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Kawachi H, Yamada T, Tamiya M, Negi Y, Kijima T, Goto Y, Nakao A, Shiotsu S, Tanimura K, Takeda T, Okada A, Harada T, Date K, Chihara Y, Hasegawa I, Tamiya N, Katayama Y, Nishioka N, Morimoto K, Iwasaku M, Tokuda S, Shimose T, Takayama K. Clinical impact of cancer cachexia on the outcome of patients with non-small cell lung cancer with PD-L1 tumor proportion scores of ≥50% receiving pembrolizumab monotherapy versus immune checkpoint inhibitor with chemotherapy. Oncoimmunology 2025; 14:2442116. [PMID: 39681395 PMCID: PMC11651275 DOI: 10.1080/2162402x.2024.2442116] [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: 05/21/2024] [Revised: 12/09/2024] [Accepted: 12/10/2024] [Indexed: 12/18/2024] Open
Abstract
This retrospective, multicenter cohort study aimed to determine whether cancer cachexia serves as a biomarker for determining the most effective treatment for patients having non-small-cell lung cancer (NSCLC) with high programmed death ligand 1 (PD-L1) expression treated with immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy (ICI/chemotherapy). We included 411 patients with advanced NSCLC with a PD-L1 tumor proportion score of ≥50%. The patients were treated with pembrolizumab monotherapy or ICI/chemotherapy. Cancer cachexia was defined as a weight loss of >5% of the total body weight or a body mass index of <20 kg/m2 coupled with an additional weight loss of >2% within 6 months before starting treatment. Eighty-five (21%) patients met the cancer cachexia criteria. Overall survival (OS) was significantly shorter in patients with cachexia than in those without cachexia in both the pembrolizumab monotherapy group (17.2 vs. 35.8 months, p < 0.001) and the ICI/chemotherapy group (27.0 months vs. not reached, p = 0.044). However, after stratifying by cancer cachexia status, no significant difference in OS was observed between the pembrolizumab monotherapy and chemoimmunotherapy groups, regardless of cachexia. In conclusion, ICI/chemotherapy offers limited benefits for NSCLC patients with high PD-L1 expression and concurrent cancer cachexia. Considering the frailty associated with cachexia, ICI monotherapy may be preferred to ICI/chemotherapy for these patients. New interventions that can better address the negative prognostic impact of cachexia in patients treated using ICIs with or without chemotherapy remain warranted.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/complications
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/pathology
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Cachexia/etiology
- Male
- Female
- Lung Neoplasms/drug therapy
- Lung Neoplasms/complications
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Aged
- Middle Aged
- Immune Checkpoint Inhibitors/therapeutic use
- Immune Checkpoint Inhibitors/adverse effects
- Immune Checkpoint Inhibitors/administration & dosage
- Retrospective Studies
- B7-H1 Antigen/antagonists & inhibitors
- B7-H1 Antigen/metabolism
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Aged, 80 and over
- Adult
- Prognosis
- Treatment Outcome
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Affiliation(s)
- Hayato Kawachi
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Tadaaki Yamada
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Motohiro Tamiya
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Osaka, Japan
| | - Yoshiki Negi
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Takashi Kijima
- Department of Respiratory Medicine and Hematology, School of Medicine, Hyogo Medical University, Nishinomiya, Hyogo, Japan
| | - Yasuhiro Goto
- Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan
| | - Akira Nakao
- Department of Respiratory Medicine, Fukuoka University Hospital, Fukuoka, Fukuoka, Japan
| | - Shinsuke Shiotsu
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Kyoto, Japan
| | - Keiko Tanimura
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Takayuki Takeda
- Department of Respiratory Medicine, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Kyoto, Japan
| | - Asuka Okada
- Department of Respiratory Medicine, Saiseikai Suita Hospital, Suita, Osaka, Japan
| | - Taishi Harada
- Department of Medical Oncology, Fukuchiyama City Hospital, Fukuchiyama, Kyoto, Japan
| | - Koji Date
- Department of Pulmonary Medicine, Kyoto Chubu Medical Center, Kyoto, Japan
| | - Yusuke Chihara
- Department of Respiratory Medicine, Uji-Tokushukai Medical Center, Uji, Kyoto, Japan
| | - Isao Hasegawa
- Department of Respiratory Medicine, Saiseikai Shigaken Hospital, Shiga, Japan
| | - Nobuyo Tamiya
- Department of Respiratory Medicine, Rakuwakai Otowa Hospital, Kyoto, Kyoto, Japan
| | - Yuki Katayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Naoya Nishioka
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Kenji Morimoto
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Masahiro Iwasaku
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Shinsaku Tokuda
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
| | - Takayuki Shimose
- Department of Statistics and Data Center, Clinical Research Support Center Kyushu, Fukuoka, Japan
| | - Koichi Takayama
- Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Kyoto, Japan
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Tang LB, Peng YL, Chen J, Li JT, Zheng MM, Wu L, Lu C, Wei XW, Cai DX, Guo Z, Ren ZR, Lv SD, Deng Y, Chen ZH, Xu CR, Zhou Q. Rechallenge with immune-checkpoint inhibitors in patients with advanced-stage lung cancer. Nat Rev Clin Oncol 2025:10.1038/s41571-025-01029-7. [PMID: 40490476 DOI: 10.1038/s41571-025-01029-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2025] [Indexed: 06/11/2025]
Abstract
Lung cancer remains the leading cause of cancer-related mortality globally, with many patients diagnosed with advanced-stage disease. Treatment in this setting relies on systemic therapies, including chemotherapy, targeted therapy and immunotherapy. Immune-checkpoint inhibitors (ICIs), which promote or restore antitumour immunity by inhibiting immunosuppressive signalling pathways, are currently the most widely used immunotherapies in these patients. However, immune-related adverse events (irAEs) or disease progression often necessitate discontinuation of these agents, leaving many patients with limited subsequent treatment options. In this scenario, ICI rechallenge has emerged as a potential strategy. Despite this potential, evidence for ICI rechallenge after either disease progression or irAEs in patients with non-small-cell lung cancer is limited and evidence for those with small cell lung cancer seems to be non-existent. In this Review, we provide a comprehensive overview of the available data on ICI rechallenge in the context of both disease progression and irAEs, including a summary of current guidance on clinical management and detailed discussions of safety and efficacy. We also highlight important unanswered questions in an attempt to guide future research in this area.
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Affiliation(s)
- Li-Bo Tang
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Ying-Long Peng
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Ji Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Jia-Ting Li
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
- Shantou University Medical College, Shantou, China
| | - Mei-Mei Zheng
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Lv Wu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Chang Lu
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xue-Wu Wei
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Dong-Xuan Cai
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zhi Guo
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zi-Rui Ren
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Si-Di Lv
- School of Art, Soochow University, Suzhou, China
| | - Yu Deng
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Zhi-Hong Chen
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Chong-Rui Xu
- School of Medicine, South China University of Technology, Guangzhou, China
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Qing Zhou
- School of Medicine, South China University of Technology, Guangzhou, China.
- Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.
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Stadler R, Roccuzzo G, Ortiz-Romero P, Bagot M, Quaglino P, Guenova E, Jonak C, Papadavid E, Stranzenbach R, Marreaud S, Musoro J, Casas-Martin J, Murray D, Drennan S, Hear JV, Moss P, Sartori D, Battistella M, Willemze R, Scarisbrick J, Knobler R. Phase II trial of atezolizumab (Anti-PD-L1) in the treatment of relapsed/refractory IIB/IVB mycosis fungoides/Sézary syndrome patients after previous systemic treatment. EORTC-1652-CLTG "PARCT". Eur J Cancer 2025; 222:115484. [PMID: 40319676 DOI: 10.1016/j.ejca.2025.115484] [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: 12/09/2024] [Revised: 01/29/2025] [Accepted: 04/25/2025] [Indexed: 05/07/2025]
Abstract
INTRODUCTION Treatment of advanced mycosis fungoides (MF) and Sézary syndrome (SS) is a challenge. In this international, multicenter, open-label phase II trial, we assessed the efficacy and safety of anti-PD-L1 atezolizumab in stage IIB-IV refractory/relapsed MF and SS. MATERIALS AND METHODS Patients received atezolizumab 1200 mg IV Q3w for up to 1 year unless progression or withdrawal. The main study endpoints were overall response rate (ORR), progression-free survival (PFS), time to next systemic treatment (TTNT), and overall survival (OS). RESULTS A total of 26 patients were enrolled from seven countries. Seventeen patients met the inclusion criteria. At a median follow-up of 36.6 months, the ORR was 15.4 % in the intention to treat (ITT) and 17.6 % in the per protocol (PP) population, respectively. In the PP group, 58.8 % of patients, and in the ITT group, 53.9 % of patients achieved partial response or stable disease as their best outcome. One complete response was observed after 1 year. Median PFS was 3 months (95 % CI 1.4-4.9) in PP and 3.1 months (95 % CI 2.4-4.0) in ITT. Median OS was not reached for PP and was 22.3 months (20.0-NE) for ITT. Median TTNT was 5.9 months (2.8-NE) in PP and 6.2 months (3.1-14.8) in ITT. The most common grade ≥ 3 adverse events were fatigue (23.1 %) and infections (15.4 %), with two sepsis-related deaths. Atezolizumab was primarily discontinued due to disease progression (50 %). CONCLUSIONS Atezolizumab shows moderate activity in pretreated refractory/relapsed MF and SS. Further studies are needed to identify reliable predictors of safety and treatment response.
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Affiliation(s)
- Rudolf Stadler
- University Clinic for Dermatology, Ruhr University of Bochum, Minden, Germany.
| | - Gabriele Roccuzzo
- Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy.
| | - Pablo Ortiz-Romero
- Department of Dermatology, Hospital Universitario 12 de Octubre, Institute i+ 12, University Complutense, Madrid, Spain
| | - Martine Bagot
- Department of Dermatology, Hôpital Saint-Louis, Université Paris Cité, Paris, France
| | - Pietro Quaglino
- Department of Medical Sciences, Section of Dermatology, University of Turin, Turin, Italy
| | - Emmanuella Guenova
- Department of Dermatology, Lausanne University Hospital (CHUV) and Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland; University Institute and Clinic for Immunodermatology, Medical Faculty, Johannes Kepler University, Linz, Austria
| | - Constanze Jonak
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Evangelia Papadavid
- Second Department of Dermatology, National and Kapodistrian University of Athens, Athens, Greece
| | - René Stranzenbach
- Department of Dermatology, St. Josef Hospital, UK RUB, Bochum, Germany
| | | | | | | | - Duncan Murray
- Department of Haematology, University Hospitals Coventry and Warwickshire and Institute of Immunology and Immunotherapy, University of Birmingham, United Kingdom
| | - Samantha Drennan
- Department of Immunology and Immunotherapy, College of Medicine and Health, University of Birmingham, United Kingdom
| | - Jimmy Van Hear
- Department of Immunology and Immunotherapy, College of Medicine and Health, University of Birmingham, United Kingdom
| | - Paul Moss
- Department of Immunology and Immunotherapy, College of Medicine and Health, University of Birmingham, United Kingdom
| | | | - Maxime Battistella
- Department of Pathology, Hôpital Saint-Louis, AP-HP, Université Paris Cité, Inserm U976, Paris, France
| | - Rein Willemze
- Department of Dermatology, Leiden University Medical Center, the Netherlands
| | - Julia Scarisbrick
- Department of Dermatology, University Hospital Birmingham, Birmingham, United Kingdom
| | - Robert Knobler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
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4
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Xu H, Fu X, Wang S, Ge Y, Zhang L, Li J, Zhang F, Yang Y, He Y, Sun Y, Gao A. Immunoglobulin-like transcript 5 polarizes M2-like tumor-associated macrophages for immunosuppression in non-small cell lung cancer. Int J Cancer 2025; 156:2225-2236. [PMID: 39910654 PMCID: PMC11970544 DOI: 10.1002/ijc.35360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 11/28/2024] [Accepted: 12/04/2024] [Indexed: 02/07/2025]
Abstract
Immune checkpoint inhibitors (ICIs) have shifted the treatment paradigm of non-small cell lung cancer (NSCLC) over the last decade. Despite notable therapeutic advancements in responders, the response rate remains limited owing to the immunosuppressive tumor microenvironment (TME). Therefore, to improve the efficacy of ICIs, it is essential to explore alternative targets or signals that mediate immunosuppression. Immunoglobulin-like transcript (ILT) 5 is a negative regulator of immune activation in myeloid cells. However, the expression and function of ILT5 in NSCLC remain unknown. Here, we found that ILT5 was highly expressed in tumor-associated macrophages (TAMs) of NSCLC tissues and predicted poor patient survival. Functionally, ILT5 induces the M2-like polarization of TAMs, which subsequently decreases the density of T cells, and increases FOXP3+T cell accumulation, leading to an immunosuppressive TME. The combination of ILT5 expression with M2-like TAM density is a more reliable biomarker of patient survival than ILT5 expression alone. ILT5 knockout mitigates the reprogramming of TAM and T cell subsets toward immunosuppressive phenotypes and inhibits tumor growth in vivo. These findings highlight that ILT5 is a potential immunotherapeutic target and a promising prognostic biomarker for NSCLC.
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Affiliation(s)
- Huijun Xu
- Jinan Central HospitalShandong UniversityJinanShandongChina
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Xuebing Fu
- Department of Thoracic Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Shuyun Wang
- Phase I Clinical Research Center, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Yihui Ge
- Phase I Clinical Research Center, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Lu Zhang
- Department of OncologyThe Fourth People's Hospital of ZiboZiboShandongChina
| | - Juan Li
- Phase I Clinical Research Center, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Fang Zhang
- Department of OncologyCentral Hospital affiliated to Shandong First Medical UniversityJinanShandongChina
| | - Yang Yang
- Department of Ultrasound, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Yifu He
- Department of Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and MedicineUniversity of Science and Technology of ChinaHefeiAnhuiChina
| | - Yuping Sun
- Phase I Clinical Research Center, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
| | - Aiqin Gao
- Department of Thoracic Radiation Oncology, Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical SciencesJinanShandongChina
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Wilson K, Salvador Flores Banda J, Raza F, Bukkapatnam S, Gangane S, Massarelli E. TREATING KRAS G12C LUNG CANCER: THERAPEUTIC POTENTIAL of INVESTIGATION DRUGS in EARLY CLINICAL STUDY. Expert Opin Investig Drugs 2025:1-13. [PMID: 40448535 DOI: 10.1080/13543784.2025.2511175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Accepted: 05/16/2025] [Indexed: 06/02/2025]
Abstract
INTRODUCTION The KRAS (Kirsten rat sarcoma viral oncogene homolog) gene is recognized as the most frequently mutated oncogene in advanced non-small cell lung cancer (NSCLC). The most prevalent mutation within this gene is G12C, formally known as KRAS G12C, which leads to the substitution of glycine with cysteine at position 12 of the KRAS protein [6]. AREAS COVERED Recent advancements in research have developed effective therapies designed to inhibit activated KRAS signaling. As a result, the first two accelerated FDA-approved KRAS inhibitors, sotorasib and adagrasib, have been successfully introduced to the market for locally advanced or metastatic KRAS G12C-mutated NSCLC who progressed after prior therapy. A second generation of KRAS inhibitors is currently being tested in clinical trials, and in combination with immunotherapy and chemotherapy. EXPERT OPINION Future research is crucial to determine the optimal timing for treatment with KRAS G12C inhibitors. Additional studies are needed to identify biomarkers that predict which patients will benefit most. This review discusses and analyzes both completed and ongoing clinical trials of first and second generation KRAS inhibitors. It also addresses mechanisms of resistance to KRAS inhibition, potential therapeutic strategies to overcome this resistance, biomarkers, side effects, and its role in central nervous system metastatic disease.
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Affiliation(s)
- Kendra Wilson
- Department of Medicine, University of Texas at Tyler School of Medicine, Tyler, TX, USA
| | | | - Fatima Raza
- Department of Medicine, University of Texas at Tyler School of Medicine, Tyler, TX, USA
| | - Sanjana Bukkapatnam
- Department of Medicine, University of Texas at Tyler School of Medicine, Tyler, TX, USA
| | - Sanjana Gangane
- Department of Medicine, University of Texas at Tyler School of Medicine, Tyler, TX, USA
| | - Erminia Massarelli
- Department of Medicine, University of Texas at Tyler School of Medicine, Tyler, TX, USA
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6
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Lara B, Snyder M, Fimbres J, Yang E, Song G, Duggineni VK, Wang Z, Sherr DH. The AhR regulates IFN-induced immune checkpoints in lung cancer cells through HNRNPH1, an RNA-binding protein, and INCR1, a novel long non-coding RNA. J Biol Chem 2025:110316. [PMID: 40449595 DOI: 10.1016/j.jbc.2025.110316] [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: 11/26/2024] [Revised: 04/28/2025] [Accepted: 05/17/2025] [Indexed: 06/03/2025] Open
Abstract
Although immune checkpoint inhibitors show great promise, not all patients respond and many do not achieve durable responses. Consequently, further investigations into potentially targetable molecules that regulate immune checkpoints are warranted. Previous studies in several cancers demonstrated that interferons produced by tumor-infiltrating leukocytes regulate immunosuppressive PD-L1, PD-L2 and IDO1 through JAK/STAT signaling. Here, we investigated a novel role for an immunosuppressive environmental chemical receptor, previously implicated in smoking-related cancers, in IFN signaling in human lung adenocarcinoma (LUAD) cells. Deletion of the aryl hydrocarbon receptor (AhR) from A549 LUAD cells significantly decreased baseline JAK2, STAT1, STAT3, IRF1 (a JAK/STAT target), PD-L1, PD-L2, and IDO1 expression. IFNγ and IFNα increased expression of JAK/STAT and immune checkpoint genes and proteins, but these increases were significantly diminished or absent in AhR-knockout cells. The AhR similarly controls IFN-induced, JAK/STAT-driven increases in multiple MHC class I- and class II-related genes. AhR control of type I and type II interferon signaling is mediated through up-regulation of a lncRNA, the IFN-stimulated non-coding RNA 1 (INCR1), and through repression of an RNA-binding protein, heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1), which sequesters JAK/STAT-related and immune checkpoint gene transcripts. The data suggest that the AhR is a key mediator of tumor immunosuppression through regulation of IFN-induced INCR1 and JAK/STAT signaling and, thereby, expression of immune checkpoints. However, that immunosuppression may be tempered by AhR control of MHC expression. Given the multiple roles of JAK/STAT signaling in the immune system, the results also suggest multiple levels on which the AhR may affect tumor immunity.
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Affiliation(s)
- Brian Lara
- Department of Environmental Health, Boston University School of Public Health
| | | | - Jocelyn Fimbres
- Department of Environmental Health, Boston University School of Public Health
| | - Eric Yang
- Department of Environmental Health, Boston University School of Public Health
| | - Gang Song
- Department of Environmental Health, Boston University School of Public Health
| | | | - Zhongyan Wang
- Department of Environmental Health, Boston University School of Public Health
| | - David H Sherr
- Department of Environmental Health, Boston University School of Public Health.
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Zheng T, Li X, Zhou L, Jin J. Predictive value of machine learning for PD-L1 expression in NSCLC: a systematic review and meta-analysis. World J Surg Oncol 2025; 23:199. [PMID: 40405177 PMCID: PMC12101016 DOI: 10.1186/s12957-025-03847-6] [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: 02/24/2025] [Accepted: 05/11/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND As machine learning (ML) continuously develops in cancer diagnosis and treatment, some researchers have attempted to predict the expression of programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) by ML. However, there is a lack of systematic evidence on the effectiveness of ML. METHODS We conducted a thorough search across Embase, PubMed, the Cochrane Library, and Web of Science from inception to December 14th, 2023.A systematic review and meta-analysis was conducted to assess the value of ML for predicting PD-L1 expression in NSCLC. RESULTS Totally 30 studies with 12,898 NSCLC patients were included. The thresholds of PD-L1 expression level were < 1%, 1-49%, and ≥ 50%. In the validation set, in the binary classification for PD-L1 ≥ 1%, the pooled C-index was 0.646 (95%CI: 0.587-0.705), 0.799 (95%CI: 0.782-0.817), 0.806 (95%CI: 0.753-0.858), and 0.800 (95%CI: 0.717-0.883), respectively, for the clinical feature-, radiomics-, radiomics + clinical feature-, and pathomics-based ML models; in the binary classification for PD-L1 ≥ 50%, the pooled C-index was 0.649 (95%CI: 0.553-0.744), 0.771 (95%CI: 0.728-0.814), and 0.826 (95%CI: 0.783-0.869), respectively, for the clinical feature-, radiomics-, and radiomics + clinical feature-based ML models. CONCLUSIONS At present, radiomics- or pathomics-based ML methods are applied for the prediction of PD-L1 expression in NSCLC, which both achieve satisfactory accuracy. In particular, the radiomics-based ML method seems to have wider clinical applicability as a non-invasive diagnostic tool. Both radiomics and pathomics serve as processing methods for medical images. In the future, we expect to develop medical image-based DL methods for intelligently predicting PD-L1 expression.
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Affiliation(s)
- Ting Zheng
- Department of Medical Oncology, The First People's Hospital of Linping District, Hangzhou, 311100, Zhejiang Province, China.
| | - Xingxing Li
- Department of Medical Oncology, The First People's Hospital of Linping District, Hangzhou, 311100, Zhejiang Province, China
| | - Li Zhou
- Department of Medical Oncology, The First People's Hospital of Linping District, Hangzhou, 311100, Zhejiang Province, China
| | - Jianjiang Jin
- Department of Medical Oncology, The First People's Hospital of Linping District, Hangzhou, 311100, Zhejiang Province, China
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8
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Srivastava MK, Zou W, McCleland M, Roder J, Asmellash S, Norman P, Net L, Maguire L, Roder H, Georgantas R, Shames DS. Development and validation of a serum proteomic test for predicting patient outcomes in advanced non-small cell lung cancer treated with atezolizumab or docetaxel. J Immunother Cancer 2025; 13:e010578. [PMID: 40404206 PMCID: PMC12096988 DOI: 10.1136/jitc-2024-010578] [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: 11/11/2024] [Accepted: 04/08/2025] [Indexed: 05/24/2025] Open
Abstract
BACKGROUND Programmed cell death-ligand 1 (PD-L1) expression is used in treatment decision-making for patients with advanced non-small cell lung cancer, determining if immune checkpoint inhibitors (ICI) are recommended. Patient selection for ICI treatment can be improved by incorporating the host response. We developed and carried out multiple independent validations of a blood-based test designed to stratify outcomes for patients treated with atezolizumab. METHODS A mass spectrometry-based test was developed from a cohort of patients treated with atezolizumab and validated in two clinical trials (n=269, 823) comparing atezolizumab with docetaxel. The test classifies patients as Good or Poor indicating better or worse outcomes, respectively. The prognostic and predictive power of the test was assessed and evaluated within PD-L1 subgroups. Protein enrichment methods were used to investigate the association of test classification with biological processes. RESULTS Approximately 50% of patients were assigned to each classification in all three cohorts. When treated with atezolizumab, the Good subgroup had superior outcomes in all cohorts. Overall survival (OS) HR (95% CI) for Good patients in each cohort was: 0.23 (0.12 to 0.44), 0.32 (0.21 to 0.51), and 0.52 (0.41 to 0.66) and persisted in all PD-L1 subgroups. The test was predictive of differential OS and progression-free survival in one cohort, but not in the other. Enrichment techniques indicated the test was associated with acute inflammatory response, acute phase response, and complement activation. CONCLUSIONS Aspects of host immune response to disease can be assessed from the circulating proteome and provide outcome stratification for patients treated with atezolizumab. Combining this information with PD-L1 measurements improves prediction of outcomes.
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Affiliation(s)
- Minu K Srivastava
- Translational Medicine, Genentech, South San Francisco, California, USA
| | - Wei Zou
- Department of Biostatistics Oncology, Genentech, South San Francisco, California, USA
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9
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Tanaka S, Nozaki K, Watanabe S, Yanagimura N, Arita M, Sato M, Tanaka T, Saida Y, Goto Y, Kushiro K, Fujisaki T, Sato K, Ishikawa D, Miyabayashi T, Ichikawa K, Ota T, Hayashi Y, Koyama K, Ishida A, Kikuchi T. Risk of lung injury with immune checkpoint inhibitors after talc pleurodesis: A retrospective study. Lung Cancer 2025; 204:108590. [PMID: 40412103 DOI: 10.1016/j.lungcan.2025.108590] [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: 04/02/2025] [Accepted: 05/20/2025] [Indexed: 05/27/2025]
Abstract
INTRODUCTION The safety of administering immune checkpoint inhibitors (ICIs) after talc pleurodesis, particularly the impact of talc on the development of immune-related interstitial lung disease (ILD), remains unclear. METHODS We retrospectively analysed patients with primary lung cancer or malignant pleural mesothelioma who received ICIs within 90 days of talc pleurodesis at facilities participating in the Niigata Lung Cancer Treatment Study Group between November 2016 and June 2023. RESULTS A total of 52 cases were included, with 17 patients (32.7 %) developing ILD following ICI administration. The median time to ILD onset after ICI administration was 62 days. The median overall survival was 6 months in patients who developed ILD and 16.4 months in those who did not (P = 0.081). Among the five patients with pre-existing interstitial changes, four (80.0 %) developed ILD after ICI administration, identifying a high-risk subgroup. CONCLUSION A high incidence of ILD was observed in patients who received ICI therapy after talc pleurodesis. Additionally, overall survival tended to be shorter in patients who developed ILD.
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Affiliation(s)
- Susumu Tanaka
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Koichiro Nozaki
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Satoshi Watanabe
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
| | - Naohiro Yanagimura
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Masashi Arita
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Miyuki Sato
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Tomohiro Tanaka
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yu Saida
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Yuka Goto
- Department of Respiratory Medicine, Saiseikai Niigata Keno Core Hospital, Niigata, Japan
| | - Kohei Kushiro
- Department of Respiratory Medicine, Kashiwazaki General Medical Center, Niigata, Japan
| | - Toshiya Fujisaki
- Department of Respiratory Medicine, Tachikawa General Hospital, Niigata, Japan
| | - Ko Sato
- Department of Respiratory Medicine, Joetsu General Hospital, Niigata, Japan
| | - Daisuke Ishikawa
- Department of Respiratory Medicine, Niigata Prefectural Central Hospital, Joetsu, Japan
| | - Takao Miyabayashi
- Department of Respiratory Medicine, Niigata City General Hospital, Niigata, Japan
| | - Kosuke Ichikawa
- Department of Respiratory Medicine, Saiseikai Niigata Hospital, Niigata, Japan
| | - Takeshi Ota
- Department of Respiratory Medicine, Niigata Prefectural Shibata Hospital, Niigata, Japan
| | - Yoshiki Hayashi
- Department of Respiratory Medicine, Nagaoka Central General Hospital, Niigata, Japan
| | - Kenichi Koyama
- Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan
| | - Akira Ishida
- Department of Respiratory Medicine, Nagaoka Red Cross Hospital, Nagaoka, Japan
| | - Toshiaki Kikuchi
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
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10
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Brune MM, Baloch Z, Bubendorf L, Savic Prince S. Diagnosing Malignant Epithelial Neoplasms of the Lung in Cytological Specimens: Cytomorphology, Ancillary Studies and Management. Cytopathology 2025. [PMID: 40400060 DOI: 10.1111/cyt.13511] [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: 03/17/2025] [Revised: 05/02/2025] [Accepted: 05/09/2025] [Indexed: 05/23/2025]
Abstract
The World Health Organization's (WHO) Reporting System for Lung Cytopathology intends to standardise the diagnosing and reporting of cytology specimens from the lung and aims at enhancing the communication between clinicians and (cyto)pathologists. It is closely connected to the 5th edition of the WHO Classification of Thoracic Tumours. The system includes five diagnostic categories, among them the 'Malignant' diagnostic category that incorporates both primary malignant tumours and metastases. Advancements in bronchoscopy have notably improved the diagnostic capacity of cytological specimens that represent the sole source of tumour material in approximately 40% of all lung carcinoma cases. An accurate diagnosis of malignancy and treatment-guiding classification into specific tumour types and subtypes can reliably be achieved with cytology specimens. They additionally serve as an excellent source for predictive immunocytochemistry (ICC) and molecular testing for targetable oncogenic alterations. This review article provides an overview of the key cytopathological features defining the 'Malignant' category of the WHO Reporting System for Lung Cytopathology for non-small cell carcinomas, neuroendocrine neoplasms and other specific carcinomas and malignancies which can be encountered in cytological specimens of the lung. It further describes the application of ancillary techniques, such as ICC and molecular testing, that have been successfully incorporated into different cytological sample types using various preparation methods.
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Affiliation(s)
- Magdalena M Brune
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Zubair Baloch
- Department of Pathology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Lukas Bubendorf
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Spasenija Savic Prince
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
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11
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Mizusaki S, Yoneshima Y, Iwama E, Nakashima T, Ibusuki R, Shibahara D, Otsubo K, Tanaka K, Okamoto I. NECTIN4 regulates the cell surface expression of CD155 in non-small cell lung cancer cells and induces tumor resistance to PD-1 inhibitors. Cancer Immunol Immunother 2025; 74:211. [PMID: 40392373 PMCID: PMC12092325 DOI: 10.1007/s00262-025-04079-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: 11/26/2024] [Accepted: 05/03/2025] [Indexed: 05/22/2025]
Abstract
The development of immune checkpoint inhibitors has changed treatment strategies for some patients with non-small cell lung cancer (NSCLC). However, resistance remains a major problem, requiring the elucidation of resistance mechanisms, which might aid the development of novel therapeutic strategies. The upregulation of CD155, a primary ligand of the immune checkpoint receptor TIGIT, has been implicated in a mechanism of resistance to PD-1/PD-L1 inhibitors, and it is therefore important to characterize the mechanisms underlying the regulation of CD155 expression in tumor cells. The aim of this study was to identify a Nectin that might regulate CD155 expression in NSCLC and affect anti-tumor immune activity. In this study, we demonstrated that NECTIN4 regulated the cell surface expression and stabilization of CD155 by interacting and co-localizing with CD155 on the cell surface. In a syngeneic mouse model, NECTIN4-overexpressing cells exhibited increased cell surface CD155 and resistance to anti-PD-1 antibodies. Of note, combination therapy with anti-PD-1 and anti-TIGIT antibodies significantly suppressed tumor growth. These findings provide new insights into the mechanisms of resistance to anti-PD-1 antibodies and suggest that NECTIN4 could serve as a valuable marker in therapeutic strategies targeting TIGIT.
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Affiliation(s)
- Shun Mizusaki
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yasuto Yoneshima
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Eiji Iwama
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Tadayuki Nakashima
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Ritsu Ibusuki
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Daisuke Shibahara
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kohei Otsubo
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kentaro Tanaka
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Isamu Okamoto
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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12
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Ji H, Zhang L, Ye L. Exosome, an important transmitter in the drug resistance of non-small cell lung cancer. Front Oncol 2025; 15:1539047. [PMID: 40444086 PMCID: PMC12119617 DOI: 10.3389/fonc.2025.1539047] [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: 12/03/2024] [Accepted: 04/28/2025] [Indexed: 06/02/2025] Open
Abstract
Recent studies have promoted new insights into the biology of non-small cell lung cancer (NSCLC) and made considerable progress in the field of treatment, including targeted therapy for driver gene mutations. Immunotherapy (IO) is another breakthrough, which has achieved amazing clinical efficacy. However, the survival status of advanced NSCLC patients is still unsatisfactory. Drug resistance is an urgent problem to be solved in almost all anti-cancer treatment schemes. Nowadays, platinum based chemotherapy remains the standard treatment for patients with driver gene negative advanced NSCLC. Previous studies have shown that the reduction of intracellular accumulation of platinum drugs, DNA damage repair and the enhancement of detoxification effect all lead to platinum resistance. The mechanisms of tyrosine kinase inhibitors (TKIs) resistance include the emergence of secondary mutation, the activation of bypass signal pathways, the abnormality of downstream signal pathways and the transformation of phenotype. The mechanisms of immune checkpoint inhibitors (ICIs) resistance are more complex. A variety of cells, cytokines and metabolites participate in it to form an immunosuppressive microenvironment, resulting in the impairment of effector T cell function. Exosomes are small molecules secreted by a variety of cells. They can carry information such as miRNA, lncRNA, and protein, and play a pivotal role in signal transduction between cells. More and more studies show that exosomes are important transmitters in lung cancer cells, which can transfer drug resistance information from drug-resistant cells to sensitive cells. However, the underling specific mechanisms need to be further explored to find a new breakthrough for overcoming drug resistance of NSCLC.
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Affiliation(s)
- Hongzhi Ji
- Department of Respiratory, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Li Zhang
- Department of Gastroenterology, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China
| | - Lingyun Ye
- Department of Oncology, Shanghai Pulmonary Hospital & Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
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13
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Kilickap S, Özgüroğlu M, Sezer A, Gümüş M, Bondarenko I, Gogishvili M, Turk HM, Cicin I, Bentsion D, Gladkov O, Sriuranpong V, Quek RGW, McIntyre DAG, He X, McGinniss J, Seebach F, Gullo G, Rietschel P, Pouliot J. Cemiplimab monotherapy as first-line treatment of patients with brain metastases from advanced non-small cell lung cancer with programmed cell death-ligand 1 ≥50. Cancer 2025; 131:e35864. [PMID: 40323717 PMCID: PMC12051739 DOI: 10.1002/cncr.35864] [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: 08/16/2024] [Revised: 02/13/2025] [Accepted: 02/20/2025] [Indexed: 05/07/2025]
Abstract
BACKGROUND In the phase 3 EMPOWER-Lung 1 study, first-line cemiplimab monotherapy provided significant survival benefit versus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥50%. This exploratory subgroup analysis investigated the clinical outcomes of cemiplimab treatment in patients with advanced NSCLC with brain metastases. METHODS Patients with advanced NSCLC were randomized (1:1) to cemiplimab 350 mg every 3 weeks or four cycles of platinum doublet chemotherapy (NCT03088540). Patients with symptomatic radiotherapy-treated brain metastases were eligible to enroll. Of the 565 patients with confirmed PD-L1 expression ≥50%, 69 (12%) had brain metastases at baseline. RESULTS Patients with brain metastases who received cemiplimab had a median overall survival (OS) of 52.4 months compared with 20.7 months for those who received chemotherapy (hazard ratio [HR], 0.40; p = .0031) and a median progression-free survival (PFS) of 12.5 versus 5.3 months (HR, 0.33; p = .0002), respectively. Patients without brain metastases had a median OS of 24.3 months with cemiplimab versus 12.5 months with chemotherapy (HR, 0.63; p < .0001); their median PFS was 6.5 months versus 5.2 months (HR, 0.55; p < .0001), respectively. Cemiplimab was associated with a significant improvement in global health status/quality of life in all patients, including those with brain metastases. The cemiplimab safety profile was generally similar in all patients. CONCLUSIONS In patients with advanced NSCLC with PD-L1 ≥50%, first-line cemiplimab monotherapy improved survival and patient-reported outcomes over chemotherapy for those who received prior radiotherapy for symptomatic brain metastases.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/pathology
- Brain Neoplasms/secondary
- Brain Neoplasms/drug therapy
- Brain Neoplasms/mortality
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Female
- Lung Neoplasms/pathology
- Lung Neoplasms/drug therapy
- Lung Neoplasms/mortality
- Male
- Middle Aged
- B7-H1 Antigen/metabolism
- Aged
- Adult
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Aged, 80 and over
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
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Affiliation(s)
- Saadettin Kilickap
- Department of Medical OncologyIstinye University Faculty of MedicineIstanbulTurkey
| | - Mustafa Özgüroğlu
- Cerrahpaşa Medical FacultyIstanbul University‐CerrahpaşaIstanbulTurkey
| | - Ahmet Sezer
- Department of Medical OncologyBaşkent UniversityAdanaTurkey
| | - Mahmut Gümüş
- Department of Medical OncologySchool of MedicineIstanbul Medeniyet UniversityIstanbulTurkey
| | - Igor Bondarenko
- Department of Oncology and Medical RadiologyDnipropetrovsk Medical AcademyDniproUkraine
| | | | - Haci M. Turk
- Department of Medical OncologyBezmialem Vakif University, Medical FacultyIstanbulTurkey
| | - Irfan Cicin
- Istinya University Faculty of Medicine, Florya Medical Park HospitalIstanbulTurkey
| | - Dmitry Bentsion
- Radiotherapy DepartmentSverdlovsk Regional Oncology CentreSverdlovskRussia
| | | | - Virote Sriuranpong
- Division of Medical OncologyDepartment of MedicineFaculty of MedicineChulalongkorn University and the King Chulalongkorn Memorial HospitalBangkokThailand
| | | | | | - Xuanyao He
- Regeneron Pharmaceuticals, IncTarrytownNew YorkUSA
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14
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Wu Y, Wang H, Gu Y, Zhang Y, Li G, Huang Y, Cao M, Chen X, Guan Y, Xu D, Wei W, Xie F. Head-to-head comparison of peptide-based and nanobody-based radiotracers in detecting PD-L1 expression in non-small cell lung cancer. Eur J Nucl Med Mol Imaging 2025:10.1007/s00259-025-07316-w. [PMID: 40338301 DOI: 10.1007/s00259-025-07316-w] [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: 12/30/2024] [Accepted: 04/24/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND Immunotherapy based on programmed cell death protein receptor 1 and its ligand (PD-1/PD-L1) has become an important method for treating non-small cell lung cancer (NSCLC). Peptide-based and nanobody-based PET tracers offer potential advantages in PD-L1 detection, yet their comparative tumor uptake and biodistribution remain unclear. This study aimed to evaluate and compare [68Ga]Ga-DOTA-WL12 (a peptide-based tracer) and [68Ga]Ga-NOTA-RW102 (a nanobody-based tracer) in assessing PD-L1 expression in primary and metastatic NSCLC, providing insights for future radiotracer design and theranostic applications. METHODS Ten patients diagnosed with NSCLC underwent [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 PET/CT scans, with four of these patients also receiving [18F]FDG PET/CT scans. The tracer uptakes, quantified by maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), and target-to-background ratio (TBR), were compared between [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 PET/CT. RESULTS DOTA-WL12 and NOTA-RW102 exhibited favorable binding affinities with PD-L1, with equilibrium dissociation constant (KD) values of 0.2 nM and 0.0047 nM, respectively. Subsequent human studies revealed significant variations (P < 0.05) in the uptake of [68Ga]Ga-DOTA-WL12 and [68Ga]Ga-NOTA-RW102 across the liver (SUVmean: 20.43 ± 4.26 vs. 6.12 ± 1.36, p = 0.015), kidney (SUVmean: 2.40 ± 0.34 vs. 22.37 ± 2.88, P = 0.015), spleen (SUVmean: 2.44 ± 0.67 vs. 18.49 ± 3.90, P = 0.015), and lung background (SUVmean: 0.18 ± 0.12 vs. 1.09 ± 0.29, P = 0.015). Meanwhile, we found that the correlation between SUVmax and PD-L1 TPS was significantly stronger with [68Ga]Ga-DOTA-WL12 compared to [68Ga]Ga-NOTA-RW102 (P < 0.0001, r = 0.9471 vs. P = 0.0241, r = 0.5235). CONCLUSION The uptake of peptide-based [68Ga]Ga-DOTA-WL12 was more strongly correlated with PD-L1 TPS in primary and metastatic tumor lesions compared to [68Ga]Ga-NOTA-RW102. They also displayed different distribution, suggesting that peptide-based and nanobody-based radiotracers may have different clinical implications, particularly in radiotherapy.
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Affiliation(s)
- Yanfei Wu
- Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Hao Wang
- Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
- Hepatobiliary Surgery, Department of General Surgery, Huashan Hospital & Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Yue Gu
- Central Research Institute, United Imaging Healthcare Group Co., Ltd, Shanghai, China
| | - You Zhang
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Guanglei Li
- Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Yuan Huang
- Rehabilitation Department, Huashan Hospital, Fudan University, Shanghai, China
| | - Min Cao
- Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Xiaofeng Chen
- Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yihui Guan
- Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China
| | - Dong Xu
- Department of Thoracic Surgery, Huashan Hospital, Fudan University, Shanghai, China.
| | - Weijun Wei
- Department of Nuclear Medicine, Institute of Clinical Nuclear Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
| | - Fang Xie
- Department of Nuclear Medicine & PET Center, Huashan Hospital, Fudan University, Shanghai, China.
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15
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Canali B, Apolone G, Ascierto PA, De Braud F, Grossi F, Perrone F, Fiorentino F, Di Costanzo A, Candelora L, Patanè G, Zapparelli G, Mezzanotte C, Didoni G, Riccaboni M. Effect of immuno-oncology on clinical and economic outcomes for a selection of cancers in Italy. Expert Rev Pharmacoecon Outcomes Res 2025:1-11. [PMID: 40329477 DOI: 10.1080/14737167.2025.2493130] [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: 10/09/2024] [Revised: 04/03/2025] [Accepted: 04/08/2025] [Indexed: 05/08/2025]
Abstract
OBJECTIVES This study assesses the impact of immune-oncology (IO) drugs' availability on cancer incidence-adjusted mortality rates from melanoma, lung, and renal cancers at population level in Italy between 2008 and 2019. METHODS We conducted a retrospective study on cross-sectional time-series aggregated data collected from publicly available sources and IQVIA proprietary databases. Three fixed-effects regression models were used to estimate how IO availability affects incidence-adjusted mortality for each cancer type. Estimated deaths were compared with deaths in a scenario with no IO drugs availability. Finally, the number of averted deaths was valued using the human capital approach. RESULTS A 1% increase in IO availability reduces incidence-adjusted mortality rates for melanoma, lung, and renal cancers by 0.125% (95% CI: 0.138-0.112; p < 0.01), 0.011% (95% CI: 0.013-0.009; p < 0.01) and 0.005% (95% CI: 0.006-0.003; p < 0.01) between the introduction of the drug in the therapeutic area and 2019. This reduction resulted in total savings of € 49.0 million, € 61.3 million, and € 10.9 million in indirect costs due to premature mortality, respectively. CONCLUSIONS IO drugs introduction in Italy between 2008 and 2019 was associated with a significant decrease in deaths from each cancer and, consequently, in savings in indirect costs related to premature mortality.
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Affiliation(s)
- Beatrice Canali
- Real World Solutions, IQVIA Solutions Italy S.r.l, Milan, Italy
| | - Giovanni Apolone
- Scientific Directorate, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Paolo A Ascierto
- Melanoma, Cancer Immunotherapy and Development Therapeutics Unit, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | - Filippo De Braud
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesco Grossi
- Department of Medicine and Technological Innovation, Università degli Studi dell'Insubria, Varese, Italy
- Medical Oncology Division, ASST Sette Laghi, Varese, Italy
| | - Francesco Perrone
- Clinical Trial Unit, Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Naples, Italy
| | | | | | - Laura Candelora
- Real World Solutions, IQVIA Solutions Italy S.r.l, Milan, Italy
| | | | | | - Claudia Mezzanotte
- Pricing, Access Strategy & Health Economics, Bristol Myers Squibb, Rome, Italy
| | - Guido Didoni
- Pricing, Access Strategy & Health Economics, Bristol Myers Squibb, Rome, Italy
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16
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Jiang D, Yoou MS, Cho S, Choi Y. Molecular Dynamics-Guided Repositioning of FDA-Approved Drugs for PD-L1 Inhibition with In Vitro Anticancer Potential. Int J Mol Sci 2025; 26:4497. [PMID: 40429641 PMCID: PMC12110937 DOI: 10.3390/ijms26104497] [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: 04/03/2025] [Revised: 05/01/2025] [Accepted: 05/07/2025] [Indexed: 05/29/2025] Open
Abstract
Programmed death-ligand 1 (PD-L1) is a crucial immune checkpoint protein that tumors often exploit to evade immune surveillance. This study systematically screened a library of 1031 FDA-approved drugs using a high-throughput molecular dynamics approach to identify potential inhibitors targeting PD-L1. From this screening, five promising compounds-vorapaxar, delafloxacin, tenofovir disoproxil, pivmecillinam, and fursultiamine-showed significant binding affinities to PD-L1 and demonstrated cytotoxic activity against A549 lung tumor cells. These candidates were further evaluated through extended molecular dynamics simulations lasting up to 150 ns to assess their structural stability, residue fluctuations, and binding free energy. Among the identified compounds, pivmecillinam demonstrated the most favorable results, exhibiting stable binding interactions and a binding free energy of -18.01 kcal/mol, comparable to that of the known PD-L1 inhibitor BMS-1. These findings suggest that pivmecillinam has promising immunomodulatory potential and could serve as a candidate for further development in cancer immunotherapy. Overall, this study underscores the value of integrating high-throughput MD and experimental approaches for drug repositioning to identify novel therapeutic agents.
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Affiliation(s)
- Dejun Jiang
- Department of Environmental Engineering, Hoseo University, Asan 31499, Republic of Korea;
| | - Myoung-Schook Yoou
- Eulji Medi-Bio Research Institute, Eulji University, Daejeon 34824, Republic of Korea;
| | - Sungjoon Cho
- Department of Bio-Applied Toxicology, Hoseo University, Asan 31499, Republic of Korea;
| | - Youngjin Choi
- Department of Bio-Applied Toxicology, Hoseo University, Asan 31499, Republic of Korea;
- Department of Food Science & Technology, Hoseo University, Asan 31499, Republic of Korea
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17
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Nagano Y, Takahashi M, Sumi T, Yokoo K, Ishikawa T, Honjo O, Kudo S, Kondo S, Tanaka Y, Shioya M, Hashimoto M, Otsuka M, Sudo Y, Yanagi M, Yabe H, Nishikiori H, Yamazoe M, Asai Y, Fukataki Y, Hinotsu S, Chiba H. Efficacy of nivolumab + ipilimumab ± chemotherapy versus pembrolizumab + chemotherapy in patients with PD-L1-negative non-small cell lung cancer (START001 PART-B): a multicenter retrospective observational study. Jpn J Clin Oncol 2025:hyaf073. [PMID: 40333938 DOI: 10.1093/jjco/hyaf073] [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: 01/24/2025] [Accepted: 04/17/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Programmed death ligand 1 (PD-L1) serves as a crucial biomarker for predicting the efficacy of immune checkpoint inhibitors in patients with non-small cell lung cancer (NSCLC). This study aimed to identify the most suitable first-line treatment regimen for patients with PD-L1 expression <1% (PD-L1-negative) NSCLC by comparing nivolumab plus ipilimumab (NI), NI combined with chemotherapy (NICT), and pembrolizumab and chemotherapy (PCT). METHODS We analyzed data from 141 patients with PD-L1-negative NSCLC treated with NI, NICT, or PCT at 14 Japanese institutions between December 2020 and November 2022. Propensity score analysis was employed to minimize selection bias, and Kaplan-Meier analysis and Cox proportional hazards regression were used to evaluate progression-free survival (PFS) and overall survival (OS). RESULTS Neither NI nor NICT demonstrated superior PFS or OS than PCT. Subgroup analyses revealed no significant differences between treatment groups across age, histological subtypes, or clinical features. Results from propensity score matching and inverse probability of treatment weighting were consistent with those observed in the overall cohort. Moreover, safety profiles showed that PCT was associated with the lowest rates of treatment discontinuation and immune-related adverse events requiring systemic corticosteroid therapy. CONCLUSIONS In patients with PD-L1-negative NSCLC, the efficacy of NI and NICT was not superior to that of PCT. Thus, we concluded that PCT could be a favorable treatment option for this patient population.
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Affiliation(s)
- Yutaro Nagano
- Department of Respiratory Medicine, Otaru General Hospital, 1-1-1 Wakamatsu, Otaru, Hokkaido 047-0017, Japan
- Department of Respiratory Medicine, Hakodate Municipal Hospital, 1-10-1 Minato-cho, Hakodate, Hokkaido 041-0821, Japan
| | - Mamoru Takahashi
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Toshiyuki Sumi
- Department of Respiratory Medicine, Hakodate Goryoukaku Hospital, 38-3 Goryokaku-cho, Hakodate, Hokkaido 041-8611, Japan
| | - Keiki Yokoo
- Department of Respiratory Medicine, Teine Keijinkai Hospital, 1-40 Maeda 1-jo 12-chome, Teine-ku, Sapporo, Hokkaido 006-0811, Japan
| | - Tatsuru Ishikawa
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Osamu Honjo
- Department of Respiratory Medicine, Sapporo Minami-Sanjo Hospital, 4-2 Minami 3-jo Nishi 6-chome, Chuo-ku, Sapporo, Hokkaido 060-0063, Japan
| | - Sayaka Kudo
- Department of Respiratory Medicine, Kushiro City General Hospital, 1-12 Shunkodai, Kushiro, Hokkaido 085-0822, Japan
| | - Shun Kondo
- Department of Respiratory Medicine, Steel Memorial Muroran Hospital, 45 Chiribetsu-cho 1-chome, Muroran, Hokkaido 050-0076, Japan
| | - Yusuke Tanaka
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
- Department of Respiratory Medicine, 3-8 Kita 4-jo Nishi 7-chome, Chuo-ku, Tonan Hospital, Sapporo, Hokkaido 060-0004, Japan
| | - Makoto Shioya
- Department of Respiratory Medicine, Otaru General Hospital, 1-1-1 Wakamatsu, Otaru, Hokkaido 047-0017, Japan
| | - Midori Hashimoto
- Department of Respiratory Medicine, NTT-East Corporation Sapporo Medical Center, Minami 1-jo Nishi 15-chome, Chuo-ku, Sapporo, Hokkaido 060-0062, Japan
| | - Mitsuo Otsuka
- Department of Respiratory Medicine, Hokkaido P.W.F.A.C Sapporo-Kosei Hospital, 5 Kita 3-jo Higashi 8-chome, Chuo-ku, Sapporo, Hokkaido 060-0033, Japan
| | - Yuta Sudo
- Department of Respiratory Medicine, Japanese Red Cross Asahikawa Hospital, 1-1 Akebono 1-jo 1-chome, Asahikawa, Hokkaido 070-0061, Japan
| | - Masahiro Yanagi
- Department of Respiratory Medicine, Muroran City General Hospital, 8-1 Yamate-cho 3-chome, Muroran, Hokkaido 051-0012, Japan
| | - Hayato Yabe
- Department of Respiratory Medicine, Japan Community Healthcare Organization Sapporo Hokushin Hospital, 2-1 Atsubetsu Chuo 2-jo 6-chome, Atsubetsu-ku, Sapporo, Hokkaido 004-8618, Japan
| | - Hirotaka Nishikiori
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Masami Yamazoe
- Department of Respiratory Medicine, Hakodate Municipal Hospital, 1-10-1 Minato-cho, Hakodate, Hokkaido 041-0821, Japan
| | - Yuichiro Asai
- Department of Respiratory Medicine, 3-8 Kita 4-jo Nishi 7-chome, Chuo-ku, Tonan Hospital, Sapporo, Hokkaido 060-0004, Japan
| | - Yasuko Fukataki
- Department of Biostatics and Data Management, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkadio 060-8543, Japan
| | - Shiro Hinotsu
- Department of Biostatics and Data Management, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkadio 060-8543, Japan
| | - Hirofumi Chiba
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 291 Minami 1-jo Nishi 16-chome, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
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18
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Peters S, Oliner KS, L'Hernault A, Ratcliffe M, Madison H, Lai Z, Stewart R, Mann H, Lowery C, Garon EB, Mok T, Johnson ML. Durvalumab with or without tremelimumab in combination with chemotherapy in first-line metastatic non-small-cell lung cancer: outcomes by tumor mutational burden in POSEIDON. ESMO Open 2025; 10:105058. [PMID: 40334315 DOI: 10.1016/j.esmoop.2025.105058] [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: 12/03/2024] [Revised: 03/21/2025] [Accepted: 03/24/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND In updated analyses from the phase III POSEIDON study, after a median follow-up of >5 years, tremelimumab plus durvalumab and chemotherapy (T + D + CT) showed durable long-term overall survival (OS) benefit versus CT alone in first-line metastatic non-small-cell lung cancer (mNSCLC). In this article, we report the associations of tumor mutational burden (TMB) with outcomes of D with or without T in combination with CT versus CT alone. PATIENTS AND METHODS A total of 1013 patients with EGFR/ALK wild-type mNSCLC were randomized (1 : 1 : 1) to T + D + CT, D + CT, or CT, stratified by programmed cell death-ligand 1 (PD-L1) tumor cell (TC) expression ≥50% versus <50%, disease stage (IVA versus IVB) and histology (squamous versus nonsquamous). Patient subgroups were defined by a range of blood TMB (bTMB) values, including at a prespecified cut-off of 20 mutations (mut)/megabase (Mb) and across further subdivisions by PD-L1 TC expression ≥1% or <1% and by tissue TMB (tTMB) values. RESULTS At the primary OS data cut-off (12 March 2021), at each bTMB or tTMB cut-off, the magnitude of OS benefit appeared greater among patients in the bTMB- or tTMB-high subgroups for the T + D + CT arm versus the CT arm but was similar between subgroups for the D + CT arm versus the CT arm. Updated OS analyses in the bTMB ≥20 and <20 mut/Mb subgroups, after median follow-up of >5 years (data cut-off 24 August 2023), were similar to those obtained at the primary OS data cut-off. CONCLUSIONS First-line treatment with T (limited course) plus D (until progression) and four cycles of CT consistently improved clinical outcomes versus CT alone in both bTMB-high and -low subgroups, and also in both high and low tTMB subgroups, in patients with mNSCLC. Benefit appeared greater in the TMB-high versus TMB-low subgroups; the addition of anti-cytotoxic T lymphocyte-associated antigen-4 to anti-PD-L1 and CT seemed to increase the magnitude of this difference.
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Affiliation(s)
- S Peters
- Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland.
| | | | | | | | | | - Z Lai
- AstraZeneca, Waltham, USA
| | | | - H Mann
- AstraZeneca, Cambridge, UK
| | | | - E B Garon
- David Geffen School of Medicine at UCLA, Los Angeles, USA
| | - T Mok
- State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China
| | - M L Johnson
- Sarah Cannon Research Institute, SCRI Oncology Partners, Nashville, USA
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19
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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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20
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van Kempen S, Gerritsen WJG, Nguyen TQ, van Dooijeweert C, Stathonikos N, Broekhuizen R, Peters L, van Diest PJ. Monitoring Immunohistochemical Staining Variations Using Artificial Intelligence on Standardized Controls. J Transl Med 2025; 105:104105. [PMID: 39952611 DOI: 10.1016/j.labinv.2025.104105] [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: 01/21/2025] [Accepted: 02/06/2025] [Indexed: 02/17/2025] Open
Abstract
Quality control of immunohistochemistry (IHC) slides is crucial to ascertain accurate patient management. Visual assessment is the most commonly used method to assess the quality of IHC slides from patient samples in daily pathology routines. Control tissues for IHC slides are typically obtained from prior cases containing normal tissues or specific antigen-expressing disease samples, especially tumors. As such samples eventually run out, and tumors may be heterogeneous, constant expression levels from one control sample to the next cannot be guaranteed. With the increasing availability of standardized cell lines, the diagnostic use of these cell lines as alternatives to traditional laboratory-derived controls can be explored. Furthermore, stain quality of this cell line material can probably be better monitored with readout methods such as image analysis and artificial intelligence (AI) than with visual readout methods, in which accuracy is influenced by the training and experience of the pathologists and technicians. In this study, we present the results of our investigation into AI-measured stain quality of standardized cell lines designed as controls for HER2 and PD-L1 IHC stainings. Using 5 IHC autostainers from the same manufacturer and type, we quantified cell membrane expression levels of these cell lines after staining using Qualitopix, an AI algorithm for measuring stain quality control. Over a 24-month period of weekly AI measurements, we observed multiple unexpected variations, particularly in low- and medium-expressing cell lines. To further investigate these fluctuations, we assessed both interstainer variations and intrarun variations, revealing differences between the stainers and the slide slots within the stainers. To finalize our study, we performed HER2 and PD-L1 stainings on calibrator slides to measure the limit of detection to detect variance per stainer and slot. Our findings prompted extra maintenance from the manufacturer in one of the highly fluctuating stainers, which reduced variation. In conclusion, AI appears to be an effective approach to monitor the IHC stain quality of standardized control cell lines for therapeutic protein targets HER2 and PD-L1, and to trace the underlying errors. This may be crucial for accurate patient management.
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Affiliation(s)
- Sven van Kempen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - W J Ghlowy Gerritsen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Tri Q Nguyen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Nikolas Stathonikos
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Roel Broekhuizen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Loïs Peters
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Paul J van Diest
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
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21
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Josephides EC, Smith D, Bille A, Patel A, Rush HL, Dunn R, Hughes DJ, Hunter S, Taniere P, Crawley D, Monroy-Iglesias M, Henry AR, Montes A, Van Hemelrijck M, Spicer J, Josephs D, Santis G, Nonaka D, Karapanagiotou EM. A Retrospective Evaluation of PD-L1 Expression and Heterogeneity in Early-Stage Non-Small Cell Lung Cancer (REPLICA). Clin Lung Cancer 2025; 26:e223-e231. [PMID: 39915192 DOI: 10.1016/j.cllc.2025.01.008] [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: 09/24/2024] [Revised: 12/10/2024] [Accepted: 01/09/2025] [Indexed: 04/30/2025]
Abstract
BACKGROUND Immune checkpoint inhibitors have improved survival in patients with non-small cell lung cancer (NSCLC). Whilst PD-L1 expression is a useful predictive biomarker, data on concordance of expression between primary tumor and nodal metastases in the surgical setting are sparse. METHODS We assessed PD-L1 expression in paired primary tumor and involved lymph node samples from 451 consecutive patients with stage IIB-IIIB NSCLC who underwent curative lung resection and lymphadenectomy at our institution between 2009 and 2018, to assess intertumor heterogeneity. Clinical records were examined to determine survival outcomes, and relationship to PD-L1 expression was explored. RESULTS Using PD-L1 expression categories of < 1%, 1% to 49% and ≥ 50% there was heterogeneity of PD-L1 expression between the primary and corresponding lymph node metastases in 24% of cases with only moderate positive correlation (Spearman's coefficient 0.7). 46% of early-stage primary tumors expressed PD-L1, although only 11% demonstrated a high (> 50%) level. It was more common for PD-L1 expression to be higher in the primary tumor than its metastatic lymph node than the converse. PD-L1 expression irrespective of site, had no significant impact on disease-free or overall survival. CONCLUSION Our study confirms the heterogeneity of PD-L1 expression in early-stage NSCLC and suggests that a biopsy specimen from a single site may not be a comprehensive representation of PD-L1 expression. The proportion of tumours with high PD-L1 expression appears lower in early-stage NSCLC than in advanced disease.
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Affiliation(s)
- Eleni C Josephides
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Daniel Smith
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Andrea Bille
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK; King's College Hospital NHS Foundation Trust, King's College Hospital, London, UK
| | - Akshay Patel
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Hannah L Rush
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK; Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, UK
| | - Roberta Dunn
- Royal College of Radiologists Fellow, Guy's and St Thomas' NHS Foundation Trust, London, UK; Comprehensive Cancer Centre, King's College, London, UK
| | - Daniel J Hughes
- Department of Cancer Imaging, School of Biomedical Engineering and Imaging Sciences, King's College London, London, UK; PET Centre, King's College London & Guy's and St. Thomas', London, UK
| | - Sarah Hunter
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Phillipe Taniere
- Clinical Laboratory Services, Queen Elizabeth Hospital Birmingham, Edgbaston, Birmingham, UK
| | - Danielle Crawley
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - Annie-Rose Henry
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Ana Montes
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - James Spicer
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Debra Josephs
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - George Santis
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK; School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Daisuke Nonaka
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK
| | - Eleni M Karapanagiotou
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, UK; School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.
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22
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Wang J, Chen Q, Shan Q, Liang T, Forde P, Zheng L. Clinical development of immuno-oncology therapeutics. Cancer Lett 2025; 617:217616. [PMID: 40054657 PMCID: PMC11930610 DOI: 10.1016/j.canlet.2025.217616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 03/03/2025] [Accepted: 03/05/2025] [Indexed: 03/15/2025]
Abstract
Immuno-oncology (IO) is one of the fastest growing therapeutic areas within oncology. IO agents work indirectly via the host's adaptive and innate immune system to recognize and eradicate tumor cells. Despite checkpoint inhibitors being only introduced to the market since 2011, they have become the second most approved product category. Current Food and Drug Administration (FDA)-approved classes of IO agents include: immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy (CAR-T), bi-specific T-cell engager (BiTE) antibody therapy, T-cell receptor (TCR) engineered T cell therapy, tumor-infiltrating lymphocyte (TIL) therapy, cytokine therapy, cancer vaccine therapy, and oncolytic virus therapy. Cancer immunotherapy has made progress in multiple cancer types including melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and urothelial carcinoma; however, several cancers remain refractory to immunotherapy. Future directions of IO include exploration in the neoadjuvant/perioperative setting, combination strategies, and optimizing patient selection through improved biomarkers.
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Affiliation(s)
- Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qi Chen
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Qiang Shan
- Department of General Surgery, Haining People's Hospital, Haining, 314400, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou, 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou, 310003, China
| | - Patrick Forde
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA
| | - Lei Zheng
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Mays Cancer Center at the University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
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23
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Mahiat C, Cadranel J, Méteyé C, Houari S, Rosencher L, Epaud C, Slomka J, Fallet V, Canellas A. Management of non-small cell lung cancer after 2 years of immunotherapy. Respir Med Res 2025; 87:101169. [PMID: 40215940 DOI: 10.1016/j.resmer.2025.101169] [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: 10/03/2024] [Revised: 03/02/2025] [Accepted: 03/22/2025] [Indexed: 06/02/2025]
Abstract
BACKGROUND The optimal management strategy for metastatic or advanced-stage non-small-cell lung cancer (NSCLC) after 2 years of immune checkpoint inhibitor (ICI) remains unclear. METHODS We conducted a single-center retrospective observational study to characterize the management of patients who received at least 2 years of ICI in the first-line setting for a metastatic or advanced-stage NSCLC. RESULTS Among the 254 patients that received ICI in the first-line setting, 39 (15%) achieved 2 years of treatment (ICI in monotherapy, n = 14; ICI with chemotherapy, n = 25). ICI was discontinued after 2 years (<30 months) in 31 (79%) of the cases. During the first 2 years, 29 patients (74%) had no disease progression (2 complete radiological responses, 25 partial radiological responses, and 2 stable diseases) and 10 patients (26%) experienced at least one oligo-progression, which was treated with local ablative treatment (LAT), allowing continuation of ICI up to 2 years. A positron emission tomography (PET) scan was performed at 2 years for 37 patients (95%), revealing a complete metabolic response (CMR) in 16 individuals (43%). None of these patients progressed subsequently (median follow-up: 13 months). After 2 years of ICI, the 12-month progression-free survival was 100% in case of CMR versus 49% (95% CI, 29-91) in the absence of CMR (p = 0.00037). CONCLUSIONS A CMR at 2 years of ICI is associated with a favorable prognosis. Further studies are needed to better establish the role of PET scan at 2 years, the relevance of LAT and the optimal duration of ICI.
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Affiliation(s)
- Cédric Mahiat
- Department of Pneumology and Thoracic Oncology, Tenon Hospital, Assistance publique-Hôpitaux de Paris and Sorbonne University, Paris, France.
| | - Jacques Cadranel
- Department of Pneumology and Thoracic Oncology, Tenon Hospital, Assistance publique-Hôpitaux de Paris and Sorbonne University, Paris, France
| | - Constance Méteyé
- Department of Pneumology and Thoracic Oncology, Tenon Hospital, Assistance publique-Hôpitaux de Paris and Sorbonne University, Paris, France
| | - Samy Houari
- Department of Pharmacy, Tenon Hospital, Assistance publique-Hôpitaux de Paris and Sorbonne University, Paris, France
| | - Lise Rosencher
- Department of Pneumology and Thoracic Oncology, Tenon Hospital, Assistance publique-Hôpitaux de Paris and Sorbonne University, Paris, France
| | - Christelle Epaud
- Department of Pneumology and Thoracic Oncology, Tenon Hospital, Assistance publique-Hôpitaux de Paris and Sorbonne University, Paris, France
| | - Jérémy Slomka
- Department of Pneumology and Thoracic Oncology, Tenon Hospital, Assistance publique-Hôpitaux de Paris and Sorbonne University, Paris, France
| | - Vincent Fallet
- Department of Pneumology and Thoracic Oncology, Tenon Hospital, Assistance publique-Hôpitaux de Paris and Sorbonne University, Paris, France
| | - Anthony Canellas
- Department of Pneumology and Thoracic Oncology, Tenon Hospital, Assistance publique-Hôpitaux de Paris and Sorbonne University, Paris, France
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Li R, Lv W, Wang DL, Chen N. A Systematic Review of Immune Cell Roles in Breast Cancer Immunotherapy. Cancer Rep (Hoboken) 2025; 8:e70217. [PMID: 40356222 PMCID: PMC12069222 DOI: 10.1002/cnr2.70217] [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: 11/29/2024] [Revised: 04/15/2025] [Accepted: 04/21/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Breast cancer (BC) is the most prevalent malignancy among women and is associated with high mortality and significant clinical challenges. Although conventional treatments such as surgery, chemotherapy, and radiotherapy have significantly improved patient survival, their efficacy remains limited by severe side effects and treatment resistance. In recent years, advances in immunotherapy have underscored the pivotal role of immune cells in treating BC. RECENT FINDINGS This systematic review summarizes the current knowledge on the roles of immune cells within the BC tumor microenvironment (TME), including their phenotypes, functions, and implications for immunotherapy. Following PRISMA guidelines, 71 studies published between 2010 and 2024 were analyzed. The results indicate that immune cell populations-such as tumor-associated macrophages (TAMs), tumor-infiltrating lymphocytes (TILs), natural killer (NK) cells, dendritic cells (DCs), and myeloid-derived suppressor cells (MDSCs)-are integral to tumor progression and therapeutic response. However, their functional heterogeneity and plasticity remain key obstacles to the development of effective and personalized immunotherapeutic strategies. CONCLUSION Further research is needed to clarify the mechanisms governing immune cell behavior within the BC TME and to advance precision immunotherapy. Such insights will lay the foundation for individualized treatment approaches, ultimately improving patient outcomes and quality of life (QoL).
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Affiliation(s)
- Rui Li
- Shandong Provincial Hospital, Affiliated to Shandong First Medical UniversityJinanShandongChina
| | - Wei Lv
- Department of General SurgeryShandong Provincial HospitalJinanShandongChina
| | | | - Na Chen
- Department of Internal MedicineShandong Provincial HospitalJinanShandongChina
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Shiraishi Y, Shimose T, Tobino K, Toi Y, Wakuda K, Matsumoto H, Sakaguchi T, Mashimoto A, Hayashi H, Ebina-Shibuya R, Mori M, Taniguchi Y, Kuyama S, Kashiwabara K, Furuyama K, Yoshimine K, Kimura Y, Kobayashi H, Kishimoto J, Okamoto I. Atezolizumab with carboplatin plus nab-paclitaxel combination therapy for advanced nonsquamous non-small cell lung cancer with impaired renal function: A multicenter, single-arm phase 2 trial (RESTART, LOGiK 2002). Lung Cancer 2025; 203:108543. [PMID: 40253945 DOI: 10.1016/j.lungcan.2025.108543] [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: 01/31/2025] [Revised: 04/10/2025] [Accepted: 04/15/2025] [Indexed: 04/22/2025]
Abstract
BACKGROUND The current standard of care for advanced non-small cell lung cancer (NSCLC) without driver oncogenes is platinum-based chemotherapy together with immune checkpoint inhibition. However, most phase 3 trials of such combination therapy have excluded patients with renal impairment, with prospective data on its efficacy and safety in such patients thus being limited. METHODS This multicenter, single-arm phase 2 study enrolled chemotherapy-naïve individuals with advanced nonsquamous NSCLC and renal impairment defined as a creatinine clearance (CCr) of 15 to <45 mL/min. Patients received four cycles of atezolizumab in combination with carboplatin plus nab-paclitaxel, followed by atezolizumab alone. The primary endpoint of the study was objective response rate as determined by Response Evaluation Criteria in Solid Tumors. RESULTS Twenty-five patients were enrolled from 13 centers. The median age was 78 years (range, 63-83 years). Median CCr was 38.0 mL/min (range, 19.0-44.3 mL/min). There were no treatment-related deaths or cases requiring hemodialysis. Worsening of chronic kidney disease to grade 4, defined as a CCr of <15 mL min-1 1.73 m-2, occurred in two patients (8 %), with the decreases in CCr being transient and both patients subsequently recovering. The objective response rate was 36.0 % (60 % confidence interval, 28.4-44.4 %), and the study did not meet its primary endpoint. Median progression-free survival and overall survival were 7.1 and 19.9 months, respectively. CONCLUSIONS Carboplatin plus nab-paclitaxel with atezolizumab is a potentially feasible treatment option for advanced nonsquamous NSCLC with renal impairment.
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Affiliation(s)
- Yoshimasa Shiraishi
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Takayuki Shimose
- Department of Statistics and Data Center, Clinical Research Support Center Kyushu, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Kazunori Tobino
- Division of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshio-machi, Iizuka, Fukuoka 820-8505, Japan.
| | - Yukihiro Toi
- Department of Pulmonary Medicine, Sendai Kousei Hospital, 1-20 Amamiyamachi, tsutsumidori, Aoba-ku, Sendai, Miyagi 981-0914, Japan.
| | - Kazushige Wakuda
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
| | - Hirotaka Matsumoto
- Department of Respiratory Medicine, Hyogo Prefectural Amagasaki General Medical Center, 2-17-77 Higashinaniwa, Amagasaki, Hyogo 660-8550, Japan
| | - Tadashi Sakaguchi
- Respiratory Center, Matsusaka Municipal Hospital, Tonomachi, 1550 Matsusaka, Mie 515-8544, Japan.
| | - Ayano Mashimoto
- Department of Respiratory Medicine, Japan Community Healthcare Organization Kyushu Hospital, 1-8-1 Kishi-no-ura, Yahatanishi-ku, Kitakyushu, Fukuoka 806-8501, Japan
| | - Hidetoshi Hayashi
- Department of Medical Oncology, Kindai University Faculty of Medicine, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 589-8511, Japan.
| | - Risa Ebina-Shibuya
- Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan.
| | - Masahide Mori
- Department of Thoracic Oncology, NHO Osaka Toneyama Medical Center, 5-1-1 Tonoyama, Toyonaka, Osaka 560-8552, Japan.
| | - Yuri Taniguchi
- Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, 1-1 Mitsuzawa Nishimachi, Kanagawa-ku, Yokohama, Kanagawa 221-0855, Japan.
| | - Shoichi Kuyama
- Department of Respiratory Medicine, NHO Iwakuni Clinical Center, 1-1-1 Atago-Machi, Iwakuni, Yamaguchi 740-8510, Japan.
| | - Kosuke Kashiwabara
- Department of Respiratory Medicine, Kumamoto Regional Medical Center, 5-16-10 Hon-jo, Kumamoto 860-0811, Japan.
| | - Kazuto Furuyama
- Department of Respiratory Medicine, Saiseikai Fukuoka General Hospital, 1-3-46 Tenjin, Chuo-ku, Fukuoka 810-0001 Japan.
| | - Kohei Yoshimine
- Division of Respiratory Medicine, Iizuka Hospital, 3-83 Yoshio-machi, Iizuka, Fukuoka 820-8505, Japan
| | - Yuichiro Kimura
- Department of Pulmonary Medicine, Sendai Kousei Hospital, 1-20 Amamiyamachi, tsutsumidori, Aoba-ku, Sendai, Miyagi 981-0914, Japan.
| | - Haruki Kobayashi
- Division of Thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka 411-8777, Japan.
| | - Junji Kishimoto
- Department of Research and Development of Next Generation Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
| | - Isamu Okamoto
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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26
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Liu B, Zhou J, He W, Xie B, Zhang R, Cheng X, Zhang Y, Xu L, Guo S. Safety of bronchial artery infusion immunotherapy: from comparative analysis in beagle canines to clinical validation. Discov Oncol 2025; 16:621. [PMID: 40285957 PMCID: PMC12033145 DOI: 10.1007/s12672-025-02398-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2025] [Accepted: 04/15/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Despite advancements in systemic chemotherapy and immune checkpoint inhibitors (ICIs), advanced non-small cell lung cancer (NSCLC) continues to exhibit poor prognosis, underscoring an urgent need for safer and more effective therapeutic strategies. This study investigates the safety profile and biological effects of bronchial arterial infusion (BAI)-administered anti-PD-1 monoclonal antibody (aPD-1 mAb) using a preclinical beagle model and a clinical cohort of advanced NSCLC patients. METHODS In preclinical evaluations, male beagles (n = 3/group) were randomized to receive 5 mg/kg aPD-1 mAb via BAI or intravenous routes (Venous group). Safety assessments included longitudinal imaging, biochemical analyses, and histopathological evaluation. Clinically, patients with advanced NSCLC meeting stringent inclusion criteria underwent BAI immunotherapy, with systematic monitoring of adverse events (AEs). RESULTS Both administration routes demonstrated comparable safety in canines, with no evidence of immune-related pneumonitis or structural lung alterations on CT or histology. Transient AEs (e.g., hematoma, lameness) resolved spontaneously. Pharmacokinetic analysis revealed similar systemic drug concentrations and tissue distribution between BAI and Venous groups (all p > 0.05). Biochemical profiling identified isolated mild LDH elevation in one BAI-treated canine. Notably, the BAI group exhibited significantly enhanced systemic IL-2 levels (80.15 ± 5.24 pg/mL vs. 66.47 ± 5.24 pg/mL in Venous groups, p = 0.001) at day 28, paralleled by elevated pulmonary IL-2 expression (626.90 ± 18.49 vs. 559.18 ± 45.61 pg/mg, p = 0.03). In the clinical cohort (n = 17; 94.1% male, mean age 61.6 ± 7.1 years), BAI immunotherapy was well-tolerated with mild AEs including nausea (n = 1), dyspnea (n = 1), atrial fibrillation (n = 1), and puncture-site hematoma (n = 1). No severe immune-related toxicities (e.g., pneumonitis) emerged during follow-up. CONCLUSION Our study suggest the preliminary safety and feasibility of delivering aPD-1 mAb via BAI in both canine models and NSCLC patients.
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Affiliation(s)
- Bin Liu
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Rd 1, Yuzhong, 400016, Chongqing, China
- Department of Pulmonary and Critical Care Medicine, Zhuzhou Central Hospital, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, No. 116, Changjiang South Road, Tianyuan District, Zhuzhou, 412007, Hunan, China
| | - Jia Zhou
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Rd 1, Yuzhong, 400016, Chongqing, China
| | - Wei He
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Rd 1, Yuzhong, 400016, Chongqing, China
| | - Bo Xie
- Department of Medical Administration, Zhuzhou Central Hospital, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou, 412007, Hunan, China
| | - Rui Zhang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Rd 1, Yuzhong, 400016, Chongqing, China
| | - Xiaocheng Cheng
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Rd 1, Yuzhong, 400016, Chongqing, China
| | - Yueming Zhang
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Rd 1, Yuzhong, 400016, Chongqing, China
| | - Li Xu
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Rd 1, Yuzhong, 400016, Chongqing, China
| | - Shuliang Guo
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chongqing Medical University, Youyi Rd 1, Yuzhong, 400016, Chongqing, China.
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27
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Yu J, Kong X, Feng Y. Tumor microenvironment-driven resistance to immunotherapy in non-small cell lung cancer: strategies for Cold-to-Hot tumor transformation. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2025; 8:21. [PMID: 40342732 PMCID: PMC12059482 DOI: 10.20517/cdr.2025.14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/19/2025] [Accepted: 04/17/2025] [Indexed: 05/11/2025]
Abstract
Non-small cell lung cancer (NSCLC) represents a formidable challenge in oncology due to its molecular heterogeneity and the dynamic suppressive nature of its tumor microenvironment (TME). Despite the transformative impact of immune checkpoint inhibitors (ICIs) on cancer therapy, the majority of NSCLC patients experience resistance, necessitating novel approaches to overcome immune evasion. This review highlights shared and subtype-specific mechanisms of immune resistance within the TME, including metabolic reprogramming, immune cell dysfunction, and physical barriers. Beyond well-characterized components such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells, emerging players - neutrophil extracellular traps, tertiary lymphoid structures, and exosomal signaling networks - underscore the TME's complexity and adaptability. A multi-dimensional framework is proposed to transform cold, immune-excluded tumors into hot, immune-reactive ones. Key strategies include enhancing immune infiltration, modulating immunosuppressive networks, and activating dormant immune pathways. Cutting-edge technologies, such as single-cell sequencing, spatial transcriptomics, and nanomedicine, are identified as pivotal tools for decoding TME heterogeneity and personalizing therapeutic interventions. By bridging mechanistic insights with translational innovations, this review advocates for integrative approaches that combine ICIs with metabolic modulators, vascular normalizers, and emerging therapies such as STING agonists and tumor vaccines. The synergistic potential of these strategies is poised to overcome resistance and achieve durable antitumor immunity. Ultimately, this vision underscores the importance of interdisciplinary collaboration and real-time TME profiling in refining precision oncology for NSCLC, offering a blueprint for extending these advances to other malignancies.
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Affiliation(s)
- Jinglu Yu
- Institute of Integrated Chinese and Western Medicine, PuDong Traditional Chinese Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201200, China
- Institute of Respiratory Medicine, PuDong Traditional Chinese Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201200, China
| | - Xiaoni Kong
- Institute of Integrated Chinese and Western Medicine, PuDong Traditional Chinese Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201200, China
- Central Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yu Feng
- Institute of Integrated Chinese and Western Medicine, PuDong Traditional Chinese Medicine Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201200, China
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28
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Sugai M, Amino Y, Fujishima S, Nibuya K, Iso H, Ito M, Tsugitomi R, Ariyasu R, Uchibori K, Yanagitani N, Nishio M. Impact of immune-related adverse event severity on overall survival in patients with advanced NSCLC receiving immune checkpoint inhibitors therapy, with a focus on combination regimens. Lung Cancer 2025; 204:108555. [PMID: 40311310 DOI: 10.1016/j.lungcan.2025.108555] [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: 01/08/2025] [Revised: 04/16/2025] [Accepted: 04/21/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND Immune-related adverse events (irAEs) associated with immune checkpoint inhibitors (ICIs) may serve as prognostic markers in non-small cell lung cancer (NSCLC). While prior studies suggest differences in overall survival (OS) based on irAE, their prognostic impact across various ICI regimens remains underexplored. METHODS This retrospective study analyzed data from patients with advanced or recurrent NSCLC treated with ICIs between January 2018 and December 2022. Patients were categorized into three groups: severe irAEs (Grade 3-5), mild irAEs (Grade 1-2), and no-irAEs. OS was assessed across three regimens: anti-programmed cell death protein 1 (anti-PD-1) monotherapy, anti-PD-1/anti-programmed death-ligand 1 (anti-PD-L1) with chemotherapy (CT), and anti-PD-1 with anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) ± CT. RESULTS Among the 256 patients included, 55 received anti-PD-1 monotherapy, 116 received anti-PD-1/L1 with CT, and 85 received anti-PD-1 with anti-CTLA-4 ± CT. For anti-PD-1 monotherapy, median OS (95 % confidence interval) was 38.3 (17.0-42.5) months in the mild irAE group, 16.1 (5.2-28.6) months in the severe irAE group, and 9.6 (12.3-37.1) months in the no-irAE group. In the anti-PD-1/L1 with CT group, median OS were 33.6 (14.2-40.3), 16.0 (1.84-not reached [NR]), and 17.7 (3.8-23.4) months, respectively. For anti-PD-1 with anti-CTLA-4 ± CT, median OS were 28.0 (21.8-NR), 10.9 (7.0-19.6), and 16.3 (8.7-23.4) months, respectively. CONCLUSIONS The relationship between irAE severity and OS was consistent across all ICI regimens, with patients experiencing mild irAEs demonstrating better OS across all ICI regimens.
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Affiliation(s)
- Mayu Sugai
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Yoshiaki Amino
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan.
| | - Shunsuke Fujishima
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Kyujiro Nibuya
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Hirokazu Iso
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Masahiro Ito
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Ryosuke Tsugitomi
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Ryo Ariyasu
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Ken Uchibori
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Noriko Yanagitani
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Makoto Nishio
- Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo 135-8550, Japan
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29
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Zhu K, Pan Z, Qin M, Huang J. The cost effectiveness of penpulimab with paclitaxel and carboplatin in first-line treatment of metastatic squamous non-small cell lung cancer. Sci Rep 2025; 15:12679. [PMID: 40221588 PMCID: PMC11993585 DOI: 10.1038/s41598-025-97591-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Accepted: 04/07/2025] [Indexed: 04/14/2025] Open
Abstract
This study aimed to evaluate the cost-effectiveness of Penpulimab versus placebo in treating metastatic squamous non-small cell lung cancer (NSCLC) from the perspective of Chinese payers. A three-state Markov model was developed to simulate clinical efficacy and cost consumption using Kaplan-Meier curves from clinical trials. The model considered only direct medical costs, with utility values derived from the published literature. The primary outcome measure was the incremental cost-effectiveness ratio (ICER), and sensitivity analysis was performed to assess the impact of parameter uncertainty on the model's robustness. The base case analysis indicated that the Penpulimab group incurred higher costs ($33,592 vs. $9,351) than the placebo group, while also providing more quality-adjusted life years (QALYs) (3.30 vs. 2.11), resulting in an incremental cost-effectiveness ratio (ICER) of $20,389.38 per QALY. Sensitivity analyses revealed that the cost of Penpulimab, along with the utilities of progression-free survival (PFS) and progression of disease (PD), were the parameters that most significantly influenced the model's outcomes. From the perspective of Chinese payers, Penpulimab offers a cost-effectiveness advantage over placebo in treating metastatic squamous NSCLC.
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MESH Headings
- Humans
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/economics
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/mortality
- Cost-Benefit Analysis
- Paclitaxel/administration & dosage
- Paclitaxel/therapeutic use
- Paclitaxel/economics
- Lung Neoplasms/drug therapy
- Lung Neoplasms/economics
- Lung Neoplasms/pathology
- Lung Neoplasms/mortality
- Carboplatin/administration & dosage
- Carboplatin/therapeutic use
- Carboplatin/economics
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/economics
- Quality-Adjusted Life Years
- Markov Chains
- Antibodies, Monoclonal, Humanized/economics
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Male
- Female
- Neoplasm Metastasis
- Progression-Free Survival
- Cost-Effectiveness Analysis
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Affiliation(s)
- Kaiqi Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Zhaoyi Pan
- Medical Record Management and Statistics Information Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Mengyao Qin
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
| | - Jin Huang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
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30
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Lu J, Liu X, Ji X, Jiang Y, Zuo A, Guo Z, Yang S, Peng H, Sun F, Lu D. Predicting PD-L1 status in NSCLC patients using deep learning radiomics based on CT images. Sci Rep 2025; 15:12495. [PMID: 40216830 PMCID: PMC11992188 DOI: 10.1038/s41598-025-91575-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 02/21/2025] [Indexed: 04/14/2025] Open
Abstract
Radiomics refers to the utilization of automated or semi-automated techniques to extract and analyze numerous quantitative features from medical images, such as computerized tomography (CT) or magnetic resonance imaging (MRI) scans. This study aims to develop a deep learning radiomics (DLR)-based approach for predicting programmed death-ligand 1 (PD-L1) expression in patients with non-small cell lung cancer (NSCLC). Data from 352 NSCLC patients with known PD-L1 expression were collected, of which 48.29% (170/352) were tested positive for PD-L1 expression. Tumor regions of interest (ROI) were semi-automatically segmented based on CT images, and DL features were extracted using Residual Network 50. The least absolute shrinkage and selection operator (LASSO) algorithm was used for feature selection and dimensionality reduction. Seven algorithms were used to build models, and the most optimal ones were identified. A combined model integrating DLR with clinical data was also developed. The predictive performance of each model was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve analysis. The DLR model, based on CT images, demonstrated an AUC of 0.85 (95% confidence interval (CI), 0.82-0.88), sensitivity of 0.80 (0.74-0.85), and specificity of 0.73 (0.70-0.77) for predicting PD-L1 status. The integrated model exhibited superior performance, with an AUC of 0.91 (0.87-0.95), sensitivity of 0.85 (0.82-0.89), and specificity of 0.75 (0.72-0.80). Our findings indicate that the DLR model holds promise as a valuable tool for predicting the PD-L1 status in patients with NSCLC, which can greatly assist in clinical decision-making and the selection of personalized treatment strategies.
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Affiliation(s)
- Jiameng Lu
- Department of Respiratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, 16766 Jingshilu, Lixia, Jinan, 250014, Shandong, People's Republic of China
- Faculty of Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, 999078, Macau Special Administrative Region, People's Republic of China
| | - Xinyi Liu
- Department of Respiratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, 16766 Jingshilu, Lixia, Jinan, 250014, Shandong, People's Republic of China
| | - Xiaoqing Ji
- Department of Nursing, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, Shandong, China
| | - Yunxiu Jiang
- Department of Respiratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, 16766 Jingshilu, Lixia, Jinan, 250014, Shandong, People's Republic of China
| | - Anli Zuo
- Department of Respiratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, 16766 Jingshilu, Lixia, Jinan, 250014, Shandong, People's Republic of China
| | - Zihan Guo
- Department of Respiratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, 16766 Jingshilu, Lixia, Jinan, 250014, Shandong, People's Republic of China
| | - Shuran Yang
- Department of Respiratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, 16766 Jingshilu, Lixia, Jinan, 250014, Shandong, People's Republic of China
| | - Haiying Peng
- Department of Respiratory and Critical Care Medicine, The Second People's Hospital of Yibin City, 644002, Yibin, People's Republic of China
| | - Fei Sun
- Department of Respiratory and Critical Care Medicine, Jining No.1 People's Hospital, 272000, Jining, People's Republic of China
| | - Degan Lu
- Department of Respiratory, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Respiratory Diseases, Shandong Institute of Anesthesia and Respiratory Critical Medicine, 16766 Jingshilu, Lixia, Jinan, 250014, Shandong, People's Republic of China.
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31
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Tarin M, Oryani MA, Javid H, Karimi-Shahri M. Exosomal PD-L1 in non-small cell lung Cancer: Implications for immune evasion and resistance to immunotherapy. Int Immunopharmacol 2025; 155:114519. [PMID: 40199140 DOI: 10.1016/j.intimp.2025.114519] [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: 11/05/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 04/10/2025]
Abstract
Exosomes, characterized by their bilayer lipid structure, are crucial in mediating intercellular signaling and contributing to various physiological processes. Tumor cells produce distinct exosomes facilitating cancer progression, angiogenesis, and metastasis by conveying signaling molecules. A notable feature of these tumor-derived exosomes is the presence of programmed death-ligand 1 (PD-L1) on their surface. The PD-L1/programmed cell death receptor-1 (PD-1) signaling axis serves as a critical immune checkpoint, enabling tumors to evade immune detection and antitumor activity. The advancement of immunotherapy targeting the PD-1/PD-L1 pathway has significantly impacted the treatment landscape for non-small cell lung cancer (NSCLC). Despite its promise, evidence indicates that many patients experience limited responses or develop resistance to PD-1/PD-L1 inhibitors. Recent studies suggest that exosomal PD-L1 contributes to this resistance by modulating immune responses and tumor adaptability. This study reviews the PD-1/PD-L1 pathway's characteristics, current clinical findings on PD-L1 inhibitors in NSCLC, and exosome-specific attributes, with a particular focus on exosomal PD-L1. Furthermore, it examines the growing body of research investigating the role of exosomal PD-L1 in cancer progression and response to immunotherapy, underscoring its potential as a target for overcoming resistance in NSCLC treatment.
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Affiliation(s)
- Mojtaba Tarin
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mahsa Akbari Oryani
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Javid
- Department of Medical Laboratory Sciences, Varastegan Institute for Medical Sciences, Mashhad, Iran; Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Mehdi Karimi-Shahri
- Department of Pathology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pathology, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran.
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Chen L, Yin J, Xu K, Cui Y, Zhu S, Li T, Lv T, Song Y, Zhan P. Novel bioengineered drugs with immunotherapies for malignant pleural effusion: Remodulate tumor immune microenvironment and activate immune system. Crit Rev Oncol Hematol 2025; 211:104717. [PMID: 40194717 DOI: 10.1016/j.critrevonc.2025.104717] [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: 02/19/2025] [Revised: 03/21/2025] [Accepted: 03/31/2025] [Indexed: 04/09/2025] Open
Abstract
Malignant pleural effusion (MPE) remains a clinical issue since it is associated with advanced-stage cancers and dismal survival, with immunosuppressive tumor microenvironment (TME) and ineffective drug delivery. Conventional therapies such as thoracentesis and pleurodesis are for symptom relief but palliative, without inducing immunity and prolonging survival. Emerging new bioengineered drugs, synergizing with immunotherapies, offer a new paradigm by dual-targeting TME remodeling and immune activation. These technologies leverage nanotechnology, gene editing, and biomaterials to offer precise spatiotemporal control. This review illustrates the molecular mechanism of the immunosuppressive TME in MPE. It examines the newest bioengineering platforms-such as cytokine-encapsulated nanoparticles and oncolytic viruses-that can reactivate immune mechanisms. We highlight preclinical and clinical evidence of the effectiveness of combinatorial strategies in overcoming local immune tolerance and potential risks in adverse events. While the clinical transformation challenge remains, future directions necessitate cross-disciplinary convergence to engineer intelligent delivery vehicles and predictive biomarkers for patient stratification. By integrating immunotherapy with bioengineering, this strategy not only restores antitumor immunity but also portends a new epoch of precision medicine for MPE.
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Affiliation(s)
- Lu Chen
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jie Yin
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Ke Xu
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - YuTing Cui
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - SuHua Zhu
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Tian Li
- Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, 8 Changjiang Avenue, Tianjin 300100, China.
| | - Tangfeng Lv
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Yong Song
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
| | - Ping Zhan
- Department of Respiratory and Critical Care Medicine, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
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Duan Q, Li R, Wang M, Cui Z, Zhu X, Chen F, Han F, Ma J. Exploring the anti-NSCLC mechanism of phillyrin targeting inhibition of the HSP90-AKT pathway. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025; 398:3789-3802. [PMID: 39356318 DOI: 10.1007/s00210-024-03481-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Accepted: 09/21/2024] [Indexed: 10/03/2024]
Abstract
Phillyrin (PHN), derived from the dried fruit of Forsythia suspensa (Thunb.) Vahl, is a kind of Chinese herbal medicine with the effect of clearing heat, and has been used in China for thousands of years in treating various tumors. However, the mechanism of its main components on non-small cell lung cancer (NSCLC) remains unclear. PHN is a distinct component extracted from Forsythia suspensa with promising anti-cancer activity against various tumor types. This study sought to elucidate the promising effects of PHN on NSCLC. Based on network pharmacology results, we identified potential PHN targets and pathways for NSCLC treatment. CCK-8 assay, wound healing assay, apoptosis assay, western blot, and in vivo experiments verified the inhibitory effect of PHN on NSCLC. Network pharmacology identified 160 potential PHN targets, 955 NSCLC-related targets, and 54 common targets, along with 132 pathways and 2 core genes. Biological experiments demonstrated that PHN significantly inhibited the growth and migration of A549 and LLC cells while promoting their apoptosis. Western blot analysis revealed down-regulation of AKT, HSP90AA1, and CDC37 expression, suggesting that PHN inhibits A549 and LLC cell proliferation by down-regulating the HSP90-AKT pathway. In vivo experiments confirmed that PHN significantly inhibited NSCLC growth with low toxicity. This study, using network pharmacology and biological experiments, verified the effectiveness of PHN against NSCLC through the HSP90-AKT pathway. These findings provide a foundation for further research and analysis.
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Affiliation(s)
- Qiong Duan
- The Affiliated Lianyungang Municipal Oriental Hospital of Xuzhou Medical University, Lianyungang, 222042, China
| | - Ruochen Li
- Sichuan Integrative Medicine Hospital, Chengdu, 610000, China
| | - Mingxiao Wang
- Sichuan Integrative Medicine Hospital, Chengdu, 610000, China
| | - Zhenting Cui
- The Affiliated Lianyungang Municipal Oriental Hospital of Xuzhou Medical University, Lianyungang, 222042, China
| | - Xia Zhu
- The Affiliated Lianyungang Municipal Oriental Hospital of Xuzhou Medical University, Lianyungang, 222042, China
| | - Fanghong Chen
- The Affiliated Lianyungang Municipal Oriental Hospital of Xuzhou Medical University, Lianyungang, 222042, China
| | - Feng Han
- The Affiliated Lianyungang Municipal Oriental Hospital of Xuzhou Medical University, Lianyungang, 222042, China.
| | - Jianxin Ma
- The Affiliated Lianyungang Municipal Oriental Hospital of Xuzhou Medical University, Lianyungang, 222042, China.
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Huang Z, Wang S, Zhou J, Chen H, Li Y. PD-L1 Scoring Models for Non-Small Cell Lung Cancer in China: Current Status, AI-Assisted Solutions and Future Perspectives. Thorac Cancer 2025; 16:e70042. [PMID: 40189932 PMCID: PMC11973252 DOI: 10.1111/1759-7714.70042] [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: 10/14/2024] [Revised: 02/27/2025] [Accepted: 03/05/2025] [Indexed: 04/10/2025] Open
Abstract
Immunotherapy has revolutionized the diagnosis and treatment model for patients with advanced non-small cell lung cancer (NSCLC). Numerous clinical trials and real-world reports have confirmed that PD-L1 status is a key factor for the successful use of immunotherapy in NSCLC, by predicting clinical outcomes and identifying patients most likely to benefit from this treatment. Therefore, accurate and standardized evaluation of PD-L1 expression is crucial. Currently, PD-L1 testing in China faces several challenges, including a heavy pathologist workload, a shortage of highly trained pathologists plus the inadequate capacity of diagnostic laboratories, confusion around different scoring methods, cut-off values, and indications, and limited concordance between PD-L1 assays. In this review, we summarize the current status and limitations of PD-L1 testing for patients with NSCLC in China and discuss recent progress in artificial intelligence-assisted PD-L1 scoring. Our review aims to support improvements in clinical PD-L1 testing practice and optimization of the prognosis and outcomes of immunotherapy in this patient population.
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Affiliation(s)
- Ziling Huang
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
| | - Shen Wang
- School of Computer ScienceFudan UniversityShanghaiChina
| | - Jiansong Zhou
- Value & Implementation, Global Medical & Scientific Affairs, MSD ChinaShanghaiChina
| | - Haiquan Chen
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
- Department of Thoracic SurgeryFudan University Shanghai Cancer CenterShanghaiChina
| | - Yuan Li
- Department of PathologyFudan University Shanghai Cancer CenterShanghaiChina
- Department of Oncology, Shanghai Medical CollegeFudan UniversityShanghaiChina
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Ziogas DC, Theocharopoulos C, Aravantinou K, Boukouris AE, Stefanou D, Anastasopoulou A, Lialios PP, Lyrarakis G, Gogas H. Clinical benefit of immune checkpoint inhibitors in elderly cancer patients: Current evidence from immunosenescence pathophysiology to clinical trial results. Crit Rev Oncol Hematol 2025; 208:104635. [PMID: 39889861 DOI: 10.1016/j.critrevonc.2025.104635] [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: 06/27/2024] [Revised: 01/20/2025] [Accepted: 01/21/2025] [Indexed: 02/03/2025] Open
Abstract
The age-related decline in immunity appears to be associated not only with cancer development but also with differential responses to immune checkpoint inhibitors (ICIs). Despite their increasing utility across various malignancies and therapeutic settings, limited data -derived primarily from subgroup analyses of randomized controlled trials (RCTs), pooled meta-analyses, and retrospective studies- are available on the effects of aging on their efficacy and toxicity. Immunosenescence, characterized by the progressive decline of the function of the immune system, and inflammaging, a state of persistent low-grade sterile inflammation, may influence ICI outcomes. Additionally, the incidence, severity, and subtypes of immune-related adverse events (irAEs) may differ between older and younger individuals due to loss of immunotolerance. In the current review, starting from a a comprehensive discussion of the pathophysiology of immunosenescence, we proceed to critically review age-related retrospective and randomized evidence supporting FDA-approved ICIs. We highlight similarities or differences across age groups and the clinical benefit of ICIs in elderly versus younger cancer patients. The optimal integration of ICIs in geriatric oncology necessitates greater inclusion of this patient demographic in RCTs along with real-world data in order to acquire robust data which will guide evidence-based treatment decisions for this population.
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Affiliation(s)
- Dimitrios C Ziogas
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Charalampos Theocharopoulos
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Katerina Aravantinou
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Aristeidis E Boukouris
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Dimitra Stefanou
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Amalia Anastasopoulou
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Panagiotis-Petros Lialios
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - George Lyrarakis
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
| | - Helen Gogas
- First Department of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
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Gridelli C, Attili I, Bennati C, Bironzo P, Bria E, Cortinovis DL, Soto Parra H, de Marinis F. Immunotherapy in advanced non-small cell lung cancer: What to do for the 'Invisible' patients after IPSOS trial results? Lung Cancer 2025; 202:108482. [PMID: 40086027 DOI: 10.1016/j.lungcan.2025.108482] [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: 02/28/2025] [Accepted: 03/02/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) are currently included in the standard of care of the first-line treatment of advanced/metastatic non-small cell lung cancer (NSCLC). However, a relevant group of clinically unfit patients, including poor Performance Status, Elderly, and those with relevant comorbidities, are not represented in most pivotal clinical trials. METHODS An expert panel meeting commentary was virtually held to point out the key issues in treating such 'invisible' patients and to review the available evidence. RESULTS Overall, clinically unfit patients represent up to 50% of patients with diagnosis of advanced/metastatic NSCLC. Few dedicated studies with immunotherapy were conducted in this population. Among them, the IPSOS trial finally answers the issue of first line immunotherapy in platinum-unfit patients with advanced NSCLC, demonstrating atezolizumab improved OS and good tolerability compared to monochemotherapy. CONCLUSIONS Atezolizumab monotherapy can be considered a valid first-line treatment in patients with advanced NSCLC who are unfit to receive platinum-based chemotherapy, including elderly, those with poor PS and/or comorbidities.
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Affiliation(s)
- Cesare Gridelli
- Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy.
| | - Ilaria Attili
- Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan, Italy
| | - Chiara Bennati
- Department of Hematology-Onco, S Maria delle Croci Hospital, Ravenna, Italy
| | - Paolo Bironzo
- Department of Oncology, University of Turin, San Luigi Hospital, 10043 Orbassano, Italy
| | - Emilio Bria
- Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Diego L Cortinovis
- Department of Medical Oncology, Fondazione IRCCS San Gerardo dei Tintori Monza, Department of Medicine, Università Milano-Bicocca, Milan, Italy
| | | | - Filippo de Marinis
- Division of Thoracic Oncology, European Institute of Oncology, IRCCS, Milan, Italy
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Zhou DDX, Dalrymple J, Klingberg D, Lin FPY, Lord SJ, Cooper WA, Zaheed M, Simes RJ, John T, Lee CK. Clinical Impact of Somatic Genomic Variants of Oncogenes and Tumor Suppressor Genes in Previously Treated Advanced Non-Small Cell Lung Cancer. JCO Precis Oncol 2025; 9:e2400673. [PMID: 40239138 DOI: 10.1200/po-24-00673] [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: 10/09/2024] [Revised: 12/18/2024] [Accepted: 03/12/2025] [Indexed: 04/18/2025] Open
Abstract
PURPOSE Next-generation sequencing in non-small cell lung cancer (NSCLC) identifies somatic genomic variants (SGVs) in cancer susceptibility genes (CSGs). We hypothesized that SGVs would be associated with poorer overall survival (OS) but greater benefit with immune checkpoint inhibitors over chemotherapy. We investigated the prevalence and predictive value of SGVs, using data from OAK and POPLAR trials comparing atezolizumab with docetaxel. METHODS We curated a list of SGVs (excluding TP53, EGFR, ALK, and ROS1) on the basis of CSGs associated with tumorigenesis. We classified participants as SGV mutant or wild-type using baseline plasma analyzed by the FoundationOne Liquid CDx assay. Cox regression analyses and interaction tests between SGV status and treatment were performed. RESULTS Of 762 participants, 29% harbored an SGV. The SGV mutant group had worse OS (hazard ratio [HR], 1.28, 95% CI, 1.06 to 1.54), and within each treatment arm (docetaxel: HR, 1.31; atezolizumab: HR, 1.27). In the atezolizumab arm, the SGV mutant group compared with wild-type had worse OS in the PD-L1 high (HR, 1.31 [95% CI, 0.59 to 2.91]) and low (HR, 1.38 [95% CI, 0.98 to 1.93]) subgroups. SGV with missense, splice, and nonsense mutations had significantly worse OS than wild-type in the docetaxel arm (log-rank P = .01) but not in the atezolizumab arm (log-rank P = .33). SGV status did not predict greater OS benefit with atezolizumab over docetaxel (interaction P = .67). CONCLUSION In advanced NSCLC after chemotherapy progression, plasma-detected SGVs are common, and associated with inferior OS. Plasma SGV status should be considered as a stratification factor in future trials.
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Affiliation(s)
- Deborah Di-Xin Zhou
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
- St George Hospital, Kogarah, NSW, Australia
| | | | | | - Frank Po-Yen Lin
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
| | - Sarah J Lord
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
| | - Wendy A Cooper
- Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, NSW Health Pathology, Camperdown, NSW, Australia
- Faculty of Medicine and Health and Western Sydney University School of Medicine, University of Sydney, Camperdown, NSW, Australia
| | - Milita Zaheed
- Prince of Wales Hereditary Cancer Centre, Randwick, NSW, Australia
| | - Robert John Simes
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
| | - Thomas John
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Chee Khoon Lee
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, NSW, Australia
- St George Hospital, Kogarah, NSW, Australia
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Chung C, Umoru G. Prognostic and predictive biomarkers with therapeutic targets in nonsmall-cell lung cancer: A 2023 update on current development, evidence, and recommendation. J Oncol Pharm Pract 2025; 31:438-461. [PMID: 38576390 DOI: 10.1177/10781552241242684] [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: 04/06/2024]
Abstract
BackgroundSince the publication of the original work in 2014, significant progress has been made in the characterization of genomic alterations that drive oncogenic addiction of nonsmall cell lung cancer (NSCLC) and how the immune system can leverage non-oncogenic pathways to modulate therapeutic outcomes. This update evaluates and validates the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in NSCLC.Data sourcesWe performed a literature search from January 2015 to October 2023 using the keywords non-small cell lung cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, circulating tumor DNA, predictive and prognostic biomarkers, and targeted therapies.Study selection and data extractionWe identified, reviewed, and evaluated relevant clinical trials, meta-analyses, seminal articles, and published clinical practice guidelines in the English language.Data synthesisRegulatory-approved targeted therapies include those somatic gene alterations of EGFR ("classic" mutations, exon 20 insertion, and rare EGFR mutations), ALK, ROS1, BRAF V600, RET, MET, NTRK, HER2, and KRAS G12C. Data for immunotherapy and circulating tumor DNA in next-generation sequencing are considered emerging, whereas the predictive role for PIK3CA gene mutation is insufficient.ConclusionsAdvances in sequencing and other genomic technologies have led to identifying novel oncogenic drivers, novel resistance mechanisms, and co-occurring mutations that characterize NSCLC, creating further therapeutic opportunities. The benefits associated with immunotherapy in the perioperative setting hold initial promise, with their long-term results awaiting.
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Affiliation(s)
- Clement Chung
- Department of Pharmacy, Houston Methodist West Hospital, Houston, TX, USA
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, USA
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You L, Wu Q. Cellular senescence in tumor immune escape: Mechanisms, implications, and therapeutic potential. Crit Rev Oncol Hematol 2025; 208:104628. [PMID: 39864532 DOI: 10.1016/j.critrevonc.2025.104628] [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: 12/23/2024] [Revised: 01/12/2025] [Accepted: 01/21/2025] [Indexed: 01/28/2025] Open
Abstract
Cellular senescence, a hallmark of aging, has emerged as a captivating area of research in tumor immunology with profound implications for cancer prevention and treatment. In the tumor microenvironment, senescent cells exhibit a dual role, simultaneously hindering tumor development through collaboration with immune cells and evading immune cell attacks by upregulating immunoinhibitory proteins. However, the intricate immune escape mechanism of cellular senescence in the tumor microenvironment remains a subject of intense investigation. Chronic inflammation is exacerbated by cellular senescence through the upregulation of pro-inflammatory factors such as interleukin-1β, thereby augmenting the risk of tumorigenesis. Additionally, the interplay between autophagy and cellular senescence adds another layer of complexity. Autophagy, known to slow down the aging process by reducing p53/p21 levels, may be downregulated by cellular senescence. To harness the therapeutic potential of cellular senescence, targeting its immunological aspects has gained significant attention. Strategies such as immune checkpoint inhibitors and T-cell senescence inhibition are being explored in the context of cellular senescence immunotherapy. In this comprehensive review, we provide a compelling overview of the regulation of cellular senescence and delve into the influencing factors, including chronic inflammation, autophagy, and circadian rhythms, associated with senescence in the tumor microenvironment. We specifically focus on unraveling the enigmatic dual role of cellular senescence in tumor immune escape. By deciphering the intricate nature of cellular senescence in the tumor microenvironment, this review aims to advance our understanding and pave the way for leveraging senescence as a promising target for tumor immunotherapy applications.
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Affiliation(s)
- Li You
- College of Physical Education and Health, Chongqing College of International Business and Economics, Chongqing 401520, China; College of Life Science, Yangtze University, Jingzhou 434025, China
| | - Qinghua Wu
- College of Life Science, Yangtze University, Jingzhou 434025, China.
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Kalkan Z, Ebinc S, Arcagok M, Bilici A, Yildiz O, Kilickap S, Guven DC, Tatli AM, Sumbul AT, Mandel NM, Ozturk A, Bardakci M, Karakaya S, Kaplan MA. Efficacy of Immunotherapy Versus Chemotherapy in Advanced Pleural Mesothelioma: A Turkish Oncology Group (TOG) Study. MEDICINA (KAUNAS, LITHUANIA) 2025; 61:638. [PMID: 40282929 PMCID: PMC12029106 DOI: 10.3390/medicina61040638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2025] [Revised: 03/26/2025] [Accepted: 03/28/2025] [Indexed: 04/29/2025]
Abstract
Background and Objectives: This study aimed to evaluate the effectiveness of immunotherapy compared to chemotherapy across different treatment lines in patients with pleural mesothelioma. It also sought to identify factors influencing the success of immunotherapy, such as histological subtype, PD-L1 expression, type of asbestos exposure, and metastatic status. Materials and Methods: A retrospective analysis was conducted with 60 patients diagnosed with pleural mesothelioma. Data on age, gender, histological subtype, and asbestos exposure were collected for all patients and PD-L1 expression was assessed in a subset of patients. Patients received either chemotherapy or immunotherapy as first-, second-, and third-line treatments, and progression-free survival (PFS) and treatment responses were evaluated. Results: Among the 60 patients, 35 (58.3%) were male and the median age was 59 years. The majority (71.7%) had epithelioid histology and 28.3% had distant metastases. Asbestos exposure was documented in 65% of the cases. PD-L1 expression of ≥1% was found in 13 of 17 patients tested. First-line treatments included immunotherapy for 11 patients and chemotherapy for the others, with immunotherapy achieving median PFS of 9 months versus 6 months for chemotherapy, although the difference was not statistically significant. In third-line treatments, immunotherapy significantly outperformed chemotherapy with median PFS of 6 months compared to 3 months (p = 0.048). Absence of metastasis and prior asbestos exposure in an endemic region were linked to better immunotherapy outcomes. Conclusion: Immunotherapy shows increased efficacy in later treatment lines for pleural mesothelioma, especially for patients without metastases or with prior endemic asbestos exposure. Tailored therapeutic strategies should be further explored in prospective studies.
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Affiliation(s)
- Ziya Kalkan
- Department of Medical Oncology, Mardin Training and Research Hospital, Mardin 47100, Türkiye
| | - Senar Ebinc
- Department of Medical Oncology, Van Yuzuncu Yil University Faculty of Medicine, Van 65100, Türkiye
| | - Murat Arcagok
- Department of Medical Oncology, Dicle University Faculty of Medicine, Diyarbakir 21100, Türkiye
| | - Ahmet Bilici
- Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul 34000, Türkiye
| | - Ozcan Yildiz
- Department of Medical Oncology, Faculty of Medicine, Medipol University, Istanbul 34000, Türkiye
| | - Saadettin Kilickap
- Department of Medical Oncology, Istinye University Faculty of Medicine, Istanbul 34000, Türkiye
| | - Deniz Can Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara 06000, Türkiye
| | - Ali Murat Tatli
- Department of Medical Oncology, Akdeniz University Faculty of Medicine, Antalya 07000, Türkiye
| | - Ahmet Taner Sumbul
- Department of Medical Oncology, Baskent University Adana Dr. Turgut Noyan Application and Research Center, Adana 01100, Türkiye
| | - Nil Molinas Mandel
- Department of Medical Oncology, American Hospital, Istanbul 34000, Türkiye
| | - Akin Ozturk
- Department of Medical Oncology, Sureyyapasa Chest Diseases and Chest Surgery Training and Research Hospital, Istanbul 34000, Türkiye
| | - Murat Bardakci
- Department of Medical Oncology, Gazi Yasargil Training and Research Hospital, Diyarbakir 21100, Türkiye
| | - Serdar Karakaya
- Department of Medical Oncology, Ankara Ataturk Sanatoryum Training and Research Hospital, Ankara 06000, Türkiye
| | - Muhammet Ali Kaplan
- Department of Medical Oncology, Dicle University Faculty of Medicine, Diyarbakir 21100, Türkiye
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Buj R, Cole AR, Danielson J, Xu J, Hurd D, Kishore A, Kedziora KM, Chen J, Yang B, Barras D, Uboveja A, Amalric A, Apiz Saab JJ, Wickramasinghe J, Tangudu NK, Levasseur E, Wang H, Minasyan A, Dadey RE, Sharrow AC, Kunning S, Vendetti FP, Rivadeneira DB, Bakkenist CJ, Bruno TC, Delgoffe GM, Hempel N, Snyder NW, Bao R, Soloff AC, Kirk-Wood JM, Dangaj Laniti D, Kossenkov AV, Muir A, Das J, Davar D, Mesaros C, Aird KM. CDKN2A Low cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.08.637227. [PMID: 39975044 PMCID: PMC11839072 DOI: 10.1101/2025.02.08.637227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Approximately 50% of cancers exhibit decreased CDKN2A expression ( CDKN2A Low ), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2A Low cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved tumor-associated macrophages (TAMs), leading to reduced phagocytic activity. Increasing zinc in TAMs through multiple approaches, including a dietary intervention that increases availability of TME zinc, re-educates these TAMs to a pro-phagocytic phenotype. Remarkably, both knockdown of Slc39a9 in cancer cells or providing a high zinc diet sensitizes Cdkn2a Low tumors to ICB. TAMs, not T cells, are indispensable for ICB response. Clinically, TAMs from CDKN2A Low cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2A Low cancer cells outcompete TAMs for zinc, directly disrupting their function and ICB efficacy.
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Koyama J, Morise M, Tanaka I, Hori S, Matsuzawa R, Ozone S, Matsushita A, Matsuo M, Asano S, Tanaka T, Shima K, Kimura T, Sakamoto K, Kondoh Y, Hashimoto N. Clinical benefit of PD-1/PD-L1 inhibitors for poor performance status patients with advanced non-small cell lung cancer. J Chemother 2025:1-10. [PMID: 40129132 DOI: 10.1080/1120009x.2025.2481349] [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: 07/29/2024] [Revised: 02/14/2025] [Accepted: 03/10/2025] [Indexed: 03/26/2025]
Abstract
The benefit of programmed cell death protein-1 (PD-1)/programmed cell death protein ligand-1 (PD-L1) inhibitors remains unclear in non-small cell lung cancer (NSCLC) patients with poor performance status (PS). In the current multi-centre retrospective cohort study, advanced or recurrent NSCLC patients treated with PD-1/PD-L1 inhibitors were enrolled. Of the 219 patients enrolled, 44 had PS 2-4. The objective response rate (ORR) of patients with PS 2-4 in 1st line was 33%. Among 1st line group, median progression-free survival (PFS) in patients with PS 2 was significantly longer compared to that in patients with PS 3-4 (15.3 months vs. 0.9 months, P = 0.039, Log-rank test). Among previously treated patients, the ORR of patients with PS 2-4 was only 4%, and PFS and overall survival was poor even in patients with PS 2. PD-1/PD-L1 inhibitors can be an option for PS 2 NSCLC patients in 1st line setting.
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Affiliation(s)
- Junji Koyama
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiro Morise
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ichidai Tanaka
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Sho Hori
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Reiko Matsuzawa
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Sachiko Ozone
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | | | - Masaki Matsuo
- Department of Respiratory Medicine, Chubu Rosai Hospital, Nagoya, Japan
| | - Shuichi Asano
- Department of Respiratory Medicine, Chukyo Hospital, Nagoya, Japan
| | - Taro Tanaka
- Department of Respiratory Medicine, Nagoya Ekisaikai Hospital, Nagoya, Japan
| | - Koichiro Shima
- Department of Respiratory Medicine, Nagoya Ekisaikai Hospital, Nagoya, Japan
| | - Tomoki Kimura
- Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan
| | - Koji Sakamoto
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kondoh
- Department of Respiratory Medicine and Allergy, Tosei General Hospital, Seto, Japan
| | - Naozumi Hashimoto
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Respiratory Medicine, Fujita Health University, Toyoake, Japan
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Gao X, Shen X, Huang S, Huang S. Classification of lung adenocarcinoma based on senescence-related genes identifies a cluster with immunotherapy resistance and poor prognosis. Discov Oncol 2025; 16:363. [PMID: 40111675 PMCID: PMC11925839 DOI: 10.1007/s12672-025-02127-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 03/11/2025] [Indexed: 03/22/2025] Open
Abstract
Lung adenocarcinoma is one of the major contributors to cancer-related mortality, with immunotherapy emerging as a key treatment. However, many patients exhibit resistance to immune checkpoint inhibitors. Cellular senescence has been linked to tumor progression and drug resistance, influencing the tumor microenvironment. This study applied consensus clustering to classify lung adenocarcinoma patients into two clusters based on senescence-related gene expression, revealing differing immune characteristics. One of the identified clusters exhibited immunosuppressive characteristics and showed resistance to immunotherapy. A senescence-related risk score was developed using machine learning to predict immunotherapy response and prognosis. High senescence-related risk score correlated with poorer survival and increased immunotherapy resistance across multiple cancer types. The senescence-related risk score model showed robust predictive ability in both the training and validation cohorts. These findings suggest a link between senescence and immunotherapy resistance, and further investigation into their relationship could reveal new perspectives for cancer treatment.
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Affiliation(s)
- Xinrui Gao
- School of Clinical Medicine, Southwest Medical University, Luzhou, Sichuan, China
| | - Xiang Shen
- Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Shasha Huang
- Department of Ultrasound, Zhongjiang People's Hospital, Deyang, Sichuan, China.
| | - Shangke Huang
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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Kilickap S, Baramidze A, Sezer A, Özgüroğlu M, Gumus M, Bondarenko I, Gogishvili M, Nechaeva M, Schenker M, Cicin I, Fuang HG, Kulyaba Y, Zyuhal K, Scheusan RI, Garassino MC, Li Y, Zhu C, Kaul M, Perez J, Seebach F, Lowy I, Pouliot JF, Kim E, Magnan H. Cemiplimab Monotherapy for First-Line Treatment of Patients with Advanced NSCLC With PD-L1 Expression of 50% or Higher: Five-Year Outcomes of EMPOWER-Lung 1. J Thorac Oncol 2025:S1556-0864(25)00178-9. [PMID: 40118215 DOI: 10.1016/j.jtho.2025.03.033] [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: 12/23/2024] [Revised: 03/04/2025] [Accepted: 03/14/2025] [Indexed: 03/23/2025]
Abstract
INTRODUCTION Earlier results from the phase 3 EMPOWER-Lung 1 trial indicated significant survival benefits and a generally acceptable safety profile of first-line cemiplimab monotherapy versus chemotherapy for patients with advanced NSCLC with programmed cell death-ligand 1 (PD-L1) expression in 50% or more tumor cells and no EGFR, ALK, or ROS1 aberrations. Here, we report the five-year outcomes. METHODS Patients were randomized 1:1 to cemiplimab 350 mg intravenously every three weeks for two years or the investigator's choice of chemotherapy. The primary endpoints were overall survival (OS) and progression-free survival. RESULTS A total of 712 patients were randomized to cemiplimab (n = 357) or chemotherapy (n = 355). The median duration of follow-up was 59.6 months (interquartile range: 55.1-66.7 months) at the data cutoff (January 16, 2024). In patients with verified 50% or higher PD-L1 (n = 565), median OS was 26.1 months for cemiplimab versus 13.3 months for chemotherapy (hazard ratio = 0.59, 95% confidence interval [CI]: 0.48-0.72); the median progression-free survival was 8.1 months versus 5.3 months (hazard ratio = 0.50, 95% confidence interval: 0.41-0.61); and the objective response rate was 46.5% versus 20.6%. The five-year OS probability was 29.0% for cemiplimab and 15.0% for chemotherapy. Improved survival outcomes were observed with both squamous and nonsquamous histology, and increasing activity of cemiplimab was correlated with higher PD-L1 expression, with the highest PD-L1 expression having the best outcome. The safety profile remains consistent with previous results. Grade 3 or higher treatment-related adverse events occurred in 18.3% of patients for cemiplimab and 39.9% for chemotherapy. CONCLUSIONS At five-year follow-up, first-line cemiplimab monotherapy continued to show durable clinical benefits versus chemotherapy in patients with advanced NSCLC with 50% or higher PD-L1. Patients with 90% or higher PD-L1 derived the largest clinical benefits.
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Affiliation(s)
- Saadettin Kilickap
- Department of Medical Oncology, Istinye University Faculty of Medicine, Istanbul, Türkiye.
| | | | - Ahmet Sezer
- Department of Medical Oncology, Başkent University, Adana, Turkey
| | - Mustafa Özgüroğlu
- Cerrahpaşa Medical Faculty, Istanbul University-Cerrahpaşa, Istanbul, Turkey
| | - Mahmut Gumus
- Department of Medical Oncology, School of Medicine, Istanbul Medeniyet University, Istanbul, Turkey
| | - Igor Bondarenko
- Department of Oncology and Medical Radiology, Dnipropetrovsk Medical Academy, Dnipro, Ukraine
| | | | - Marina Nechaeva
- Division Arkhangelsk Clinical Oncology Center, Arkhangelsk, Russia
| | | | - Irfan Cicin
- Department of Medical Oncology, Istinye University Faculty of Medicine, Istanbul, Turkey
| | - Ho Gwo Fuang
- Clinical Oncology Department, Faculty of Medicine, Universiti Malaya, Kuala Lumpur, Malaysia
| | | | - Kasimova Zyuhal
- Multiprofile Hospital for Active Treatment, Dobrich, Bulgaria
| | | | - Marina Chiara Garassino
- Department of Medicine, Section of Hematology/Oncology, Knapp Center for Biomedical Discovery, The University of Chicago, Chicago, Illinois
| | - Yuntong Li
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Cong Zhu
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Manika Kaul
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Javier Perez
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Frank Seebach
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Israel Lowy
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | | | - Eric Kim
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
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Ghazali N, Garassino MC, Leighl NB, Bestvina CM. Immunotherapy in advanced, KRAS G12C-mutant non-small-cell lung cancer: current strategies and future directions. Ther Adv Med Oncol 2025; 17:17588359251323985. [PMID: 40093982 PMCID: PMC11907553 DOI: 10.1177/17588359251323985] [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: 11/15/2024] [Accepted: 02/05/2025] [Indexed: 03/19/2025] Open
Abstract
Kirsten rat sarcoma (KRAS) mutations are present in up to 25% of non-small-cell lung cancer (NSCLC). KRAS G12C is the most common type of mutation, representing approximately half of the cases in KRAS-mutant NSCLC. Mutations in KRAS activate the RAF-MEK-ERK pathway, leading to increased cell proliferation and survival. Recent advances in drug development have led to the approval of KRAS G12C inhibitors sotorasib and adagrasib. This review explores the emerging therapeutic strategies in KRAS G12C-mutant NSCLC, including dual checkpoint blockade and combinations with checkpoint inhibitors, with a focus on the setting of advanced disease.
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Affiliation(s)
- Nadia Ghazali
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | | | - Natasha B Leighl
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Christine M Bestvina
- Department of Medicine, The University of Chicago Medicine, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637, USA
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Yang L, Gui J, Sheng Y, Liu J, Wang C, Fang Z, Huang L, Tu Z, Zhu X, Huang K. Identification of TAP2 as a novel immune target in human cancers: insights from integrated bioinformatics and experimental approaches. Eur J Med Res 2025; 30:163. [PMID: 40075453 PMCID: PMC11905508 DOI: 10.1186/s40001-025-02360-6] [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: 06/08/2024] [Accepted: 02/05/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Transporter 2, ATP binding cassette (ABC) subfamily B member (TAP2), encodes a protein within the ABC transporter superfamily. TAP2 plays a role in the progression of cancers, such as cervical, breast, and lung cancers. However, the relationship between TAP2 and cancer prognosis, immune cell infiltration, tumor microenvironment, and immunotherapy remains unexplored. Therefore, this study aims to investigate the effect of TAP2 expression on its role in predicting tumor prognosis and immunotherapy efficacy. METHODS Bioinformatics analyses such as Gene Set Enrichment Analysis, single-cell, and Connectivity Map analyses were used to comprehensively assess TAP2-related genomic alterations, prognostic value, enrichment pathways, single-cell expression patterns, and potential targeting inhibitors. In addition, molecular docking techniques were used to simulate drug binding to TAP2. WB and RT-qPCR were used to detect differences in TAP2 expression in glioma cell lines. The U251MG cell line was established with TAP2 overexpression. The effects of elevated TAP2 expression on GBM cell function was evaluated using various assays, including the Transwell migration, scratch, and clonal formation assays. RESULTS TAP2 exhibited aberrantly expression in tumor tissues with genomic alterations. TAP2 significantly correlates with poor prognosis across various cancers. It was also involved in immune-related pathways, immune infiltration, and immune checkpoint regulation, thereby influencing the tumor microenvironment and immune response to cancer. TAP2 was identified as a potential predictor of immunotherapy response and screened for potential targeted inhibitors for future therapeutic interventions. CONCLUSIONS Our findings suggest that TAP2 may serve as a promising prognostic marker and immune target in human cancers, warranting further investigation into its role in tumor immunity.
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MESH Headings
- Humans
- Computational Biology/methods
- Prognosis
- Tumor Microenvironment/immunology
- Gene Expression Regulation, Neoplastic
- Neoplasms/immunology
- Neoplasms/genetics
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cell Line, Tumor
- Molecular Docking Simulation
- Immunotherapy/methods
- ATP Binding Cassette Transporter, Subfamily B, Member 2/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 2/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 3
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Affiliation(s)
- Lufei Yang
- The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Jiawei Gui
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- HuanKui Academy, Jiangxi Medical College, Nanchang, 330031, China
| | - Yilei Sheng
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- HuanKui Academy, Jiangxi Medical College, Nanchang, 330031, China
| | - Junzhe Liu
- The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Chong Wang
- The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Zhansheng Fang
- The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
| | - Le Huang
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China
- HuanKui Academy, Jiangxi Medical College, Nanchang, 330031, China
| | - Zewei Tu
- The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China.
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China.
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
| | - Xingen Zhu
- The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China.
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China.
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
| | - Kai Huang
- The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
- Jiangxi Province Key Laboratory of Neurological Diseases, Nanchang, 330006, Jiangxi, China.
- JXHC Key Laboratory of Neurological Medicine, Nanchang, 330006, Jiangxi, China.
- Institute of Neuroscience, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, 330006, Jiangxi, China.
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Xiong A, Wang L, Chen J, Wu L, Liu B, Yao J, Zhong H, Li J, Cheng Y, Sun Y, Ge H, Yao J, Shi Q, Zhou M, Chen B, Han Z, Wang J, Bu Q, Zhao Y, Chen J, Nie L, Li G, Li X, Yu X, Ji Y, Sun D, Ai X, Chu Q, Lin Y, Hao J, Huang D, Zhou C, Shan J, Yang H, Liu X, Wang J, Shang Y, Mei X, Yang J, Lu D, Hu M, Wang ZM, Li B, Xia M, Zhou C. Ivonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in China. Lancet 2025; 405:839-849. [PMID: 40057343 DOI: 10.1016/s0140-6736(24)02722-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/11/2024] [Accepted: 12/12/2024] [Indexed: 05/13/2025]
Abstract
BACKGROUND Ivonescimab is a bispecific antibody against programmed cell death protein 1 and vascular endothelial growth factor, yielding promising clinical outcomes for patients with advanced non-small cell lung cancer in early-phase studies. We compared the efficacy and safety of ivonescimab with pembrolizumab in patients with programmed cell death ligand-1 (PD-L1)-positive advanced non-small cell lung cancer. METHODS HARMONi-2 is a randomised, double-blind, phase 3 trial across 55 hospitals in China. Eligible patients were aged 18 years or older and had locally advanced or metastatic PD-L1-positive non-small cell lung cancer without sensitising epidermal growth factor receptor mutations or anaplastic lymphoma kinase translocations and an Eastern Cooperative Oncology Group performance-status of 0 or 1. Patients were randomly assigned (1:1) to receive 20 mg/kg ivonescimab or 200 mg pembrolizumab intravenously every 3 weeks. Randomisation was stratified by histology, clinical stage, and PD-L1 expression. The primary endpoint was progression-free survival (PFS) assessed by a masked independent radiographic review committee per RECIST v1.1 in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT05499390; recruitment is complete, with the trial ongoing and final analysis to be reported later. FINDINGS Between Nov 9, 2022, and Aug 26, 2023, 398 (45%) of 879 screened patients were randomly assigned to receive ivonescimab (n=198) or pembrolizumab (n=200). At the preplanned interim analysis, median PFS was significantly longer with ivonescimab than with pembrolizumab (11·1 vs 5·8 months; stratified hazard ratio [HR] 0·51 [95% CI 0·38-0·69]; one-sided p<0·0001). The PFS benefit of ivonescimab over pembrolizumab was broadly consistent within prespecified subgroups, including patients with PD-L1 tumour proportion score (TPS) 1-49% (HR 0·54 [95% CI 0·37-0·78]) and PD-L1 TPS of 50% of higher (HR 0·48 [0·29-0·79]). Grade 3 or higher treatment-related adverse events occurred in 58 (29%) patients with ivonescimab and 31 (16%) patients with pembrolizumab. Immune-related adverse events of grade 3 or higher were observed in 14 (7%) of 197 patients on ivonescimab and 16 (8%) of 199 patients on pembrolizumab. Ivonescimab demonstrated a manageable safety profile in patients with both squamous and non-squamous non-small cell lung cancer. In patients with squamous cell carcinoma, grade 3 or higher treatment-related adverse events were comparable between the two groups. INTERPRETATION Ivonescimab significantly improved PFS compared with pembrolizumab in previously untreated patients with advanced PD-L1 positive non-small cell lung cancer. Therefore, ivonescimab might represent another treatment option in the first-line setting for PD-L1-positive advanced non-small cell lung cancer. FUNDING Akeso Biopharma.
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MESH Headings
- Humans
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Carcinoma, Non-Small-Cell Lung/drug therapy
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/pathology
- Male
- Female
- Lung Neoplasms/drug therapy
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Middle Aged
- Double-Blind Method
- Aged
- China
- B7-H1 Antigen/metabolism
- Antibodies, Bispecific/therapeutic use
- Antibodies, Bispecific/adverse effects
- Antibodies, Bispecific/administration & dosage
- Adult
- Antineoplastic Agents, Immunological/therapeutic use
- Antineoplastic Agents, Immunological/adverse effects
- Antineoplastic Agents, Immunological/administration & dosage
- Progression-Free Survival
- Immune Checkpoint Inhibitors/therapeutic use
- Immune Checkpoint Inhibitors/adverse effects
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Affiliation(s)
- Anwen Xiong
- Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Lei Wang
- Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | | | - Lin Wu
- Hunan Cancer Hospital, Changsha, China
| | - Baogang Liu
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Jun Yao
- The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
| | - Hua Zhong
- Shanghai Chest Hospital, Shanghai, China
| | - Jie Li
- The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | | | - Yulan Sun
- Shandong Cancer Hospital and Institute, Jinan, China
| | - Hui Ge
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jifang Yao
- The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Qin Shi
- Fuzhou Tuberculosis Prevention and Treatment Hospital, Fuzhou, China
| | - Ming Zhou
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, China
| | | | - Zhengxiang Han
- The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Jinliang Wang
- The Fifth Medical Center of the Chinese People's Liberation Army General Hospital, Beijing, China
| | - Qing Bu
- The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | | | | | - Ligong Nie
- Peking University First Hospital, Beijing, China
| | | | - Xingya Li
- First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xinmin Yu
- Zhejiang Cancer Hospital, Hangzhou, China
| | - Yinghua Ji
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | | | - Xiaohong Ai
- The First Affiliated Hospital of University of South China, Hengyang, China
| | - Qian Chu
- Huazhong University of Science and Technology Tongji Hospital, Tongji Medical College, Wuhan, China
| | - Yu Lin
- Fujian Cancer Hospital, Fuzhou, China
| | - Jiqing Hao
- The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Dingzhi Huang
- Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Chengzhi Zhou
- The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jinlu Shan
- Daping Hospital, Army Medical University, Chongqing, China
| | | | - Xuewen Liu
- Third Xiangya Hospital of Central South University, Changsha, China
| | - Jing Wang
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Yanhong Shang
- Affiliated Hospital of Hebei University, Baoding, China
| | - Xiaodong Mei
- The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Hefei, China
| | - Jie Yang
- Akeso Biopharma, Zhongshan, China
| | | | | | | | | | | | - Caicun Zhou
- Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China; Shanghai East Hospital, Shanghai, China.
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Almawash S. Revolutionary Cancer Therapy for Personalization and Improved Efficacy: Strategies to Overcome Resistance to Immune Checkpoint Inhibitor Therapy. Cancers (Basel) 2025; 17:880. [PMID: 40075727 PMCID: PMC11899125 DOI: 10.3390/cancers17050880] [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: 01/06/2025] [Revised: 02/09/2025] [Accepted: 02/12/2025] [Indexed: 03/14/2025] Open
Abstract
Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].
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Affiliation(s)
- Saud Almawash
- Department of Pharmaceutics, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
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Schuler M. Facts and Hopes in Neoadjuvant Immunotherapy Combinations in Resectable Non-Small Cell Lung Cancer. Clin Cancer Res 2025; 31:801-807. [PMID: 39745266 DOI: 10.1158/1078-0432.ccr-24-1441] [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: 09/23/2024] [Revised: 11/13/2024] [Accepted: 12/19/2024] [Indexed: 03/04/2025]
Abstract
Antibodies targeting immune checkpoints, such as PD-1, PD-L1, or CTLA-4, have transformed the treatment of patients with lung cancers. Unprecedented rates of durable responses are achieved in an imperfectly characterized population of patients with metastatic disease. More recently, immune checkpoint inhibitors have been explored in patients with resectable non-small cell lung cancers. Following a traditional paradigm, antibody therapies were first studied in the adjuvant setting, after surgery and chemotherapy. Pivotal trials supported global approvals of the PD-L1/-1 antibodies atezolizumab and pembrolizumab in this setting. Exciting observations were made when checkpoint inhibitors were moved to the preoperative window. Several signal-finding studies explored a limited number of cycles prior to surgery and reproducibly reported complete or major histopathologic responses. So far, six published phase III trials have demonstrated the superiority of combining the PD-1/-L1 antibodies nivolumab, pembrolizumab, durvalumab, tislelizumab, or toripalimab with 3 to 4 courses of preoperative platinum-based chemotherapy over preoperative chemotherapy alone in terms of response rates and survival endpoints. Those patients achieving complete or major histopathologic responses experienced particularly favorable long-term outcomes. It is yet unclear whether there is true synergism between immunotherapy and chemotherapy and whether outcomes are further improved by adding postoperative checkpoint inhibition. Although these pivotal trials qualify neoadjuvant chemoimmunotherapy as another option in curative lung cancer treatment, there is hope that the chemotherapy backbone will be ultimately replaced by rationally selected and targeted combination partners. In this work, the current status and future avenues of neoadjuvant combination immunotherapies in patients with non-small cell lung cancer are reviewed.
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Affiliation(s)
- Martin Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
- Medical Faculty, University Duisburg-Essen, Essen, Germany
- National Center of Tumor Diseases (NCT), NCT West, a partnership between DKFZ, University Hospital Essen, University Duisburg-Essen, University Hospital Cologne and University Cologne, Essen, Germany
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50
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Nagase W, Kudo Y, Matsubayashi J, Takahashi S, Murakami K, Furumoto H, Shimada Y, Hagiwara M, Kakihana M, Ohira T, Nagao T, Ikeda N. Immunotherapy-extended survival in patients with recurrent pulmonary pleomorphic carcinoma following surgery. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109565. [PMID: 39874612 DOI: 10.1016/j.ejso.2024.109565] [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: 10/08/2024] [Revised: 12/09/2024] [Accepted: 12/23/2024] [Indexed: 01/30/2025]
Abstract
OBJECTIVE Pulmonary pleomorphic carcinoma is a relatively rare and aggressive subtype of non-small cell lung cancer (NSCLC), with a poor prognosis and early recurrence, and is resistant to conventional therapies. This study investigated the efficacy of immune checkpoint inhibitors (ICIs) in improving the survival outcomes of patients with pulmonary pleomorphic carcinoma with postoperative recurrence. METHODS We conducted a retrospective analysis of 71 patients with pulmonary pleomorphic carcinoma who underwent pulmonary resection at Tokyo Medical University Hospital between 2008 and 2022. Clinicopathological data, programmed cell death ligand 1 (PD-L1) expression, and postoperative recurrence treatment outcomes were reviewed. RESULTS Among the 71 patients with pulmonary pleomorphic carcinoma, the 5-year overall survival (OS) rate was 48.6 %, and high PD-L1 expression (28-8 clone) was observed in 87 %. The median recurrence-free survival (RFS) was 19.4 months, and postoperative recurrence occurred in 38 patients (54 %). Treatment after recurrence was administered to 24 patients (63 %), and immunotherapy was administered to 10 patients (26 %). In patients treated with ICI, the overall response rate (ORR) was significantly higher (50 %) compared to those treated without ICI (7 %). The median survival time after relapse was notably longer in the ICI-treated group (83.9 months), compared to the non-ICI group (10.1 months). CONCLUSION ICIs significantly improve survival outcomes in patients with recurrent pulmonary pleomorphic carcinoma, particularly in those with high PD-L1 expression. Early postoperative recurrence and rapid progression have been observed, making therapeutic intervention challenging. Close follow-up is crucial, and ICIs become a pivotal treatment option for managing this highly aggressive cancer.
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Affiliation(s)
- Wakako Nagase
- Department of Surgery, Tokyo Medical University, Japan
| | - Yujin Kudo
- Department of Surgery, Tokyo Medical University, Japan.
| | - Jun Matsubayashi
- Department of Anatomic Pathology, Tokyo Medical University, Japan.
| | | | | | | | | | | | | | - Tatsuo Ohira
- Department of Surgery, Tokyo Medical University, Japan
| | - Toshitaka Nagao
- Department of Anatomic Pathology, Tokyo Medical University, Japan
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