict outcomes. CONCLUSION The addition of XRT for OPD led to clinically meaningful time on continued osimertinib beyond progression, irrespective of molecular characteristics or resistance mechanisms.
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Affiliation(s)
- Monica F Chen
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
| | - Mark Y Jeng
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
| | - Jennifer Ma
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Prashasti Agrawal
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
| | - Elizabeth Dunne
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lillian A Boe
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mark G Kris
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
| | - James Huang
- Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Harini Veeraraghavan
- Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Daniel Gomez
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Helena A Yu
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
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13
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Kim MH, Lee MK, Park JE, Park SH, Jang TW, Jung CY, Kim I, Yoon SH, Ahn JH, Lee HK, Park JH, Choi SH, Eom JS. Impact of Modifying Lazertinib Doses on Effectiveness and Safety in Patients With EGFR-Positive Advanced Lung Cancer: A Multicenter, Prospective Observational Cohort Study. Thorac Cancer 2025; 16:e70083. [PMID: 40396522 DOI: 10.1111/1759-7714.70083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 04/14/2025] [Accepted: 04/27/2025] [Indexed: 05/22/2025] Open
Abstract
INTRODUCTION The clinical application of lazertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has extended to the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC); however, the effects of its dose modification on its efficacy and safety have not yet been adequately established. METHODS This prospective, multicenter, observational cohort study aims to evaluate the clinical implications of adjusting the lazertinib dose. Patients will be categorized into two groups based on the lazertinib dose administered during the initial 12 weeks of treatment in routine clinical practice: 160 and 240 mg groups. The primary endpoints are progression-free survival in the 160 mg group and identifying risk factors associated with dose modification during the 12-week period. DISCUSSION The findings from the present study will provide real-world insights into the clinical factors leading to lazertinib dose adjustments and deepen our understanding of the efficacy and safety of lazertinib in patients with NSCLC. Our research will contribute toward optimizing medical strategies for NSCLC treatment and aid clinicians in making accurate clinical decisions regarding dose modifications in routine practice.
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Affiliation(s)
- Mi-Hyun Kim
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Republic of Korea
| | - Min Ki Lee
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Republic of Korea
| | - Ji Eun Park
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Sun Hyo Park
- Division of Pulmonology, Respiratory Center, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Tae Won Jang
- Department of Internal Medicine, Kosin University Medical College, Busan, Republic of Korea
| | - Chi Young Jung
- Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Insu Kim
- Department of Internal Medicine, College of Medicine, Dong-A University, Busan, Republic of Korea
| | - Seong Hoon Yoon
- Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Republic of Korea
| | - June Hong Ahn
- Department of Internal Medicine, College of Medicine, Yeungnam University, Daegu, Republic of Korea
| | - Hyun-Kyung Lee
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, Inje University Busan Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Jin Han Park
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Sun Ha Choi
- Department of Internal Medicine, School of Medicine, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - Jung Seop Eom
- Department of Internal Medicine, Pusan National University School of Medicine, Busan, Republic of Korea
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14
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Sun L, Marmarelis ME, Aggarwal C. Management of Patients With EGFR Exon 20-Mutant Advanced Non-Small Cell Lung Cancer. J Clin Oncol 2025; 43:1527-1533. [PMID: 40053885 DOI: 10.1200/jco-24-02624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/27/2025] [Accepted: 02/06/2025] [Indexed: 03/09/2025] Open
Abstract
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
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Affiliation(s)
- Lova Sun
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
| | - Melina E Marmarelis
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
- Penn Center for Cancer Care Innovation, University of Pennsylvania, Philadelphia, PA
| | - Charu Aggarwal
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
- Penn Center for Cancer Care Innovation, University of Pennsylvania, Philadelphia, PA
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15
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Remon J, Saw SPL. Telisotuzumab vedotin and osimertinib: the METamorphosis of epidermal growth factor receptor-mutant lung cancer? Ann Oncol 2025; 36:484-487. [PMID: 39855428 DOI: 10.1016/j.annonc.2025.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2025] [Accepted: 01/16/2025] [Indexed: 01/27/2025] Open
Affiliation(s)
- J Remon
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France.
| | - S P L Saw
- Department of Medical Oncology, National Cancer Centre Singapore, Duke-NUS Oncology Academic Clinical Programme, Singapore, Singapore
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16
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Horinouchi H, Cho BC, Camidge DR, Goto K, Tomasini P, Li Y, Vasilopoulos A, Brunsdon P, Hoffman D, Shi W, Bolotin E, Blot V, Goldman J. Results from a phase Ib study of telisotuzumab vedotin in combination with osimertinib in patients with c-Met protein-overexpressing, EGFR-mutated locally advanced/metastatic non-small-cell lung cancer (NSCLC) after progression on prior osimertinib. Ann Oncol 2025; 36:583-591. [PMID: 39805351 DOI: 10.1016/j.annonc.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 12/20/2024] [Accepted: 01/02/2025] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND Osimertinib is the standard first-line treatment for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC). However, treatment resistance is inevitable and increased c-Met protein expression correlates with resistance. Telisotuzumab vedotin (Teliso-V) is an antibody-drug conjugate that targets c-Met protein overexpression. In this article, we report the results of a phase I/Ib trial evaluating Teliso-V plus osimertinib in patients with NSCLC after progression on osimertinib. PATIENTS AND METHODS This multicenter, open-label study (NCT02099058) enrolled patients with advanced EGFR-mutated, c-Met protein-overexpressing, non-squamous NSCLC that had progressed on prior osimertinib. Patients received Teliso-V (intravenously, every 2 weeks) plus osimertinib (orally, 80 mg once daily). Teliso-V was evaluated at 1.6 mg/kg in a safety lead-in phase and escalated to 1.9 mg/kg. Dose expansion included both doses. Endpoints included safety and tolerability, pharmacokinetics, objective response rate (ORR), duration of response (DOR), and progression-free survival (PFS). RESULTS A total of 38 patients received Teliso-V (1.6 mg/kg, n = 20; 1.9 mg/kg, n = 18) plus osimertinib and were included in this analysis. No dose-limiting toxicities were observed. Most frequent any-grade treatment-emergent adverse events (TEAEs) were peripheral sensory neuropathy (50%), peripheral edema (32%), and nausea (24%). Most common grade 3/4 TEAEs were anemia (11%) and pulmonary embolism (8%). Five TEAEs led to death; none were reported as being related to Teliso-V or osimertinib. The pharmacokinetic profile of Teliso-V plus osimertinib was similar to Teliso-V monotherapy. After a median follow-up of 7.4 months, the ORR was 50.0% per independent central review (ICR) (DOR not reached), and median PFS per ICR was 7.4 months (95% confidence interval 5.4 months-not reached). CONCLUSIONS Teliso-V plus osimertinib had promising activity and a manageable safety profile in patients with c-Met protein-overexpressing, EGFR-mutated non-squamous NSCLC after progression on osimertinib. This combination has the potential to address an unmet medical need in this patient population.
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Affiliation(s)
| | - B C Cho
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - D R Camidge
- Department of Medicine, University of Colorado Cancer Center, Aurora, USA
| | - K Goto
- National Cancer Center Hospital East, Kashiwa, Japan
| | - P Tomasini
- Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University, APHM, INSERM, CNRS, CRCM, Hôpital Nord, Marseille, France
| | - Y Li
- AbbVie Inc, North Chicago, USA
| | | | | | | | - W Shi
- AbbVie Inc, North Chicago, USA
| | | | - V Blot
- AbbVie Inc, North Chicago, USA
| | - J Goldman
- David Geffen School of Medicine at UCLA, Los Angeles, USA.
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17
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Pilotto S, Singh PK. Further-Line Treatment With Amivantamab Plus Lazertinib in EGFR-Mutant NSCLC: New Answers to Old Questions? J Thorac Oncol 2025; 20:549-554. [PMID: 40348479 DOI: 10.1016/j.jtho.2025.02.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2025] [Accepted: 02/10/2025] [Indexed: 05/14/2025]
Affiliation(s)
- Sara Pilotto
- Section of Innovation Biomedicine - Oncology Area, Department of Engineering for Innovation Medicine (DIMI), University of Verona and Verona University Hospital Trust, Verona, Italy.
| | - Pawan Kumar Singh
- Department of Pulmonary and Critical Care Medicine, Pandit Bhagwat Dayal Sharma Post Graduate Institute of Medical Sciences, Rohtak, India
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18
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Zhou X, Zeng L, Huang Z, Ruan Z, Yan H, Zou C, Xu S, Zhang Y. Strategies Beyond 3rd EGFR-TKI Acquired Resistance: Opportunities and Challenges. Cancer Med 2025; 14:e70921. [PMID: 40322930 PMCID: PMC12051098 DOI: 10.1002/cam4.70921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Accepted: 04/16/2025] [Indexed: 05/08/2025] Open
Abstract
The seminal identification of epidermal growth factor receptor (EGFR) mutations as pivotal oncogenic drivers in non-small cell lung cancer (NSCLC) has catalyzed the evolution of biomarker-guided therapeutic paradigms for advanced disease. Currently, third-generation EGFR tyrosine kinase inhibitors (EGFR-TKI) have revolutionized first-line treatment for advanced EGFR-mutated NSCLC, yet acquired resistance remains an inevitable and formidable clinical challenge. This review systematically summarizes molecular mechanisms underlying treatment resistance, with a focus on clinical challenges associated with central nervous system (CNS) metastases. Therapeutic resistance mechanisms are categorized into EGFR-dependent (on-target) pathways, typified by acquired kinase domain mutations (e.g., C797S), and EGFR-independent (off-target) pathways, involving compensatory activation of parallel signaling effectors (e.g., MET amplification, HER2 activation) or phenotypic transformation. We further evaluated contemporary diagnostic modalities for identifying resistance drivers and appraised emerging therapeutic strategies, including fourth-generation EGFR-TKI, various combination therapies, and antibody-drug conjugates (ADCs), and so forth, with emphasis on ongoing clinical trials that may transform the existing treatment paradigm. By synthesizing preclinical and clinical insights, this review aims to advance mechanistic understanding and propose therapeutic strategies to overcome acquired resistance to third-generation EGFR-TKI in first-line treatment.
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Affiliation(s)
- Xuexue Zhou
- Medical CollegeJishou UniversityJishouChina
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
| | - Liang Zeng
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
| | - Zhe Huang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
- Department of Pathology and Pathophysiology, School of Basic Medical SciencesCentral South UniversityChangshaChina
| | - Zhaohui Ruan
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
- Department of Pathology and Pathophysiology, School of Basic Medical SciencesCentral South UniversityChangshaChina
| | - Huan Yan
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
| | - Chun Zou
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
| | - Shidong Xu
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
- Department of Pathology and Pathophysiology, School of Basic Medical SciencesCentral South UniversityChangshaChina
| | - Yongchang Zhang
- Medical CollegeJishou UniversityJishouChina
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/the Affiliated Cancer Hospital of Xiangya School of MedicineCentral South UniversityChangshaChina
- Department of Pathology and Pathophysiology, School of Basic Medical SciencesCentral South UniversityChangshaChina
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19
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Wong WKY, Mok KKS, Tsui GPC, Chen OH, Loong HHF, Chan LL, Yan K, Mo F, Lee KWC, Lam KC, Mok FST, Johnson D, Chen ACC, Lam B, Lee M, Mok TSK, Li MSC. CNS Outcomes of Osimertinib Plus Chemotherapy in Patients With EGFR Mutation Positive Lung Cancer Beyond Osimertinib Progression. Clin Lung Cancer 2025; 26:e214-e222.e5. [PMID: 39933981 DOI: 10.1016/j.cllc.2025.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2024] [Accepted: 01/09/2025] [Indexed: 02/13/2025]
Abstract
BACKGROUND Central nervous system (CNS) metastases are common among patients with epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC). Osimertinib in combination with chemotherapy beyond osimertinib progression may minimize CNS progression. METHOD In this retrospective analysis, patients with advanced EGFR mutation positive NSCLC and brain metastases who received platinum-based chemotherapy (PbChT) after disease progression on osimertinib were enrolled. The primary endpoint was real-world CNS progression-free survival (rwCNS-PFS) between patients who received PbChT with and without osimertinib continuation. Secondary endpoints included competing risk analysis of CNS progression and incidence of salvage radiotherapy to brain. RESULTS A total of 101 patients were analyzed, out of which, 39 (39%) continued osimertinib with chemotherapy (OSI+ cohort) and 62 (61%) received chemotherapy alone (OSI- cohort). Median rwCNS-PFS was significantly longer in the OSI+ cohort (9.0 months, 95% CI 6.6-11.4) than the OSI- cohort (5.7 months, 95% CI 4.6-6.9) (HR 0.37, 95% CI 0.18-0.76, P = .007). This remained significant after adjustment for EGFR mutation, line of osimertinib treatment, prior radiotherapy to brain, and CNS progression on osimertinib monotherapy. Estimated probability of CNS progression at 6 months was 5.6% in OSI+ cohort versus 20.9% in OSI- cohort. Incidence of salvage radiotherapy to brain was lower in the OSI+ cohort (15%) compared to OSI- cohort (24%). CONCLUSION In patients with EGFR mutation positive NSCLC and brain metastases, continuing osimertinib with chemotherapy after progression on osimertinib significantly reduced risk of CNS progression. Prospective studies are warranted to define the optimal treatment strategy for this patient population.
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Affiliation(s)
- Wesley K Y Wong
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - Kevin K S Mok
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - Giselle P C Tsui
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - Olivia H Chen
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - Herbert H F Loong
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Landon L Chan
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Kelvin Yan
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Frankie Mo
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Kirsty W C Lee
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - K C Lam
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - Florence S T Mok
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - David Johnson
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - Allen C C Chen
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - Benjamin Lam
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - Matthew Lee
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, China
| | - Tony S K Mok
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - Molly S C Li
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China; State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China.
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20
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Besse B, Goto K, Wang Y, Lee SH, Marmarelis ME, Ohe Y, Bernabe Caro R, Kim DW, Lee JS, Cousin S, Ichihara E, Li Y, Paz-Ares L, Ono A, Sanborn RE, Watanabe N, de Miguel MJ, Helissey C, Shu CA, Spira AI, Tomasini P, Yang JCH, Zhang Y, Felip E, Griesinger F, Waqar SN, Calles A, Neal JW, Baik CS, Jänne PA, Shreeve SM, Curtin JC, Patel B, Gormley M, Lyu X, Chen J, Chu PL, Mahoney J, Trani L, Bauml JM, Thayu M, Knoblauch RE, Cho BC. Amivantamab Plus Lazertinib in Patients With EGFR-Mutant NSCLC After Progression on Osimertinib and Platinum-Based Chemotherapy: Results From CHRYSALIS-2 Cohort A. J Thorac Oncol 2025; 20:651-664. [PMID: 39755170 DOI: 10.1016/j.jtho.2024.12.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 12/20/2024] [Accepted: 12/28/2024] [Indexed: 01/06/2025]
Abstract
INTRODUCTION Treatment options for patients with EGFR-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy are limited. METHODS CHRYSALIS-2 cohort A evaluated amivantamab plus lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on or after osimertinib and platinum-based chemotherapy. Primary end point was investigator-assessed objective response rate (ORR). The patients received 1050 mg of intravenous amivantamab (1400 mg if ≥ 80 kg) plus 240 mg of oral lazertinib. RESULTS In cohort A (N = 162), the investigator-assessed ORR was 28% (95% confidence interval [CI]: 22-36). The blinded independent central review-assessed ORR was 35% (95% CI: 27-42), with a median duration of response of 8.3 months (95% CI: 6.7-10.9) and a clinical benefit rate of 58% (95% CI: 50-66). At a median follow-up of 12 months, 32 of 56 responders (57%) achieved a duration of response of more than or equal to 6 months. Median progression-free survival by blinded independent central review was 4.5 months (95% CI: 4.1-5.8); median overall survival was 14.8 months (95% CI: 12.2-18.0). Preliminary evidence of central nervous system antitumor activity was reported in seven patients with baseline brain lesions and no previous brain radiation or surgery. Exploratory biomarker analyses using next-generation sequencing of circulating tumor DNA revealed responses in patients with and without EGFR- or MET-dependent resistance. The most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). The most common grade greater than or equal to 3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%). CONCLUSIONS For patients with limited treatment options, amivantamab plus lazertinib demonstrated an antitumor activity with a safety profile characterized by EGFR- or MET-related adverse events, which were generally manageable.
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Affiliation(s)
- Benjamin Besse
- Paris-Saclay University, Institut Gustave Roussy, Villejuif, France
| | - Koichi Goto
- National Cancer Center Hospital East, Kashiwa, Japan
| | - Yongsheng Wang
- Institute of Clinical Trial Center and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Se-Hoon Lee
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Melina E Marmarelis
- University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania
| | | | | | - Dong-Wan Kim
- Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea
| | - Jong-Seok Lee
- Seoul National University College of Medicine and Seoul National University Hospital, Seoul, Republic of Korea
| | | | - Eiki Ichihara
- Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan
| | - Yongsheng Li
- Chongqing University Cancer Hospital, Chongqing, People's Republic of China
| | | | - Akira Ono
- Shizuoka Cancer Center, Shizuoka, Japan
| | - Rachel E Sanborn
- Earle A. Chiles Research Institute, Providence Cancer Institute, Portland, Oregon
| | - Naohiro Watanabe
- Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | | | - Carole Helissey
- Clinical Research unit, Military Hospital Begin, Saint-Mandé, France
| | | | | | - Pascale Tomasini
- Aix Marseille University - CNRS, INSERM, CRCM; CEPCM - AP-HM Hopital de La Timone, Marseille, France
| | | | - Yiping Zhang
- Zhejiang Cancer Hospital, Hangzhou, People's Republic of China
| | - Enriqueta Felip
- Medical Oncology Service, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital Campus, Universitat Autonoma de Barcelona, Barcelona, Spain
| | - Frank Griesinger
- Pius-Hospital, University Medicine of Oldenburg, Oldenburg, Germany
| | - Saiama N Waqar
- Division of Oncology, Washington University School of Medicine, St. Louis, Missouri
| | - Antonio Calles
- Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Joel W Neal
- Stanford University Medical Center, Stanford, California
| | - Christina S Baik
- University of Washington, Fred Hutchinson Cancer Center, Seattle, Washington
| | - Pasi A Jänne
- Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, Massachusetts
| | | | | | | | | | - Xuesong Lyu
- Johnson & Johnson, Shanghai, People's Republic of China
| | - Jun Chen
- Johnson & Johnson, Spring House, Pennsylvania
| | | | | | | | | | - Meena Thayu
- Johnson & Johnson, Spring House, Pennsylvania
| | | | - Byoung Chul Cho
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
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21
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Barbe-Richaud JB, Fattori A, Lindner V, Schuster C, Malouf G, Pencreach E, Somme L. EGFR-Mutant Urothelial Carcinoma Harboring an Ala750_Ile759delinsGlyGly Alteration with a Primary Resistance to Polychemotherapy and a Sensitivity to Osimertinib: A Literature Review on EGFR Alterations and Response to EGFR Tyrosine Kinase Inhibitors in Cancers. J Clin Med 2025; 14:3129. [PMID: 40364160 PMCID: PMC12072851 DOI: 10.3390/jcm14093129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2025] [Revised: 04/20/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
Urothelial carcinoma is three to four times more common in men than in women, with a 73-year old mean age at diagnosis which is older than the average age at diagnosis of all cancers. Urothelial carcinoma is rare in people under 40 years of age. Smoking, exposure to industrial chemicals, and family history influence the development of bladder cancer, but age remains one of the most important risk factors. It is well established that women are more likely to be diagnosed with an advanced disease, impacting the prognosis and a higher stage-for-stage mortality compared to men. A gender difference is also observed when considering molecular features; for example, there a higher male/female ratio in Fibroblast Growth Factor Receptor 3 (FGFR3)-mutated bladder cancer. Epidermal Growth Factor Receptor (EGFR) amplifications, which are roughly depicted in 25-50% of urothelial carcinoma, have been correlated with a worse prognosis. Genomic alterations of clinical interest are mainly Human Epidermal Growth Factor Receptor 2 mutations and amplifications, as well as FGFR 3 alterations; however, no EGFR mutation has been routinely reported despite the frequency of its amplifications. Recurrently, no targeted inhibitors have demonstrated a benefit compared to platinum-based chemotherapy. We report a rare case of a 35-year-old woman presenting bone, hepatic, and lymph node metastatic urothelial carcinoma, harboring a deletion of 24 nucleotides in exon 19 of the EGFR gene with a 5-month response to osimertinib, a third-generation EGFR tyrosine kinase inhibitor.
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Affiliation(s)
- Jean-Baptiste Barbe-Richaud
- Oncology Department, Institut de Cancérologie Strasbourg Europe, 17 Rue Albert Calmette, 67200 Strasbourg, France; (J.-B.B.-R.); (C.S.); (G.M.)
| | - Antonin Fattori
- Pathological Department, Hôpital de Hautepierre, 1 Avenue Molière, 67200 Strasbourg, France; (A.F.); (V.L.)
| | - Véronique Lindner
- Pathological Department, Hôpital de Hautepierre, 1 Avenue Molière, 67200 Strasbourg, France; (A.F.); (V.L.)
| | - Caroline Schuster
- Oncology Department, Institut de Cancérologie Strasbourg Europe, 17 Rue Albert Calmette, 67200 Strasbourg, France; (J.-B.B.-R.); (C.S.); (G.M.)
| | - Gabriel Malouf
- Oncology Department, Institut de Cancérologie Strasbourg Europe, 17 Rue Albert Calmette, 67200 Strasbourg, France; (J.-B.B.-R.); (C.S.); (G.M.)
| | - Erwan Pencreach
- Molecular Departement, Hôpital de Hautepierre, 1 Avenue Molière, 67200 Strasbourg, France;
| | - Laura Somme
- Oncology Department, Institut de Cancérologie Strasbourg Europe, 17 Rue Albert Calmette, 67200 Strasbourg, France; (J.-B.B.-R.); (C.S.); (G.M.)
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22
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Stanzione B, Del Conte A, Bertoli E, De Carlo E, Bortolot M, Torresan S, Spina M, Bearz A. Non-Small Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Common Mutations: New Strategies. Cancers (Basel) 2025; 17:1515. [PMID: 40361442 PMCID: PMC12071048 DOI: 10.3390/cancers17091515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Revised: 04/23/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
Epidermal growth factor receptor (EGFR) mutations are described in 10-15% of Caucasian patients and in 50% of Asian patients with non-squamous non-small cell lung cancer (NSCLC). The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the therapeutic scenario and has changed the natural history of the disease. Despite the results obtained with osimertinib, a third-generation TKI, most patients experience disease progression. The search for new therapeutic strategies both to enhance first-line treatment and to ensure adequate second-line therapies represents an unmet medical need, towards which all efforts are being concentrated. In this review, we describe the main strategies identified to improve the prognosis of patients with EGFR-mutated NSCLC.
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Affiliation(s)
- Brigida Stanzione
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.D.C.); (E.B.); (E.D.C.); (M.B.); (S.T.); (M.S.); (A.B.)
| | - Alessandro Del Conte
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.D.C.); (E.B.); (E.D.C.); (M.B.); (S.T.); (M.S.); (A.B.)
| | - Elisa Bertoli
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.D.C.); (E.B.); (E.D.C.); (M.B.); (S.T.); (M.S.); (A.B.)
| | - Elisa De Carlo
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.D.C.); (E.B.); (E.D.C.); (M.B.); (S.T.); (M.S.); (A.B.)
| | - Martina Bortolot
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.D.C.); (E.B.); (E.D.C.); (M.B.); (S.T.); (M.S.); (A.B.)
- Department of Medicine (DME), University of Udine, 33100 Udine, Italy
| | - Sara Torresan
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.D.C.); (E.B.); (E.D.C.); (M.B.); (S.T.); (M.S.); (A.B.)
- Department of Medicine (DME), University of Udine, 33100 Udine, Italy
| | - Michele Spina
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.D.C.); (E.B.); (E.D.C.); (M.B.); (S.T.); (M.S.); (A.B.)
| | - Alessandra Bearz
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (A.D.C.); (E.B.); (E.D.C.); (M.B.); (S.T.); (M.S.); (A.B.)
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23
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Yan Y, Yuan J, Peng Y, Zhou C, Liu X, Sun L, Song Q. Bispecific antibodies combined with chemotherapy in solid tumor treatment, the path forward? Front Immunol 2025; 16:1568724. [PMID: 40352940 PMCID: PMC12061958 DOI: 10.3389/fimmu.2025.1568724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2025] [Accepted: 04/03/2025] [Indexed: 05/14/2025] Open
Abstract
Background Bispecific antibodies (bsAbs) introduced a novel strategy in anticancer therapy when chemotherapy alone could not meet life expectancy. Nonetheless, the efficacy of monotherapy was limited, and the safety profile of bsAbs combined with chemotherapy remained uncertain. Methods Literature retrieval was carried out through PubMed, Embase, and Cochrane from inception to January, 2025. Progression-free survival (PFS), overall survival (OS), and overall response rate (ORR), along with adverse effects (AEs), were utilized to assess the efficacy and safety. Publication bias was calculated using Funnel plots and Egger's test. Heterogeneity was examined through subgroup and sensitivity analyses. The protocol was preregistered in the International Prospective Register of Systematic Reviews (CRD42025633628). Results A total of 8 eligible clinical studies with 2,495 patients were included. Compared with chemotherapy alone, bsAb+chemotherapy exhibited positive outcomes in PFS (hazard ratio (HR): 0.52; 95% confidence interval (CI): 0.44-0.60; p<0.01), OS (HR: 0.67, 95% CI: 0.57-0.77; p<0.01), and ORR (HR: 0.31, 95% CI: 0.16-0.47; p<0.01). Subgroup analysis revealed that female patients, Asian patients, those under 65 years of age, and patients treated with IgG-like bsAb were more likely to benefit from the survival advantages of bsAb+chemotherapy. Despite the occurrence of leukopenia, metabolism-related, and skin-related AEs, RR of AEs in other systems showed no statistical significance. Conclusion BsAb+chemotherapy was superior to chemotherapy alone, especially in female patients, Asian patients, those under 65 years of age, and patients receiving IgG-like bsAb. Additionally, while the AEs associated with bsAb+chemotherapy are generally manageable, there is still room for improvement. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42025633628.
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Affiliation(s)
- Yici Yan
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Jing Yuan
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Yanyang Peng
- School of Humanities and Management, Zhejiang Chinese Medical University, Hangzhou, China
| | - Chenxi Zhou
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Xinbo Liu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
| | - Leitao Sun
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
- Academy of Chinese Medical Science, Zhejiang Chinese Medical University, Hangzhou, China
- Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiaoling Song
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China
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24
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Raez LE, Baca Y, Ribeiro JR, Nieva JJ, Mamdani H, Lopes G, Borghaei H, Socinski M, Wozniak AJ, Vanderwalde A, Uribe CC, Sumarriva D, Khan H, Liu SV, Nagasaka M. Prevalence and molecular correlates of acquired EGFR resistance mutations in non-small cell lung cancer (NSCLC). Expert Rev Anticancer Ther 2025:1-8. [PMID: 40237370 DOI: 10.1080/14737140.2025.2491648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/05/2025] [Indexed: 04/18/2025]
Abstract
BACKGROUND While EGFR tyrosine kinase inhibitors (TKIs) are effective in treating patients with non-small cell lung cancer (NSCLC) with EGFR mutations, acquired resistance is expected. We aimed to determine the prevalence and molecular correlates of EGFR resistance mutations in a large, real-world cohort of EGFR-mutated NSCLC. RESEARCH DESIGN AND METHODS NSCLC tumors (N = 46,505) were profiled by next-generation sequencing (NGS) and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Patient treatments and outcomes were obtained from insurance claims data. RESULTS EGFR sensitizing mutations (exon 19 deletions, L858R mutations) were present in 3,885 patients with NSCLC, and EGFR resistance mutations (C797, T790M, L718, G724, G721) in 71 patients; 58 patients had both sensitizing and resistance mutations. Among tumors with resistance mutations, the most prevalent co-alterations were TP53 (50%), PD-L1 positivity (40%), gLOH (20%), and CTNNB1 (23.2%). L718 mutations predominantly co-occurred with L858R without T790M, and 9/16 developed post-osimertinib treatment. CONCLUSIONS Acquired resistance mutations in EGFR-mutant NSCLC have a low observed frequency among molecularly-profiled tumors, possibly due to infrequent re-testing of resistant tumors. While T790M and C797S mutations are well-described, we also observed a significant number of L718 mutations in osimertinib-treated patients. These data support NGS evaluation of NSCLC that has become resistant to EGFR TKIs.
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Affiliation(s)
- Luis E Raez
- Thoracic Oncology Program, Memorial Cancer Institute/Florida Atlantic University, Miami, FL, USA
| | | | | | - Jorge J Nieva
- Norris Cancer Center, University of Southern California, Los Angeles, CA, USA
| | - Hirva Mamdani
- Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
| | - Gilberto Lopes
- University of Miami Miller School of Medicine, Miami, FL, USA
| | | | | | | | | | | | | | - Hina Khan
- Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - Stephen V Liu
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Misako Nagasaka
- University of California Irvine School of Medicine and Chao Family Comprehensive Cancer Center, Orange, CA, USA
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25
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Zieliński P, Stępień M, Chowaniec H, Kalyta K, Czerniak J, Borowczyk M, Dwojak E, Mroczek M, Dworacki G, Ślubowska A, Markiewicz H, Ałtyn R, Dobosz P. Resistance in Lung Cancer Immunotherapy and How to Overcome It: Insights from the Genetics Perspective and Combination Therapies Approach. Cells 2025; 14:587. [PMID: 40277912 PMCID: PMC12026305 DOI: 10.3390/cells14080587] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/26/2025] Open
Abstract
Lung cancer with the highest number of new cases diagnosed in Europe and in Poland, remains an example of malignancy with a very poor prognosis despite the recent progress in medicine. Different treatment strategies are now available for cancer therapy based on its type, molecular subtype and other factors including overall health, the stage of disease and cancer molecular profile. Immunotherapy is emerging as a potential addition to surgery, chemotherapy, radiotherapy or other targeted therapies, but also considered a mainstay therapy mode. This combination is an area of active investigation in order to enhance efficacy and overcome resistance. Due to the complexity and dynamic of cancer's ecosystem, novel therapeutic targets and strategies need continued research into the cellular and molecular mechanisms within the tumour microenvironment. From the genetic point of view, several signatures ranging from a few mutated genes to hundreds of them have been identified and associated with therapy resistance and metastatic potential. ML techniques and AI can enhance the predictive potential of genetic signatures and model the prognosis. Here, we present the overview of already existing treatment approaches, the current findings of key aspects of immunotherapy, such as immune checkpoint inhibitors (ICIs), existing molecular biomarkers like PD-L1 expression, tumour mutation burden, immunoscore, and neoantigens, as well as their roles as predictive markers for treatment response and resistance.
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Affiliation(s)
- Paweł Zieliński
- Chair of Pathomorphology and Clinical Immunology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (H.C.); (J.C.); (E.D.); (G.D.); (P.D.)
| | - Maria Stępień
- Université Paris-Saclay, UVSQ, INSERM, END-ICAP, 94805 Versailles, France;
- Doctoral School, Medical University of Lublin, 20-954 Lublin, Poland
| | - Hanna Chowaniec
- Chair of Pathomorphology and Clinical Immunology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (H.C.); (J.C.); (E.D.); (G.D.); (P.D.)
| | - Kateryna Kalyta
- Faculty of Biology, University of Basel, 4123 Basel, Switzerland;
| | - Joanna Czerniak
- Chair of Pathomorphology and Clinical Immunology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (H.C.); (J.C.); (E.D.); (G.D.); (P.D.)
| | - Martyna Borowczyk
- Department of Endocrinology, Internal Medicine and Metabolism, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
| | - Ewa Dwojak
- Chair of Pathomorphology and Clinical Immunology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (H.C.); (J.C.); (E.D.); (G.D.); (P.D.)
- Department of Pathomorphology, University Clinical Hospital, 61-701 Poznan, Poland
| | - Magdalena Mroczek
- Department of Neurology, University Hospital Basel, 4123 Basel, Switzerland;
| | - Grzegorz Dworacki
- Chair of Pathomorphology and Clinical Immunology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (H.C.); (J.C.); (E.D.); (G.D.); (P.D.)
| | - Antonina Ślubowska
- Department of Biostatistics and Research Methodology, Faculty of Medicine, Collegium Medicum, Cardinal Stefan Wyszynski University of Warsaw, 02-004 Warsaw, Poland;
| | - Hanna Markiewicz
- Department of Histology and Embryology, Faculty of Medicine, Medical University of Warsaw, 02-004 Warsaw, Poland
- Department of Methodology, Faculty of Medicine, Medical University of Warsaw, 02-004 Warsaw, Poland
| | - Rafał Ałtyn
- IT Department, Poznan University of Medical Sciences, 61-701 Poznan, Poland;
| | - Paula Dobosz
- Chair of Pathomorphology and Clinical Immunology, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (H.C.); (J.C.); (E.D.); (G.D.); (P.D.)
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26
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Xia Y, Wang K, Zhao J, Arter Z, Zhang Y, Zhou J, Lu Y, Zeng L, Du R, Owens JA, Elamin YY, Gay CM, Skoulidis F, Tsao AS, Lu C, Cascone T, Gibbons DL, Zhang J, Chen O, Mok KKS, Nagasaka M, Li W, Heymach JV, Ignatius Ou SH, Li M, Le X. Receptor Tyrosine Kinase Fusion-Mediated Resistance to EGFR TKI in EGFR-Mutant NSCLC: A Multi-Center Analysis and Literature Review. J Thorac Oncol 2025; 20:465-474. [PMID: 39622411 DOI: 10.1016/j.jtho.2024.11.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 11/05/2024] [Accepted: 11/27/2024] [Indexed: 01/12/2025]
Abstract
INTRODUCTION Drug resistance remains a major clinical challenge in EGFR-mutant NSCLC tumors owing to pathway reactivation, pathway bypass, and pathway indifference resistance mechanisms to evade tyrosine kinase inhibitor (TKI) suppression. Fusion of receptor tyrosine kinases (RTKs), such as RET, ALK, and FGFR3, has been reported to mediate EGFR TKI resistance. Given the rarity of these fusions and the heterogeneous nature of the condition, no prospective clinical trials evaluated the incidence, safety, and therapeutic benefit of dual EGFR-RTK inhibition. METHODS We queried clinical databases from multiple institutions to identify patients who had RTK fusions detected on next-generation sequencing testing results from tissue or blood at five institutions: the Second Affiliated Hospital Zhejiang University School of Medicine, Hunan Cancer Hospital, Prince of Wales Hospital Chinese University of Hong Kong, Chao Family Cancer Center, and the University of Texas MD Anderson Cancer Center from March 1, 2016, to September 30, 2023. The data analyzed included objective response rate (ORR) to treatment post RTK fusion detection, duration of treatment, and safety. A comprehensive literature search was conducted to identify patients with RTK fusion as the primary resistance mechanism in EGFR-mutated NSCLC patients. RESULTS Twenty-seven patients were identified to be eligible in the analysis. ALK fusions were most reported (42.9%), followed by RET fusions (35.7%). Fifteen patients received dual TKI after fusion detection and nine received fusion targeting single TKIs. The median time on treatment was 169 days or 5.8 months (35-1050 d). ORR by the Response Evaluation Criteria in Solid Tumors in the evaluable 25 patients was 24% and the disease control rate was 80%. In 14 evaluable patients who received dual TKI therapy, ORR by the Response Evaluation Criteria in Solid Tumors was 21.4%, and the disease control rate was 78.6%. No new toxicities were observed with dual EGFR-RTK inhibition. In the literature review, after pooling 291 patients from 59 studies, RET fusions were the most common (50.0%), followed by BRAF (13.3%), ALK (13.3%), FGFR (10%), NTRK (5.3%), EGFR (1.7%), ROS1 (1.3%), MET (1%), and ERBB (0.7%). CONCLUSION The emergence of RTK fusions is one of the mechanisms of bypass resistance of EGFR TKI. Dual inhibition of EGFR-RTK was safe and efficacious in patients with targetable RTK fusion after progression to EGFR TKIs.
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Affiliation(s)
- Yang Xia
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Kaiwen Wang
- Division of Pharmacy, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jing Zhao
- Department of Medical Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Zhaohui Arter
- Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California
| | - Yongchang Zhang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People's Republic of China
| | - Jiaqi Zhou
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Yuefei Lu
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - Liang Zeng
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People's Republic of China
| | - Robyn Du
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer A Owens
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Yasir Y Elamin
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Carl M Gay
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ferdinandos Skoulidis
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anne S Tsao
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Charles Lu
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Tina Cascone
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Don L Gibbons
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jianjun Zhang
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Olivia Chen
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, People's Republic of China
| | - Kevin K S Mok
- Department of Clinical Oncology, Prince of Wales Hospital, Hong Kong, People's Republic of China
| | - Misako Nagasaka
- Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California
| | - Wen Li
- Department of Respiratory and Critical Care Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China
| | - John V Heymach
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sai-Hong Ignatius Ou
- Division of Hematology-Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California
| | - Molly Li
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Xiuning Le
- Department of Thoracic, Head, and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
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27
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Sands J, Ahn MJ, Lisberg A, Cho BC, Blumenschein G, Shum E, Pons Tostivint E, Goto Y, Yoh K, Heist R, Shimizu J, Lee JS, Baas P, Planchard D, Pérol M, Felip E, Su WC, Zebger-Gong H, Lan L, Liu C, Howarth P, Chiaverelli R, Paz-Ares L. Datopotamab Deruxtecan in Advanced or Metastatic Non-Small Cell Lung Cancer With Actionable Genomic Alterations: Results From the Phase II TROPION-Lung05 Study. J Clin Oncol 2025; 43:1254-1265. [PMID: 39761483 PMCID: PMC11949215 DOI: 10.1200/jco-24-01349] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 09/05/2024] [Accepted: 11/14/2024] [Indexed: 03/29/2025] Open
Abstract
PURPOSE Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2-directed antibody-drug conjugate with a highly potent topoisomerase I inhibitor payload. The TROPION-Lung05 phase II trial (ClinicalTrials.gov identifier: NCT04484142) evaluated the safety and clinical activity of Dato-DXd in patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations progressing on or after targeted therapy and platinum-based chemotherapy. PATIENTS AND METHODS Patients received Dato-DXd 6 mg/kg once every 3 weeks. The primary end point was objective response rate (ORR) by blinded independent central review. Secondary end points included duration of response (DOR), safety, tolerability, and survival. RESULTS Among 137 patients who received at least 1 dose of Dato-DXd, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6). The confirmed ORR was 35.8% (95% CI, 27.8 to 44.4) overall, and 43.6% (95% CI, 32.4 to 55.3) and 23.5% (95% CI, 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements, respectively. The median DOR was 7.0 months (95% CI, 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI, 71.0 to 85.3). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (preferred term; any grade: 56.2%; grade ≥3: 9.5%). Five (3.6%) patients experienced adjudicated treatment-related interstitial lung disease/pneumonitis, with 1 (0.7%) grade 5 event. CONCLUSION Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ≥3 toxicities was comparable with previous observations, and no new safety signals were observed.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Kiyotaka Yoh
- National Cancer Center Hospital East, Kashiwa, Japan
| | - Rebecca Heist
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Harvard University, Boston, MA
| | | | - Jong-Seok Lee
- Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Paul Baas
- Dana-Farber Cancer Institute, Boston, MA
| | | | | | | | - Wu-Chou Su
- Dana-Farber Cancer Institute, Boston, MA
| | | | - Lan Lan
- Daiichi Sankyo, Inc, Basking Ridge, NJ
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Ou HT, Tsai JH, Chen YL, Wu TI, Chen LJ, Yang SC. Cost Effectiveness of Exclusionary EGFR Testing for Taiwanese Patients Newly Diagnosed with Advanced Lung Adenocarcinoma. PHARMACOECONOMICS 2025; 43:429-440. [PMID: 39752129 DOI: 10.1007/s40273-024-01462-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 12/01/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND AND OBJECTIVE Approximately half of lung adenocarcinomas in East Asia harbor epidermal growth factor receptor (EGFR) mutations. EGFR testing followed by tissue-based next-generation sequencing (NGS), upfront tissue-based NGS, and complementary NGS approaches have emerged on the front line to guide personalized therapy. We study the cost effectiveness of exclusionary EGFR testing for Taiwanese patients newly diagnosed with advanced lung adenocarcinoma. METHODS This economic evaluation was conducted from the perspective of the healthcare sector with a lifetime horizon. Simulated patients were entered into a joint model combining decision trees and partitioned survival models upon diagnosis of advanced lung adenocarcinoma. We compared exclusionary EGFR testing with upfront tissue-based NGS and complementary NGS approaches. The model inputs were derived from regional estimates (prevalence of targetable gene alterations), trials (testing accuracy, survival outcomes, and adverse events), ACT Genomics (testing costs), National Health Insurance payments, retail prices (drug costs), and hospital cohorts (utility values). All costs were made equivalent to 2023 US dollars. An annual discount rate of 3% was applied. We adopted a willingness-to-pay threshold of US$70,000 per quality-adjusted life-year. One-way deterministic and probabilistic analyses were performed. RESULTS The incremental cost-effectiveness ratio of exclusionary EGFR testing versus upfront tissue-based NGS was US$15,521 per quality-adjusted life-year, whereas the incremental net monetary benefit was US$2530. The costs of osimertinib and pembrolizumab were the major determinants. The incremental net monetary benefit of exclusionary EGFR testing versus complementary NGS approach was US$2174, and its major determinants included the true-negative rate of EGFR testing and the prevalence rate of an EGFR mutation. Given the willingness-to-pay thresholds of US$35,000, US$70,000, and US$105,000 (1, 2, and 3 per capita gross domestic product) per quality-adjusted life-year, the probabilities that exclusionary EGFR testing would be cost effective were 79.1%, 95.6%, and 91.2%, respectively. CONCLUSIONS Our analysis suggests that exclusionary EGFR testing is a cost-effective strategy for Taiwanese patients newly diagnosed with advanced lung adenocarcinoma.
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Affiliation(s)
- Huang-Tz Ou
- Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jui-Hung Tsai
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Yi-Lin Chen
- Molecular Diagnosis Laboratory, Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan
| | - Tzu-I Wu
- Division of Pulmonology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Shengli Road, Tainan, 704, Taiwan
| | - Li-Jun Chen
- Division of Pulmonology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Shengli Road, Tainan, 704, Taiwan
| | - Szu-Chun Yang
- Division of Pulmonology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Shengli Road, Tainan, 704, Taiwan.
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Lan Y, Sun J, Xu J, Chen X. Anti-lung cancer activity of lotusine in non-small cell lung cancer HCC827 via reducing proliferation, oxidative stress, induction of apoptosis, and G0/G1 cell cycle arrest via suppressing EGFR-Akt-ERK signalling. In Vitro Cell Dev Biol Anim 2025; 61:450-458. [PMID: 40392483 DOI: 10.1007/s11626-025-01048-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 04/10/2025] [Indexed: 05/22/2025]
Abstract
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide, with resistance to targeted therapies and the need for novel therapeutic agents driving ongoing research. In this study, we investigated the anti-lung cancer activity of lotusine, a natural alkaloid, in the A549 (non-EGFR mutant), and EGFR-mutant HCC827 NSCLC cell line (deletion in exon 19). Our results demonstrated that lotusine significantly inhibited cell proliferation in a concentration- and time-dependent manner of HCC827 cells in comparison to A549 cells. Mechanistic analysis revealed that lotusine induced apoptosis in HCC827 cells, as evidenced by increased expression of pro-apoptotic markers (Bax and cleaved caspase-3) and decreased levels of anti-apoptotic proteins (Bcl-2). Cell cycle analysis indicated that lotusine caused G0/G1 phase arrest. Importantly, lotusine exerted its effects through the inhibition of the epidermal growth factor receptor (EGFR) EGFR-Akt-ERK signaling pathway, as evidenced by reduction of p-EGFR, p-Akt, and p-ERK in a western blot analysis in HCC827 cells. These findings suggest that lotusine exerts potent anti-cancer effects via a multifaceted mechanism, including inhibition of proliferation, apoptosis induction, and cell cycle arrest, predominantly mediated by EGFR suppression. This study highlights lotusine as a promising therapeutic candidate for the treatment of EGFR-mutant NSCLC and provides insights into its molecular mechanisms of action, paving the way for further preclinical and clinical evaluations.
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Affiliation(s)
- Yuanmin Lan
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen and Longgang District People's Hospital of Shenzhen, Guangdong, Guangdong, 518172, China
| | - Jing Sun
- Department Of Oncology, The Fifth People's Hospital Of Dalian, Dalian Liaoning, 116021, China
| | - Jiqing Xu
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen and Longgang District People's Hospital of Shenzhen, Guangdong, Guangdong, 518172, China
| | - Xiaoying Chen
- Department of Respiratory and Critical Care Medicine, Lishui Second People's Hospital, Lishui Zhejiang, 323000, China.
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30
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Soo RA, Vervita K, Früh M, Cho BC, Majem M, Rodriguez Abreu D, Ribi K, Callejo A, Moran T, Domine Gomez M, Provencio M, Addeo A, Han JY, Ortega Granados AL, Reck M, Blasco A, Garcia Campelo R, Sala González MA, Britschgi C, Roschitzki-Voser H, Ruepp B, Gasca-Ruchti A, Haberecker M, Dafni U, Peters S, Stahel RA. A randomised non-comparative phase II study of atezolizumab, bevacizumab and chemotherapy in EGFR-mutant NSCLC with acquired resistance - The ETOP 15-19 ABC-lung trial. Lung Cancer 2025; 202:108454. [PMID: 40023017 DOI: 10.1016/j.lungcan.2025.108454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2024] [Revised: 01/29/2025] [Accepted: 02/16/2025] [Indexed: 03/04/2025]
Abstract
BACKGROUND ABC-lung explores the potential effect of combining atezolizumab and bevacizumab with either carboplatin/paclitaxel (ABCPac) or pemetrexed (ABPem) in patients with EGFR-mutant NSCLC, resistant to tyrosine kinase inhibitors (TKIs). METHODS ABC-lung is a 1:1 randomised, non-comparative, phase II trial, stratified by prior treatment with a third-generation EGFR TKI, evaluating atezolizumab (1200 mg, Q3W) and bevacizumab (15mg/kg, Q3W) with either 4-6 cycles of carboplatin (AUC5, Q3W) and paclitaxel (175-200mg/m2, Q3W) or pemetrexed (500 mg/m2, Q3W) until progression (PD). The study aimed to improve the 1-year progression-free survival (PFS) rate from 18% to 37%, assessed per RECISTv1.1, separately in each arm. To reject the null hypothesis, at least 14 of 45 evaluable patients in each arm needed to be progression-free at 1-year (power 83%, 1-sided a=0.023). Secondary endpoints included overall survival (OS), objective response rate (ORR), PFS, quality of life (QoL) and adverse events (AEs). RESULTS Between 09/2020 and 09/2022, 95 patients were randomized (ABCPac:45; ABPem:50) with median follow-up time of 19 months. From the evaluable patients, 9 in ABCPac and 11 in ABPem arms reached 1-year without progression, lower than the success criterion of 14patients. Median PFS was 6.4 months in ABCPac and 7.6 months in the ABPem arms, while median OS was 15.4 months and 15.6 months, respectively. Grade ≥3 treatment-related AEs were experienced by 50% and 42% of patients in ABCPac and ABPem arms, respectively, while no grade 5 AEs were recorded. CONCLUSIONS The observed 1-year PFS rate with atezolizumab, bevacizumab in combination with either carboplatin-paclitaxel or pemetrexed was below the aspired rate of 37% in both arms. The safety is consistent with the known toxicity profiles. Clinical trial identification: NCT04245085.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/pathology
- Bevacizumab/administration & dosage
- Bevacizumab/therapeutic use
- Lung Neoplasms/drug therapy
- Lung Neoplasms/mortality
- Lung Neoplasms/genetics
- Lung Neoplasms/pathology
- Female
- Male
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Middle Aged
- Aged
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Drug Resistance, Neoplasm
- ErbB Receptors/genetics
- Mutation
- Adult
- Paclitaxel/administration & dosage
- Carboplatin/administration & dosage
- Pemetrexed/administration & dosage
- Aged, 80 and over
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Affiliation(s)
- R A Soo
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - K Vervita
- ETOP Statistical Office, FSF-H - Frontier Science Foundation Hellas, Athens, Greece
| | - M Früh
- Klinik für Medizinische Onkologie und Hämatologie, Kantonsspital St. Gallen, St. Gallen, Switzerland; Department of Medical Oncology, University of Bern, Bern, Switzerland
| | - B C Cho
- Medical Oncology Department, Yonsei University, Seoul, Republic of Korea
| | - M Majem
- Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Spanish Lung Cancer Group (GECP), Barcelona, Spain
| | - D Rodriguez Abreu
- Spanish Lung Cancer Group (GECP), Barcelona, Spain; Medical Oncology Department, Hospital Universitario Insular de Gran Canaria - Complejo Hospitalario Materno-Insular, Las Palmas De Gran Canaria, Spain
| | - K Ribi
- Coordinating Center, ETOP IBCSG Partners Foundation, Bern, Switzerland
| | - A Callejo
- Spanish Lung Cancer Group (GECP), Barcelona, Spain; Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - T Moran
- Spanish Lung Cancer Group (GECP), Barcelona, Spain; Medical Oncology Dept, ICO - Institut Català d'Oncologia Badalona (Hospital Universitario Germans Trias i Pujol), Badalona, Spain
| | - M Domine Gomez
- Spanish Lung Cancer Group (GECP), Barcelona, Spain; Oncology Dept., Hospital Universitario Fundacion Jimenez Diaz, IIS-FJD, Madrid, Spain
| | - M Provencio
- Spanish Lung Cancer Group (GECP), Barcelona, Spain; Universidad Autónoma de Madrid, University Hospital Puerta de Hierro Majadahonda, Majadahonda, Spain
| | - A Addeo
- Oncology Dept., HUG - Hopitaux Universitaires de Geneve, Geneva, Switzerland
| | - J Y Han
- Center for Lung Cancer, National Cancer Center, Goyang, Republic of Korea
| | - A L Ortega Granados
- Spanish Lung Cancer Group (GECP), Barcelona, Spain; Medical Oncology Department, Hospital Universitario de Jaén, Jaén, Spain
| | - M Reck
- Airway Research Center North (ARCN), German Center for Lung Research (DZL), LungenClinic, Grosshansdorf, Germany
| | - A Blasco
- Spanish Lung Cancer Group (GECP), Barcelona, Spain; Hospital General de Valencia, Spain
| | - R Garcia Campelo
- Spanish Lung Cancer Group (GECP), Barcelona, Spain; Hospital Teresa Herrera, La Coruña, Spain
| | - M A Sala González
- Spanish Lung Cancer Group (GECP), Barcelona, Spain; Medical Oncology Department, Hospital Universitario Basurto, Bilbao, Spain
| | - C Britschgi
- Medical Oncology and Haematology, Universitätsspital Zürich (USZ), Zürich, Switzerland
| | | | - B Ruepp
- Coordinating Center, ETOP IBCSG Partners Foundation, Bern, Switzerland
| | - A Gasca-Ruchti
- Coordinating Center, ETOP IBCSG Partners Foundation, Bern, Switzerland
| | - M Haberecker
- Department of Pathology and Molecular Pathology, USZ - University Hospital Zurich, Zurich, Switzerland
| | - U Dafni
- Department of Medical Oncology, University of Bern, Bern, Switzerland; National and Kapodistrian University of Athens, Athens, Greece
| | - S Peters
- Oncology Dept., CHUV - Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - R A Stahel
- Coordinating Center, ETOP IBCSG Partners Foundation, Bern, Switzerland.
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Khan SR, Breadner D. Unveiling the Synergistic Potential: Bispecific Antibodies in Conjunction with Chemotherapy for Advanced Non-Small-Cell Lung Cancer Treatment. Curr Oncol 2025; 32:206. [PMID: 40277763 PMCID: PMC12025875 DOI: 10.3390/curroncol32040206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 03/23/2025] [Accepted: 03/27/2025] [Indexed: 04/26/2025] Open
Abstract
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small-cell lung cancer (NSCLC) accounting for the majority of the cases. Despite advancements in targeted therapies and immunotherapies, many patients still rely on chemotherapy, highlighting the need for innovative treatment strategies. Bispecific antibodies (bsAbs), which feature two distinct binding sites capable of targeting different antigens, have emerged as a promising therapeutic approach, particularly in combination with chemotherapy. This review explores the scientific evolution and clinical application of bsAbs in NSCLC, focusing on their synergistic potential with chemotherapy. BsAbs, such as amivantamab, which targets EGFR and MET, have demonstrated significant efficacy in clinical trials, particularly in patients with EGFR mutations. The combination of bsAbs with chemotherapy enhances immune-mediated tumor destruction by modulating the tumor microenvironment and overcoming resistance mechanisms. Recent clinical trials have shown improved progression-free survival and overall survival when bsAbs such as amivantamab are combined with chemotherapy, underscoring their potential to transform NSCLC treatment. Many other clinical trials are underway that are evaluating newer bsAbs, such as ivonescimab, which targets PD1 and VEGF. This review also discusses ongoing clinical trials investigating various bsAbs targeting EGFR, PD-1, PD-L1, HER2, and other pathways, highlighting the future directions of bsAb-based therapies. As the field evolves, bsAbs are poised to become a cornerstone of multimodal NSCLC treatment, offering more effective and personalized therapeutic options for patients with advanced disease.
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Affiliation(s)
- Saqib Raza Khan
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada;
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
| | - Daniel Breadner
- Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada;
- Verspeeten Family Cancer Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada
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32
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Romaniello D, Morselli A, Marrocco I. Strategies to Overcome Resistance to Osimertinib in EGFR-Mutated Lung Cancer. Int J Mol Sci 2025; 26:2957. [PMID: 40243603 PMCID: PMC11988377 DOI: 10.3390/ijms26072957] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Revised: 03/22/2025] [Accepted: 03/23/2025] [Indexed: 04/18/2025] Open
Abstract
Non-small-cell lung cancer (NSCLC) represents the most common type of lung cancer. The majority of patients with lung cancer characterized by activating mutations in the epidermal growth factor receptor (EGFR), benefit from therapies entailing tyrosine kinase inhibitors (TKIs). In this regard, osimertinib, a third-generation EGFR TKI, has greatly improved the outcome for patients with EGFR-mutated lung cancer. The AURA and FLAURA trials displayed the superiority of the third-generation TKI in both first- and second-line settings, making it the drug of choice for treating patients with EGFR-mutated lung cancer. Unfortunately, the onset of resistance is almost inevitable. On-target mechanisms of resistance include new mutations (e.g., C797S) in the kinase domain of EGFR, while among the off-target mechanisms, amplification of MET or HER2, mutations in downstream signaling molecules, oncogenic fusions, and phenotypic changes (e.g., EMT) have been described. This review focuses on the strategies that are currently being investigated, in preclinical and clinical settings, to overcome resistance to osimertinib, including the use of fourth-generation TKIs, PROTACs, bispecific antibodies, and ADCs, as monotherapy and as part of combination therapies.
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Affiliation(s)
- Donatella Romaniello
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (D.R.); (A.M.)
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Alessandra Morselli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy; (D.R.); (A.M.)
| | - Ilaria Marrocco
- Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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33
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Byeon H. Enhancing recovery in non-small cell lung cancer patients through mindfulness training and Jinshui Liujun decoction supplementation. World J Psychiatry 2025; 15:101876. [PMID: 40110006 PMCID: PMC11886325 DOI: 10.5498/wjp.v15.i3.101876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 01/03/2025] [Accepted: 01/11/2025] [Indexed: 02/26/2025] Open
Abstract
This article delves into the research conducted by Liu DW et al on the integration of mindfulness-based stress reduction training (MSRT) and flavored Jinshui Liujun decoction (FJLD) with conventional chemotherapy (CC) in the treatment of non-small cell lung cancer. The study investigates the impact of this combined approach on immune function and emotional well-being of non-small cell lung cancer patients. Patients were divided into a control group (CG) receiving CC alone and a treatment group (TG) receiving MSRT + FJLD alongside CC. The primary outcomes were progression-free survival and overall survival, with secondary outcomes including Karnofsky performance status scores, clinical efficacy, immune function markers, and emotional state assessments. The findings underscore significant improvements in median progression-free survival (20.50 months in TG vs 13.10 months in CG, P < 0.05), Karnofsky performance status scores (60 in TG vs 50 in CG, P < 0.05), and immune cell ratios, along with reductions in negative emotions (self-rating anxiety scale and self-rating depression scale scores significantly lower in TG, P < 0.05) among patients receiving MSRT + FJLD in conjunction with CC. This article highlights the potential of combining traditional Chinese medicine and modern psychological interventions to enhance the efficacy of conventional cancer treatments and improve patient outcomes.
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Affiliation(s)
- Haewon Byeon
- Workcare Digital Health Lab, Department of Convergence, Korea University of Technology and Education, Cheonan 31253, South Korea
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Patel KB, Heppner DE. Lazertinib: breaking the mold of third-generation EGFR inhibitors. RSC Med Chem 2025; 16:1049-1066. [PMID: 39867588 PMCID: PMC11758113 DOI: 10.1039/d4md00800f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 01/02/2025] [Indexed: 01/28/2025] Open
Abstract
Small molecules targeting activating mutations within the epidermal growth factor receptor (EGFR) are efficacious anticancer agents, particularly in non-small cell lung cancer (NSCLC). Among these, lazertinib, a third-generation tyrosine kinase inhibitor (TKI), has recently gained FDA approval for use in combination with amivantamab, a dual EGFR/MET-targeting monoclonal antibody. This review delves into the discovery and development of lazertinib underscoring the improvements in medicinal chemistry properties, especially in comparison with osimertinib. Analysis of its structure-activity relationships (SAR), as outlined in the patent literature, reveals the structural diversity explored enroute to the candidate molecule. The resulting structure of lazertinib is distinguished among other TKIs due to the combination of the hydrophobic phenyl and hydrophilic amine substituents on the pyrazole. The structural basis for the selectivity against the T790M mutation is enabled by the substituted pyrazole moiety, which facilitates both van der Waals and H-bonding interactions with the EGFR kinase domain. Insights from this case study offer lessons that can inform the future design of kinase inhibitors with improved safety and efficacy profiles for cancer treatment and other diseases.
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Affiliation(s)
- Kishan B Patel
- Department of Chemistry, The State University of New York at Buffalo Natural Sciences Complex Buffalo NY 14260 USA
| | - David E Heppner
- Department of Chemistry, The State University of New York at Buffalo Natural Sciences Complex Buffalo NY 14260 USA
- Jacobs School of Medicine and Biomedical Sciences, Department of Structural Biology, The State University of New York at Buffalo Buffalo NY USA
- Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center Buffalo NY USA
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Sattler M, Salgia R. The expanding role of the receptor tyrosine kinase MET as a therapeutic target in non-small cell lung cancer. Cell Rep Med 2025; 6:101983. [PMID: 40020676 PMCID: PMC11970332 DOI: 10.1016/j.xcrm.2025.101983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 01/27/2025] [Accepted: 01/31/2025] [Indexed: 03/03/2025]
Abstract
Aberrant regulation of MET receptor tyrosine kinase activity is a frequent event in non-small cell lung cancer (NSCLC), even though the frequency of oncogenic driver mutations of MET is low. Our discovery of oncogenic MET exon 14 skipping mutations, the characterization of the first prototype MET kinase inhibitor, and characterization of MET expression levels have led the way to novel therapeutic approaches with improved outcomes in NSCLC. MET exon 14 mutations are the most consequential but not the only alterations that can be targeted through small molecule tyrosine kinase inhibitors. The abundant expression of cellular MET (c-MET) in cancer cells has provided new opportunities for immuno-oncology approaches in a broader patient population, and the integration of MET-targeted personalized medicine with immunotherapy has not been fully exploited yet. Here, we highlight essential facets of MET as a therapeutic target in NSCLC and provide an outlook for future approaches.
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Affiliation(s)
- Martin Sattler
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
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36
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Kim J, Park S, Ku BM, Ahn MJ. Updates on the treatment of epidermal growth factor receptor-mutant non-small cell lung cancer. Cancer 2025; 131 Suppl 1:e35778. [PMID: 40171939 DOI: 10.1002/cncr.35778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 08/28/2024] [Accepted: 09/30/2024] [Indexed: 04/04/2025]
Abstract
This review provides a comprehensive update on the evolving landscape of treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, particularly focusing on advances in precision medicine and overcoming acquired resistance. Initial success with first-generation EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC has paved the way for precision oncology and subsequent development of third-generation EGFR TKIs, the current standard of care as first-line therapy in advanced stage NSCLC. Furthermore, a combinational approach of third-generation EGFR TKI with chemotherapy or amivantamab was associated with prolonged progression-free survival. The role of EGFR TKIs also has been investigated in locally advanced and early stage NSCLC, including perioperative and neoadjuvant settings. However, most patients experience acquired resistance, and the resistance mechanism is quite complex and heterogeneous, highlighting the importance of tailored subsequent therapeutic approaches. Overall, this review underscores the dynamic landscape of EGFR-mutated NSCLC treatment, emphasizing the need for personalized strategies to optimize patient outcomes.
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Affiliation(s)
- Jinyong Kim
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Sehhoon Park
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea
| | - Bo Mi Ku
- Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Myung-Ju Ahn
- Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Seoul, Republic of Korea
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37
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Cho BC, Hayashi H, Lee JS, Lee SH, Danchaivijitr P, Cheng Y, Liu B, Alip A, Xiong H, How SH, Chang GC, Yang JCH, Yoshioka H, Nahit Şendur MA, Prabhash K, Azuma K, Lee YG, Lin CC, Matsumoto S, Sunpaweravong P, Xia Y, Martinez M, Bauml JM, Sethi S, Lu S. Amivantamab plus lazertinib versus osimertinib as first-line treatment in EGFR-mutated advanced non-small cell lung cancer: MARIPOSA Asian subset. Lung Cancer 2025; 204:108496. [PMID: 40300278 DOI: 10.1016/j.lungcan.2025.108496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Accepted: 03/14/2025] [Indexed: 05/01/2025]
Abstract
INTRODUCTION The incidence of epidermal growth factor receptor (EGFR) mutations is higher among Asian patients with advanced non-small cell lung cancer than the general advanced non-small cell lung cancer population. We evaluated the efficacy and safety of amivantamab in combination with lazertinib versus osimertinib in Asian participants from the phase 3 MARIPOSA study who had treatment-naïve advanced non-small cell lung cancer with common EGFR mutations. METHODS Participants were randomized 2:2:1 to receive amivantamab-lazertinib, osimertinib alone, or lazertinib alone. The primary endpoint was progression-free survival based on blinded independent central review per RECIST v1.1. Secondary endpoints included overall survival, objective response rate, duration of response, and safety. Exploratory endpoints included extracranial progression-free survival and post-progression outcomes. RESULTS Of 1074 randomized participants, 629 were Asian, with 250 and 251 randomized to the amivantamab-lazertinib and osimertinib arms, respectively. Among Asian participants, at a median follow-up of 22.5 months, amivantamab-lazertinib showed a 35 % reduction in the risk of disease progression or death versus osimertinib (hazard ratio, 0.65; P < 0.001). Consistent with the overall population, median progression-free survival was 27.5 and 18.3 months in the amivantamab-lazertinib and osimertinib arms, respectively. The objective response rate was 88 % for amivantamab-lazertinib versus 85 % for osimertinib. The median duration of response among confirmed responders improved by 8.6 months for amivantamab-lazertinib versus osimertinib. Favorable trends were also seen for overall survival, extracranial progression-free survival, and post-progression outcomes for amivantamab-lazertinib over osimertinib. Adverse events in Asian participants were similar to those in the overall population. CONCLUSIONS Amivantamab-lazertinib demonstrated superior progression-free survival versus osimertinib in Asian participants, with a tolerable safety profile. These results were consistent with those in the overall population.
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Affiliation(s)
- Byoung Chul Cho
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | - Jong-Seok Lee
- Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Se-Hoon Lee
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Pongwut Danchaivijitr
- Faculty of Medicine, Siriraj Hospital, Mahidol University Bangkok Noi Campus, Bangkok, Thailand
| | | | - Baogang Liu
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Adlinda Alip
- Clinical Oncology Department, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Hailin Xiong
- Huizhou Municipal Central Hospital of Guangdong Province, Huizhou, China
| | - Soon Hin How
- International Islamic University Malaysia, Selangor, Malaysia
| | - Gee-Chen Chang
- School of Medicine and Institute of Medicine, Chung Shan Medical University and Division of Pulmonary Medicine, Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung City, Taiwan
| | | | - Hiroshige Yoshioka
- Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka, Japan
| | - Mehmet Ali Nahit Şendur
- Department of Medical Oncology, Ankara Yıldırım Beyazıt Üniversitesi, Ankara Bilkent City Hospital, Ankara, Turkey
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Centre, Mumbai, India
| | - Koichi Azuma
- Kurume University School of Medicine, Kurume, Japan
| | - Yun-Gyoo Lee
- Department of Internal Medicine, Gangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Chien-Chung Lin
- National Cheng Kung University Hospital, Tainan City, Taiwan and Tainan Hospital, Ministry of Health & Welfare, Tainan City, Taiwan
| | - Shingo Matsumoto
- Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Patrapim Sunpaweravong
- Division of Medical Oncology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | | | | | | | | | - Shun Lu
- Department of Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Bouchard N, Daaboul N. Lung Cancer: Targeted Therapy in 2025. Curr Oncol 2025; 32:146. [PMID: 40136350 PMCID: PMC11941068 DOI: 10.3390/curroncol32030146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/23/2025] [Accepted: 02/26/2025] [Indexed: 03/27/2025] Open
Abstract
Lung cancer treatment has changed in the last twenty years since the discovery of EGFR mutations. In this article, we will review the current state of the art for non-small cell lung cancer (NSCLC) actionable genomic alterations (AGA). AGAs are mostly found in lung adenocarcinomas, a subtype of non-small cell lung cancers. We will focus on the current treatment for EGFR mutations, ALK fusions, ROS1 fusions, BRAF V600E mutations, MET exon 14-skipping mutations, RET fusions, KRAS G12C mutations, ERBB2 mutations (also called HER2 mutations), and NTRK fusions. We will also touch on the key toxicities associated with these medications. Treatments are mostly available for the metastatic stage, but we will also discuss adjuvant therapy for EGFR mutations and ALK fusions, as well as stage III post-chemoradiotherapy treatment for EGFR lung cancer.
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Affiliation(s)
- Nicole Bouchard
- Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada;
| | - Nathalie Daaboul
- Centre Intégré de Cancérologie de la Montérégie, Université de Sherbrooke, Longueuil, QC J4V 2H1, Canada
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Czogalla M, Stöhr J, Gleim N, Papsdorf K, Klagges S, Hambsch P, Kuhnt T, Nägler F, Barrantes-Freer A, Wach J, Nicolay N, Seidel C. Short-term survivors with brain metastases have modest benefits from focal and systemic therapies and remain frequent despite improving treatment landscape. Clin Transl Radiat Oncol 2025; 51:100919. [PMID: 39877301 PMCID: PMC11772985 DOI: 10.1016/j.ctro.2025.100919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 12/22/2024] [Accepted: 01/09/2025] [Indexed: 01/31/2025] Open
Abstract
Purpose Therapeutic options for patients with brain metastases (BM) increase. While these lead to considerable survival effects in subgroups, there is limited knowledge about characteristics, prognosticators and treatment effects in patients with BM and short survival. Methods Patients with a survival time of ≤ 6 months (short-term survivors, STS), diagnosed with BM between 2009-2021 at a large tertiary cancer center were analysed. Clinical and treatment characteristics, pathological data and causes of death were documented. Descriptive statistics, treatment-specific univariate Kaplan-Meier estimator analyses and multivariate Cox regression were performed. Results Among 1248 patients with BM, 480 (38 %) were STS. 256 STS with detailed clinical records were included in this analysis. In univariate and multivariate analysis, Karnofsky Performance Status (KPS) (p < 0.001) and number of BM (p = 0.004) were prognostic. In 75 % of patients, the ds-GPA score predicted short-term survival. Use of resection with focal radiotherapy (p < 0.001) and systemic treatment (p < 0.001) appeared prognostically favourable compared to whole brain radiotherapy (WBRT) alone. However, survival benefits were very modest, with a median gain of 6 weeks following resection and focal radiotherapy compared to whole-brain radiotherapy, and 3 weeks from systemic treatment. Systemic tumor progression was documented as the cause of death in the majority of patients. Over the examined time period, the ratio between STS and other patients remained without significant change. Conclusion Within STS, KPS and number of BM are of prognostic relevance. There is benefit from local and systemic therapy to a limited extent. Shared and carefully discussed individual therapy decisions are necessary.
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Affiliation(s)
- M. Czogalla
- Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
| | - J. Stöhr
- Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
| | - N. Gleim
- Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
| | - K. Papsdorf
- Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
| | - S. Klagges
- Clinical Cancer Registry Leipzig, Philipp-Rosenthal-Straße 27b, 04103 Leipzig, Germany
| | - P. Hambsch
- Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
| | - T. Kuhnt
- Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
| | - F. Nägler
- Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
| | - A. Barrantes-Freer
- Department of Neuropathology,University of Leipzig Medical Center, Liebigstraße 26, 04103 Leipzig, Germany
| | - J. Wach
- Department of Neurosurgery, University of Leipzig Medical Center, Liebigstraße 20, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
| | - N.H. Nicolay
- Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
| | - C. Seidel
- Department of Radiation Oncology, University of Leipzig Medical Center, Stephanstraße 9a, 04103 Leipzig, Germany
- Comprehensive Cancer Center Central Germany, Partner Site Leipzig, Liebigstraße 22, 04103 Leipzig, Germany
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Brazel D, Smith J, Ou SHI, Nagasaka M. The User's Guide to Amivantamab. Target Oncol 2025; 20:235-245. [PMID: 39903428 PMCID: PMC11933153 DOI: 10.1007/s11523-025-01128-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/20/2025] [Indexed: 02/06/2025]
Abstract
Targeted therapies have revolutionized treatment of non-small-cell lung cancer (NSCLC); however, epidermal growth factor receptor (EGFR) exon20ins mutations are resistant to tyrosine kinase inhibitors. Amivantamab utilizes multiple mechanisms of action to bypass the altered binding site conformation and recruits immune cells for anti-cancer activity. Amivantamab is approved in the frontline setting of EGFR exon20ins-mutated NSCLC in combination with carboplatin plus pemetrexed. Single-agent amivantamab is approved in second line or later for EGFR exon20ins. Furthermore, amivantamab with lazertinib for first line as well as amivantamab in combination with carboplatin and pemetrexed for second line after osimertinib have both been approved in the treatment of NSCLC harboring EGFR-sensitizing mutations. Now with multiple indications, we must learn how to manage the unique side effects of amivantamab to maximize treatment benefit for the patients. Side effects of amivantamab can be associated with inhibition of the EGFR and/or mesenchymal epithelial transcription factor (MET) signaling pathways. This work reviews the mechanism of action, pharmacology, clinical trial data, and covers management of toxicities. This guide is designed as a practical reference tool for clinicians, pharmacists, and basic science researchers.
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Affiliation(s)
- Danielle Brazel
- Department of Hematology/Oncology, Scripps Clinic/Scripps Green Hospital, La Jolla, CA, USA
| | - Janellen Smith
- Chao Family Cancer Center, University of California Irvine School of Medicine, 101 The City Drive, Orange, CA, 92868, USA
| | - Sai-Hong Ignatius Ou
- Chao Family Cancer Center, University of California Irvine School of Medicine, 101 The City Drive, Orange, CA, 92868, USA
| | - Misako Nagasaka
- Chao Family Cancer Center, University of California Irvine School of Medicine, 101 The City Drive, Orange, CA, 92868, USA.
- St. Marianna University School of Medicine, Kawasaki, Japan.
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Lefèvre A, Besse B. [Standard of care of EGFR mutated metastatic NSCLC in first treatment and beyond progression]. Bull Cancer 2025; 112:3S75-3S85. [PMID: 40155080 DOI: 10.1016/s0007-4551(25)00160-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Among the oncogenic alterations of non-small cell lung cancer (NSCLC), the EGFR gene mutation is observed in 15% of patients in France, particularly among non-smokers and women. Treatment mainly relies on tyrosine kinase inhibitors (TKIs) targeting EGFR. In first-line metastatic treatment, osimertinib, a third-generation TKI, has become the standard, improving progression-free survival (PFS) and overall survival (OS) compared to first- or second-generation TKIs. The combination of TKI/chemotherapy (osimertinib/carboplatine-pemetrexed) and TKI/bispecific antibodies (e.g., amivantamab/lazertinib) are alternatives under evaluation, with benefits in PFS but increased toxicity. In case of progression under first- or second-generation TKIs, the most common resistance is the T790M mutation, which can be targeted by osimertinib. For other resistances, platinum-based chemotherapy remains an option. Amivantamab combined with chemotherapy has shown an improvement in PFS in the second line and has early access in France. Other emerging approaches include conjugated antibodies (patritumab deruxtecan, datopotamab deruxtecan) and next-generation TKIs. In the future, personalized treatment based on the molecular profile and early response to TKIs could optimize management, particularly by integrating predictive markers such as EGFR clearance under treatment.
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Affiliation(s)
- Antoine Lefèvre
- Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, Villejuif, France
| | - Benjamin Besse
- Département d'Oncologie Médicale, Gustave Roussy Cancer Campus, Villejuif, France; Université Paris-Saclay, Orsay, France.
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Gridelli C, Mok T, Jänne P, Passaro A, Felip E, Ramalingam SS, Attili I, de Marinis F. Debate on first-line treatment strategies in advanced non-small cell lung cancer with EGFR mutation: An expert panel meeting by the Italian Association of Thoracic Oncology (AIOT). Lung Cancer 2025; 201:108100. [PMID: 39986216 DOI: 10.1016/j.lungcan.2025.108100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 02/24/2025]
Abstract
BACKGROUND The front-line treatment options and regulatory approval scenario for epidermal growth factor receptor (EGFR) mutation positive metastatic non-small cell lung cancer (NSCLC) have rapidly evolved in the recent months, with newly presented positive trial results of novel compounds and combination strategies in the setting of common activating mutations, uncommon mutations, and exon 20 insertions. In this context, international lively debate is emerging on how to choose among the available regimens, based on efficacy and safety results. METHODS A virtual International Expert Panel was held in July 2024 to review data on front-line regimens in patients with NSCLC harboring EGFR mutations, including common, uncommon and exon 20 insertions. The panel discussed available evidence, and reached common considerations for clinical practice and clinical research. RESULTS In the setting of EGFR common activating mutations, all panelists agreed that single agent osimertinib, the combination of osimertinib with platinum-pemetrexed, and the combination of amivantamab and lazertinib, are first-line treatment options. Overall, panelists defined characteristics of patients in which combination treatments should be avoided. Subsequent treatment strategies at disease progression were discussed according to the different front-line options. With regards to uncommon EGFR mutations, panelists agreed that afatinib remains the only drug with phase 3 results available, and that afatinib and osimertinib are the preferred first-line options. In EGFR exon20 insertion positive disease, the combination of carboplatin, pemetrexed and amivantamab has been identified as the preferred front-line treatment, with second-line amivantamab to be used in the second-line setting whenever not available in front-line. The panelists defined priorities in clinical research, with high priority attributed to investigating resistance mechanisms, novel generation of tyrosine kinase inhibitors, and selection biomarkers. CONCLUSIONS Different toxicity profiles and sequential strategies were considered, together with efficacy results, to reach common considerations for the front-line treatment strategies in EGFR mutant NSCLC, however clinical research should be prioritized to identify further selection features.
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Affiliation(s)
- Cesare Gridelli
- Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy
| | - Tony Mok
- Department of Clinical Oncology, Faculty of Medicine, State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Pasi Jänne
- Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Antonio Passaro
- Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Enriqueta Felip
- Oncology Department, Vall d'Hebron University Hospital and Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | | | - Ilaria Attili
- Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Filippo de Marinis
- Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan, Italy.
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Spagnuolo A, Gridelli C. Investigating osimertinib plus chemotherapy in EGFR-mutated advanced non-small cell lung cancer. Expert Opin Pharmacother 2025; 26:491-501. [PMID: 39935000 DOI: 10.1080/14656566.2025.2464903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 02/05/2025] [Indexed: 02/13/2025]
Abstract
INTRODUCTION Worldwide, 15-40% of advanced-stage non-small cell lung cancers (NSCLCs) have an activating EGFR mutation, treatable with tyrosine-kinase inhibitors (TKIs) such as osimertinib, recommended as front-line therapy. Despite the efficacy of first-line osimertinib, most patients will experience disease progression. Therefore, combining it with chemotherapy has become an area of interest. AREAS COVERED Osimertinib is a third-generation EGFR-TKI that has extended survival in NSCLC patients with EGFR mutation. However, resistance eventually leads to treatment failure. This has driven the advancement of strategies to overcome resistance to osimertinib. In this setting, the FLAURA2 trial yielded positive results by combining osimertinib with chemotherapy. Additionally, a range of other approaches, including the use of bispecific antibodies and antibody-drug conjugates alongside third-generation EGFR-TKIs or chemotherapy, support the development of novel therapeutic combinations, some of which have already been approved for EGFR-mutated advanced NSCLC. EXPERT OPINION Next to osimertinib monotherapy, expanded upfront treatment options for patients with EGFR-mutated advanced NSCLC require patient selection considering disease extent, toxicity and tolerability, dosing schedule and what the patient can expect through shared decision-making. Further studies are needed to identify the patients who will benefit the most from combination therapies and to sequence the new drugs into the treatment algorithm.
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Affiliation(s)
- Alessia Spagnuolo
- Division of Medical Oncology, 'S. G. Moscati' Hospital, Avellino, Italy
| | - Cesare Gridelli
- Division of Medical Oncology, 'S. G. Moscati' Hospital, Avellino, Italy
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Nishi T, Morita A, Hara N, Makimoto G, Ninomiya K, Fujii M, Rai K, Ohashi K, Hotta K, Tabata M, Togashi Y, Maeda Y, Ichihara E. Efficacy of amivantamab, a bi-specific antibody targeting EGFR and MET, in ALK-rearranged non-small-cell lung cancer cell lines. Lung Cancer 2025; 201:108415. [PMID: 39922174 DOI: 10.1016/j.lungcan.2025.108415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 01/21/2025] [Accepted: 01/30/2025] [Indexed: 02/10/2025]
Abstract
BACKGROUND Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are highly effective in treating ALK-rearranged non-small-cell lung cancer (NSCLC). However, at least 40% of patients develop acquired resistance during treatment. Adaptive or acquired resistance to ALK TKIs could be mediated through epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) signaling. Sixteen percent of acquired resistance cases are linked to bypass signaling. METHODS In this study, we evaluated the effects of amivantamab, a bi-specific antibody targeting both EGFR and MET, on ALK-rearranged NSCLC cells. We investigated the effect of amivantamab on the ALK-rearranged NSCLC cell lines H3122, ABC-19, and ABC-11. RESULTS Combining alectinib with amivantamab resulted in greater inhibition of cell growth inhibition in H3122 and ABC-19 cells compared to alectinib alone, but not in ABC-11 cells. EGFR TKI erlotinib showed similar efficacy in H3122 and ABC-19 cells, whereas MET TKI tepotinib was ineffective in both, suggesting that the efficacy of amivantamab is through EGFR inhibition. Unlike H3122 and ABC-19 cells, ABC-11 cells were resistant to EGFR/MET signaling inhibition. Interestingly, amivantamab enhanced alectinib efficacy against ABC-11 cells in the presence of peripheral blood mononuclear cells (PBMCs), despite showing no effect alone without PBMCs, suggesting action through non-signal inhibitory mechanisms. Finally, we treated alectinib-resistant cellswith alectinib, with or without amivantamab, and found that amivantamab restored the sensitivity of these cells to alectinib. CONCLUSION The bi-specific antibody amivantamab, which targets EGFR and MET, enhanced the efficacy of alectinib through both signal and non-signal inhibitory mechanisms in ALK-rearranged NSCLC cells.
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Affiliation(s)
- Tatsuya Nishi
- Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Ayako Morita
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Naofumi Hara
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Go Makimoto
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Kiichiro Ninomiya
- Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan
| | - Masanori Fujii
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Kammei Rai
- Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Kadoaki Ohashi
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan
| | - Katsuyuki Hotta
- Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan
| | - Masahiro Tabata
- Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan
| | - Yosuke Togashi
- Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan; Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan; Kindai University Faculty of Medicine, Osaka, Japan
| | - Yoshinobu Maeda
- Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Eiki Ichihara
- Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan.
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Maione P, Palma V, Pucillo G, Gridelli C. New Treatment Strategies in Advanced Epidermal Growth Factor Receptor-Driven Non-Small Cell Lung Cancer: Beyond Single Agent Osimertinib. Cancers (Basel) 2025; 17:847. [PMID: 40075694 PMCID: PMC11898774 DOI: 10.3390/cancers17050847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 02/22/2025] [Accepted: 02/27/2025] [Indexed: 03/14/2025] Open
Abstract
Osimertinib has been the standard treatment for advanced Epidermal Growth Factor Receptor (EGFR)-driven non-small cell lung cancer (NSCLC) for many years. However, even with remarkable response rate, progression-free survival (PFS) and survival benefit as compared to the old generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, treatment outcomes for these subsets of patients remain a challenge. Recently, in order to go beyond osimertinib, new treatment strategies have been developed. In particular, in the FLAURA 2 phase III randomized trial, the combination of platin-based chemotherapy and osimertinib showed impressive PFS benefits as compared to single-agent osimertinib. Furthermore, in the MARIPOSA phase III randomized study, the combination of the anti-EGFR and anti-MET monoclonal antibody amivantamab combined with the new anti-EGFR TKI lazertinib demonstrated remarkable PFS benefit as compared to single agent osimertinib. This paper will discuss these new treatment options and potential selection criteria for personalized treatment of patients.
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Affiliation(s)
- Paolo Maione
- Division of Medical Oncology, S.G. Moscati Hospital, 83100 Avellino, Italy;
| | - Valentina Palma
- Division of Medical Oncology, S.G. Moscati Hospital, Università degli Studi della Campania “Luigi Vanvitelli”, 83100 Avellino, Italy; (V.P.); (G.P.)
| | - Giuseppina Pucillo
- Division of Medical Oncology, S.G. Moscati Hospital, Università degli Studi della Campania “Luigi Vanvitelli”, 83100 Avellino, Italy; (V.P.); (G.P.)
| | - Cesare Gridelli
- Division of Medical Oncology, S.G. Moscati Hospital, 83100 Avellino, Italy;
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Ramos R, Moura CS, Costa M, Lamas NJ, Correia R, Garcez D, Pereira JM, Lindahl T, Sousa C, Vale N. Lung Cancer Therapy: The Role of Personalized Medicine. Cancers (Basel) 2025; 17:725. [PMID: 40075573 PMCID: PMC11899562 DOI: 10.3390/cancers17050725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Lung cancer is the deadliest cancer worldwide, exhibiting the highest incidence rate among all cancer types. Poor outcomes often characterize this cancer as it is commonly diagnosed in advanced stages due to its unspecific symptoms. After diagnosis, the therapeutic choice is a crucial stage that profoundly affects patients' survival. Treatment choices for lung cancer must be made carefully, acknowledging the histological type and genetic characteristics of the tumor. Non-small cell lung cancer, the most common and complex type, has a high mutational burden, making next-generation sequencing (NGS) essential for identifying specific mutations and guiding treatment. With several approved targeted therapies already available, this approach highlights the critical role of personalized medicine in lung cancer care. Despite the current therapeutic pipeline, research trying to develop new tailored drugs considering individual patient characteristics has evolved over the years. This article aims to outline the current therapeutic approach for each type of lung cancer and present the latest insights into emerging therapies, highlighting the role of personalized medicine in enhancing treatment outcomes and improving patients' quality of life.
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Affiliation(s)
- Raquel Ramos
- PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; (R.R.); (C.S.)
- RISE-Health, Department of Pathology, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Molecular Diagnostics Laboratory, Unilabs Portugal, Centro Empresarial Lionesa Porto, Rua Lionesa, 4465-671 Leça do Balio, Portugal; (M.C.); (N.J.L.)
| | - Conceição Souto Moura
- Pathology Laboratory, Unilabs Portugal, Rua Manuel Pinto de Azevedo 173, 4100-321 Porto, Portugal;
| | - Mariana Costa
- Molecular Diagnostics Laboratory, Unilabs Portugal, Centro Empresarial Lionesa Porto, Rua Lionesa, 4465-671 Leça do Balio, Portugal; (M.C.); (N.J.L.)
| | - Nuno Jorge Lamas
- Molecular Diagnostics Laboratory, Unilabs Portugal, Centro Empresarial Lionesa Porto, Rua Lionesa, 4465-671 Leça do Balio, Portugal; (M.C.); (N.J.L.)
- Anatomic Pathology Service, Pathology Department, Centro Hospitalar Universitário de Santo António (CHUdSA), Largo Professor Abel Salazar, 4099-001 Porto, Portugal
- Life and Health Sciences Research Institute (ICVS), School of Medicine, Campus de Gualtar, University of Minho, Rua da Universidade, 4710-057 Braga, Portugal
| | - Renato Correia
- Technology & Innovation Department, Unilabs Portugal, Rua Manuel Pinto de Azevedo 173, 4100-321 Porto, Portugal; (R.C.); (D.G.)
| | - Diogo Garcez
- Technology & Innovation Department, Unilabs Portugal, Rua Manuel Pinto de Azevedo 173, 4100-321 Porto, Portugal; (R.C.); (D.G.)
| | - José Miguel Pereira
- Radiology Department, Unilabs Portugal, Rua de Diogo Botelho 485, 4150-255 Porto, Portugal;
| | - Thomas Lindahl
- Unilabs Group Services, Succursale d’Unilabs, Laboratoire d’Analyses Médicales SA, Rue de Lausanne 15, 1201 Geneva, Switzerland;
| | - Carlos Sousa
- PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; (R.R.); (C.S.)
- Molecular Diagnostics Laboratory, Unilabs Portugal, Centro Empresarial Lionesa Porto, Rua Lionesa, 4465-671 Leça do Balio, Portugal; (M.C.); (N.J.L.)
| | - Nuno Vale
- PerMed Research Group, RISE-Health, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; (R.R.); (C.S.)
- RISE-Health, Department of Pathology, Faculty of Medicine, University of Porto, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal
- Laboratory of Personalized Medicine, Department of Community Medicine, Health Information and Decision (MEDCIDS), Faculty of Medicine, University of Porto, Rua Doutor Plácido da Costa, 4200-450 Porto, Portugal
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Hasan N, Nagasaka M. Amivantamab plus lazertinib vs. osimertinib in first-line EGFR-mutant advanced non-small cell lung cancer. Expert Rev Respir Med 2025:1-10. [PMID: 39965618 DOI: 10.1080/17476348.2025.2467338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/18/2025] [Accepted: 02/11/2025] [Indexed: 02/20/2025]
Abstract
INTRODUCTION The first-line treatment landscape for patients with NSCLC harboring sensitizing EGFR mutations is rapidly evolving. Initially, osimertinib was the one and only option over earlier generation EGFR inhibitors based on the positive PFS and OS results from the FLAURA study. AREAS COVERED This paper reviews and compares the pivotal studies that led to the approval of combination treatment with a focus on the efficacy and safety of amivantamab plus lazertinib in the front-line setting. The literature reviewed in this paper primarily includes key studies published in well-established journals and oncological conferences, such as ASCO, ESMO, and NEJM, between 2018 and 2024. EXPERT OPINION Recent advancements, including the results of FLAURA-2 and MARIPOSA, have introduced combination therapies that demonstrate enhanced efficacy.
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Affiliation(s)
- Nazmul Hasan
- University of California Irvine School of Medicine, Orange, CA, USA
| | - Misako Nagasaka
- University of California Irvine School of Medicine, Orange, CA, USA
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Lim JU, Jung J, Kim YW, Kim CY, Lee SH, Park DW, Choi SI, Ji W, Yeo CD, Lee SH. Targeting the Tumor Microenvironment in EGFR-Mutant Lung Cancer: Opportunities and Challenges. Biomedicines 2025; 13:470. [PMID: 40002883 PMCID: PMC11852785 DOI: 10.3390/biomedicines13020470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/11/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have transformed the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. However, treatment resistance remains a major challenge in clinical practice. The tumor microenvironment (TME) is a complex system composed of tumor cells, immune and non-immune cells, and non-cellular components. Evidence indicates that dynamic changes in TME during TKI treatment are associated with the development of resistance. Research has focused on identifying how each component of the TME interacts with tumors and TKIs to understand therapeutic targets that could address TKI resistance. In this review, we describe how TME components, such as immune cells, fibroblasts, blood vessels, immune checkpoint proteins, and cytokines, interact with EGFR-mutant tumors and how they can promote resistance to TKIs. Furthermore, we discuss potential strategies targeting TME as a novel therapeutic approach.
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Affiliation(s)
- Jeong Uk Lim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Junyang Jung
- Department of Anatomy and Neurobiology, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Yeon Wook Kim
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Chi Young Kim
- Division of Pulmonology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Sang Hoon Lee
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Institute of Chest Diseases, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Dong Won Park
- Division of Pulmonary Medicine and Allergy, Department of Internal Medicine, Hanyang University College of Medicine, Seoul 04763, Republic of Korea;
| | - Sue In Choi
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Korea University College of Medicine, Seoul 02841, Republic of Korea
| | - Wonjun Ji
- Division of Pulmonology and Critical Care Medicine, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul 44610, Republic of Korea
| | - Chang Dong Yeo
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03083, Republic of Korea
| | - Seung Hyeun Lee
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
- Department of Precision Medicine, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea
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Nicoś M, Sroka-Bartnicka A, Kalinka E, Krawczyk P. Possibilities of Overcoming Resistance to Osimertinib in NSCLC Patients with Mutations in the EGFR Gene. Cancers (Basel) 2025; 17:563. [PMID: 40002158 PMCID: PMC11852969 DOI: 10.3390/cancers17040563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 02/04/2025] [Accepted: 02/05/2025] [Indexed: 02/27/2025] Open
Abstract
The advancement of genetic research has changed the treatment management of non-small cell lung cancer (NSCLC) and opened the era of personalized medicine. Currently, three generations of EGFR tyrosine kinase inhibitors (TKIs) are used in the treatment of NSCLC patients with activating mutations in the EGFR gene, and ongoing clinical trials examine the safety and effectiveness of new third and fourth generations. Osimertinib, a third generation of TKIs that binds irreversibly to abnormal tyrosine kinase, may be applied in various indications in patients with NSCLC: (i) in the second and subsequent lines of therapy in patients with resistance to first-generation or second-generation EGFR TKIs, (ii) in the first line of treatment in monotherapy in NSCLC patients with frequent or rare EGFR mutations, (iii) in combination with chemotherapy in patients with locally advanced or metastatic NSCLC with frequent EGFR mutations, (iv) in consolidation therapy in patients with locally advanced NSCLC who had previously received chemoradiotherapy, (v) in adjuvant treatment of NSCLC patients with stage IB-IIIA undergoing radical surgical resection. Despite the high efficacy of osimertinib in NSCLC patients harboring EGFR mutations, resistance driven in EGFR-dependent or EGFR-independent mechanisms may occur. Since resistance to osimertinib is poorly understood, the following review presents the overview of resistance mechanisms to osimertinib, methodological approaches for the resistance diagnosis, and the up-to-date treatment possibilities for overcoming the resistance process.
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Affiliation(s)
- Marcin Nicoś
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-059 Lublin, Poland;
| | - Anna Sroka-Bartnicka
- Independent Unit of Spectroscopy and Chemical Imaging, Medical University of Lublin, 20-059 Lublin, Poland;
| | - Ewa Kalinka
- Department of Oncology, Polish Mother’s Memorial Hospital-Research Institute, 93-338 Lodz, Poland;
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-059 Lublin, Poland;
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Zhang J, Li W. Real-world pharmacovigilance analysis unveils the toxicity profile of amivantamab targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. BMC Pulm Med 2025; 25:63. [PMID: 39915804 PMCID: PMC11800505 DOI: 10.1186/s12890-025-03509-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 01/20/2025] [Indexed: 02/11/2025] Open
Abstract
BACKGROUND While clinical trials have demonstrated enduring responses to amivantamab among advanced non-small cell lung cancer (NSCLC) patients bearing EGFR exon 20 insertion mutations, the associated toxicity profile in real-world scenarios remains elusive. METHODS This pharmacovigilance study analyzed data from the FDA Adverse Event Reporting System (FAERS) to investigate adverse events associated with amivantamab over the period from September 2021 to December 2023. A comprehensive disproportionality analysis was performed, employing the reporting odds ratio (ROR), proportional reporting ratio (PRR), Empirical Bayes Geometric Mean (EBGM), and the Bayesian confidence propagation neural network to calculate information components (ICs), to identify statistically significant adverse events. RESULTS A significant proportion of adverse events (AEs) was attributable to injury, poisoning, and procedural complications, cutaneous disorders, respiratory ailments, infections, as well as vascular and lymphatic system disturbances. There were noteworthy incidences of AEs including infusion-related reactions, rash, dyspnea, pneumonitis, paronychia, pulmonary embolism, thrombocytopenia, nausea, acneiform dermatitis, deep vein thrombosis, febrile neutropenia, peripheral edema, hypokalemia, and neutropenia. Furthermore, the majority of AEs occurred within the first month following the initiation of amivantamab treatment, accounting for 51.74% of cases. CONCLUSION The reversibility of amivantamab-related toxicities suggests its promising utility in patients with EGFR exon 20 insertion mutations NSCLC.
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Affiliation(s)
- Jing Zhang
- The Second Department of Infectious Disease, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
- Center of Community-Based Health Research, Fudan University, 801 Heqing Road, Shanghai, China.
| | - Wenjie Li
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.
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