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Zhang Y, Fan W, Su F, Zhang X, Du Y, Li W, Gao Y, Hu W, Zhao J. Discussion on the mechanism of HER2 resistance in esophagogastric junction and gastric cancer in the era of immunotherapy. Hum Vaccin Immunother 2025; 21:2459458. [PMID: 39875210 PMCID: PMC11776468 DOI: 10.1080/21645515.2025.2459458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/11/2025] [Accepted: 01/24/2025] [Indexed: 01/30/2025] Open
Abstract
Human epidermal growth factor receptor 2 (HER2) is a critical biomarker and therapeutic target in gastric/gastroesophageal junction (G/GEJ) cancers, despite the initial success of HER2-targeted therapies, such as trastuzumab, resistance to these drugs has emerged as a major impediment to effective long-term treatment. This review examines the mechanisms of drug resistance in HER2-positive G/GEJ cancer, the primary mechanisms of resistance explored include alterations in the HER2 receptor itself, such as mutations and changes in expression levels, as well as downstream signaling pathways, and interactions with the tumor microenvironment (TME). Furthermore, the review discusses the Novel therapeutic approaches, including the use of antibody-drug conjugates (ADCs) and combination therapies are assessed for their potential to enhance outcomes. By integrating recent research findings and clinical trials, this review aims to provide oncologists and researchers with insights into developing more effective treatments for patients with drug-resistant HER2-positive G/GEJ cancer.
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Affiliation(s)
- Yan Zhang
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Changzhi Medical College, Changzhi, Shanxi, China
| | - Wenxuan Fan
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Fei Su
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaoling Zhang
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Yunyi Du
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Weiling Li
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
- Graduate School, Changzhi Medical College, Changzhi, Shanxi, China
| | - Yangjun Gao
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Wenqing Hu
- Department of Gastrointestinal Surgery, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
| | - Jun Zhao
- Department of Oncology, Changzhi People’s Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, China
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Zhang SH, Li W, Chen XY, Nie LL. Combining immune checkpoint inhibitors with standard treatment regimens in advanced human epidermal growth factor receptor-2 positive gastric cancer patients. World J Gastrointest Oncol 2025; 17:103855. [DOI: 10.4251/wjgo.v17.i4.103855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 01/12/2025] [Accepted: 02/07/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND Gastric cancer is one of the most common malignant tumors worldwide, with its incidence and mortality rates ranking among the highest in gastrointestinal cancers. The overexpression or gene amplification of human epidermal growth factor receptor 2 (HER-2) occurs in approximately 15%-20% of gastric cancers and serves as a critical molecular target influencing prognosis and treatment outcomes. For patients with HER-2-positive gastric cancer, trastuzumab combined with platinum-based chemotherapy has been established as the standard first-line treatment. However, despite the demonstrated clinical benefits in prolonging survival, the overall efficacy remains limited. In recent years, with the successful application of immune checkpoint inhibitors (ICIs) in various malignant tumors, combining ICIs with existing standard treatment regimens has emerged as a promising approach to enhance the therapeutic efficacy of HER-2-positive gastric cancer. Nevertheless, the efficacy and prognostic factors of ICIs combined with trastuzumab and chemotherapy in HER-2-positive gastric cancer remain unclear.
AIM To analyze the efficacy of ICIs combined with standard treatment regimens and the prognostic factors in patients with advanced HER-2-positive gastric cancer.
METHODS Clinical data from 104 patients with advanced HER-2-positive gastric cancer who were treated at our hospital between March 2021 and May 2023 were retrospectively analyzed. Patients were divided into a control group (n = 54, treated with trastuzumab combined with platinum-based chemotherapy as the standard regimen) and an observation group (n = 50, treated with ICIs in addition to the standard regimen). The therapeutic efficacy, survival outcomes, and adverse reactions were compared between the two groups. Univariate and Cox multivariate analyses were performed to identify factors influencing patient prognosis.
RESULTS With a median follow-up time of 14.6 months, there were no significant differences between the two groups in terms of objective response rate or disease control rate (P > 0.05). The median progression-free survival (mPFS) and mPFS for patients with immunohistochemistry 3 + in the observation group were significantly higher than those in the control group (P < 0.05). Among patients in the observation group, those with positive programmed death-ligand 1 (PD-L1) expression had a significantly higher mPFS than those with negative PD-L1 expression (P < 0.05). Regarding adverse events, significant differences were observed between the two groups in hypothyroidism and neutropenia (P < 0.05). Cox multivariate analysis showed that Eastern Cooperative Oncology Group (ECOG) performance status, peritoneal metastasis, positive programmed death-1 expression, and treatment regimen were independent factors influencing PFS (hazard ratio > 1, P < 0.05).
CONCLUSION ICIs combined with standard treatment regimens for patients with advanced HER-2-positive gastric cancer demonstrate favorable clinical efficacy, significantly prolonging PFS with manageable safety. ECOG performance status, peritoneal metastasis, positive PD-L1 expression, and treatment regimen are independent factors influencing PFS, warranting increased clinical attention to patients exhibiting these factors.
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Affiliation(s)
- Sheng-Hu Zhang
- Department of Oncology, Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Yangtze university, Jingzhou 434020, Hubei Province, China
| | - Wan Li
- Department of Ultrasound Medicine, Jingzhou Central Hospital, Jingzhou Hospital Affiliated to Yangtze university, Jingzhou 434020, Hubei Province, China
| | - Xi-Yan Chen
- Department of Medicine Imaging, The First People’s Hospital of Fuzhou City, Fuzhou 344000, Jiangxi Province, China
| | - Le-Le Nie
- Department of General Surgery, The First People’s Hospital of Fuzhou City, Fuzhou 344000, Jiangxi Province, China
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Liu D, Gong J, Li J, Qi C, Niu Z, Liu B, Peng Z, Luo S, Wang X, Wang Y, Zhao R, Chen L, Deng T, Li Z, Chen L, Fang M, Yang H, Lu L, Zhang Y, Kang F, Xu T, Zhang X, Shen L. Efficacy and safety of KN026, a bispecific anti-HER2 antibody, in combination with KN046, an anti-CTLA4/PD-L1 antibody, in patients with advanced HER2-positive nonbreast cancer: a combined analysis of a phase Ib and a phase II study. Signal Transduct Target Ther 2025; 10:104. [PMID: 40108113 PMCID: PMC11923254 DOI: 10.1038/s41392-025-02195-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2024] [Revised: 02/26/2025] [Accepted: 02/27/2025] [Indexed: 03/22/2025] Open
Abstract
To evaluate the efficacy and safety of KN026, a novel bispecific HER2 (ECD2 and ECD4) antibody, plus KN046, a PD-L1, and CTLA4 bispecific antibody, in patients with advanced HER2-positive solid tumors. We conducted two sequentially designed phase Ib and II studies with similar target populations and evaluation schedules. The primary endpoints included safety, maximum tolerated dose (MTD), the recommended phase II dose (RP2D) for the phase Ib study, and the objective response rate (ORR) and duration of response (DoR) for the phase II study. Hereby, we solely report the results from 113 nonbreast cancer patients. In phase Ib, MTD was not reached. Dose 3 was confirmed to be acceptable for the phase II study. An objective response has been exclusively observed in HER2-positive patients. Any grade treatment-related adverse events (TRAEs) were reported in 108 (95.6%) patients. The most common TRAEs were infusion reactions (38.9%), anemia (37.2%), elevated AST (31.0%), and diarrhea (30.1%). Among the 108 patients evaluated for efficacy, the overall ORR was 55.6% (95%CI, 45.7%, 65.1%). In the HER2-positive GC subgroup, 38 patients received this regimen as the 1st-line treatment and 30 patients achieved an objective response, with an ORR of 78.9% (95%CI, 62.7%, 90.4%). Among 27 pretreated patients, the ORR was 44.4% (95%CI, 25.5%, 64.7%). In the other HER2-positive solid tumor subgroup (n = 34), the ORR was 52.9% (95%CI 35.1%,70.2%). Thus, KN026 plus KN04 exhibits promising efficacy and acceptable safety profiles in HER2-positive nonbreast cancer, as does the 1st-line treatment for GC.
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Affiliation(s)
- Dan Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Center, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jifang Gong
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jian Li
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Changsong Qi
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Early Drug Development Center, Peking University Cancer Hospital and Institute, Beijing, China
| | - Zuoxing Niu
- Department of Medical Oncology, Cancer Hospital of Shandong First Medical University (Shandong Cancer Hospital), Jinan, Shandong, China
| | - Bo Liu
- Department of Medical Oncology, Cancer Hospital of Shandong First Medical University (Shandong Cancer Hospital), Jinan, Shandong, China
| | - Zhi Peng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Suxia Luo
- Department of Internal Medicine, Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Xicheng Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Yakun Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Rusen Zhao
- Department of Medical Oncology, Zibo Municipal Hospital, Zibo, Shandong, China
| | - Lilin Chen
- Department of Medical Oncology, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China
| | - Ting Deng
- Department of GI Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Zhen Li
- Department of Internal Medicine Ward 5, Linyi Cancer Hospital, Linyi, Shandong, China
| | - Lei Chen
- Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Meimei Fang
- Department of Medical Oncology, Cancer Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Hongwei Yang
- Department of Breast and Thyroid Surgery, Suining Central Hospital, Suining, Sichuan, China
| | - Linzhi Lu
- Gastroenterology Department, Gansu Wuwei Tumour Hospital, Wuwei, Gansu, China
| | - Yanming Zhang
- Oncology Inpatient Area 2/3, Linfen Central Hospital, Linfen, Shanxi, China
| | - Fengling Kang
- Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Suzhou, Jiang Su, China
| | - Ting Xu
- Jiangsu Alphamab Biopharmaceuticals Co., Ltd., Suzhou, Jiang Su, China
| | - Xiaotian Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China.
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Ma Y, Yang Y, Huang Y, Fang W, Xue J, Meng X, Fan Y, Fu S, Wu L, Zheng Y, Liu J, Liu Z, Zhuang W, Rosen S, Qu S, Li B, Li M, Zhao Y, Yang S, Ji Y, Sommerhalder D, Luo S, Yang K, Li J, Lv D, Zhang P, Zhao Y, Hong S, Zhang Y, Zhao S, Chin S, Zhang X, Lian W, Cai J, Xue T, Zhang L, Zhao H. A B7H3-targeting antibody-drug conjugate in advanced solid tumors: a phase 1/1b trial. Nat Med 2025:10.1038/s41591-025-03600-2. [PMID: 40082695 DOI: 10.1038/s41591-025-03600-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Accepted: 02/20/2025] [Indexed: 03/16/2025]
Abstract
Antibody-drug conjugates (ADCs) have emerged as a transformative modality in the treatment of solid tumors. YL201, a novel B7H3-targeting ADC, leverages a tumor microenvironment activable linker-payload platform, coupled with a novel topoisomerase 1 inhibitor via a protease-cleavable linker. Here we report the findings from a large-scale, global, multicenter, phase 1 trial evaluating the safety, pharmacokinetics and preliminary efficacy of YL201 in patients with advanced solid tumors refractory to standard therapies. The trial included a dose-escalation part (phase 1) and a dose-expansion part (phase 1b). A total of 312 patients were enrolled across multiple tumor types, including extensive-stage small cell lung cancer (ES-SCLC), nasopharyngeal carcinoma (NPC), non-small cell lung cancer, esophageal squamous cell carcinoma and other solid tumors. The maximum tolerated dose was determined to be 2.8 mg kg-1, and the recommended expansion dose was selected as 2.0 mg kg-1 and 2.4 mg kg-1 every 3 weeks. The most common grade 3 or higher treatment-related adverse events included neutropenia (31.7%), leukopenia (29.5%) and anemia (25.0%). Only 4 cases of interstitial lung disease (1.3%) and 1 case of infusion reactions (0.3%) were observed. Encouraging anti-tumor activity was observed, particularly in patients with ES-SCLC (objective response rate (ORR), 63.9%), NPC (ORR, 48.6%), lung adenocarcinoma (ORR, 28.6%) and lymphoepithelioma-like carcinoma (ORR, 54.2%). No significant correlation between B7H3 membrane expression and the ORR was found. YL201 demonstrated an acceptable safety profile and a promising efficacy in heavily pretreated patients with advanced solid tumors, particularly in those with ES-SCLC, NPC or lymphoepithelioma-like carcinoma. Phase 3 clinical trials for patients with SCLC and NPC have already been initiated. ClinicalTrials.gov identifiers: NCT05434234 and NCT06057922 .
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Affiliation(s)
- Yuxiang Ma
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Yunpeng Yang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Yan Huang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Wenfeng Fang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Jinhui Xue
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Xiangjiao Meng
- Department of Chest Radiotherapy IV, Shandong Cancer Hospital and Institute, Jinan, China
| | - Yun Fan
- Department of Chest Medicine, Zhejiang Cancer Hospital, Hangzhou, China
| | - Siqing Fu
- The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lin Wu
- Department of Internal Thoracic, Hunan Cancer Hospital, Changsha, China
| | - Yulong Zheng
- Department of Medical Oncology/Clinical Pharmacy Research Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jian Liu
- Department of Medical Oncology/Clinical Pharmacy Research Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Zhihua Liu
- Department of Thoracic Tumor Radiotherapy I, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Wu Zhuang
- Department of Thoracic Oncology, Fujian Cancer Hospital, Fuzhou, China
| | - Seth Rosen
- Hematology Oncology Associates of the Treasure Coast, Port Saint Lucie, FL, USA
| | - Song Qu
- Department of Radiotherapy, Affiliated Cancer Hospital of Guangxi Medical University, Nanning, China
| | - Bihui Li
- Department of Medical Oncology, The Second Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Mingjun Li
- Department of Oncology II, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanqiu Zhao
- Department of Respiratory Medicine I, Henan Cancer Hospital, Zhengzhou, China
| | - Shujun Yang
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Yinghua Ji
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | | | - Suxia Luo
- Phase I Clinical Trial Center, Henan Cancer Hospital, Zhengzhou, China
| | - Kunyu Yang
- Department of Head and Neck Oncology, Union Hospital Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingao Li
- Department of Head and Neck Radiotherapy II, Jiangxi Cancer Hospital (Jiangxi Second People's Hospital), Nanchang, China
| | - Dongqing Lv
- Department of Respiratory Medicine, Taizhou Hospital of Zhejiang Province, Taizhou, China
| | - Peng Zhang
- Department of Radiotherapy, Sichuan Cancer Hospital, Chengdu, China
| | - Yuanyuan Zhao
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Shaodong Hong
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Yang Zhang
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Shen Zhao
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China
| | - Steve Chin
- MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China
| | - Xian Zhang
- MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China
| | - Wei Lian
- MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China
| | - Jiaqiang Cai
- MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China
| | - Tongtong Xue
- MediLink Therapeutics (Suzhou) Co., Ltd., Suzhou, China.
| | - Li Zhang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
| | - Hongyun Zhao
- Department of Clinical Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Guangzhou, China.
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Alsina Maqueda M, Teijo Quintáns A, Cuatrecasas M, Fernández Aceñero MJ, Fernández Montes A, Gómez Martín C, Jiménez Fonseca P, Martínez Ciarpaglini C, Rivera Herrero F, Iglesias Coma M. Biomarkers in gastroesophageal cancer 2025: an updated consensus statement by the Spanish Society of Medical Oncology (SEOM) and the Spanish Society of Pathology (SEAP). Clin Transl Oncol 2025:10.1007/s12094-025-03865-6. [PMID: 40072752 DOI: 10.1007/s12094-025-03865-6] [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: 01/28/2025] [Indexed: 03/14/2025]
Abstract
Gastroesophageal carcinomas, including gastroesophageal adenocarcinoma (GEA) and esophageal squamous cell carcinoma (ESCC), pose a global health challenge due to their heterogeneity. The approach to diagnosis and treatment should first differentiate between GEA and ESCC. Over the past decade, therapies for metastatic or advanced GEA/ESCC have expanded, with several new therapeutic targets alongside trastuzumab for metastatic HER2-positive GEA. Four key biomarkers are essential for targeted therapy: HER2 overexpression/amplification, deficient mismatch repair/microsatellite instability (dMMR/MSI), PD-L1, and Claudin18.2 expression. Immunohistochemistry is the recommended method for these biomarkers evaluation. In addition, the assessment of biomarkers like FGFR2b is likely to become routine in the near future. Experts from the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM) have formed a consensus to optimize biomarker detection and usage in clinical practice. Their recommendations aim to improve personalized treatment strategies for GEA and ESCC patients, integrating new diagnostic insights into routine care.
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Affiliation(s)
- Maria Alsina Maqueda
- Medical Oncology Department, Unidad de Oncología Médica Traslacional, Hospital Universitario de Navarra, Navarrabiomed - Centro de Investigación Sanitaria de Navarra, Pamplona, Spain.
| | - Ana Teijo Quintáns
- Pathology Department, Gastrointestinal and Neuroendocrine Tumors Research Group, Hospital Universitario 12 de Octubre, Research Institute (Imas12), Madrid, Spain
| | - Miriam Cuatrecasas
- Pathology Department, Hospital Clinic de Barcelona, Biomedical Research Institute IDIBAPS, University of Barcelona, Barcelona, Spain
| | - Maria Jesús Fernández Aceñero
- Department of Legal Medicine, Psychiatry and Pathology, Surgical Pathology Department, Hospital Clínico Universitario San Carlos, nstituto de Investigación Sanitaria Clínico San Carlos (IdISSC), Universidad Complutense, Madrid, Spain
- , Madrid, Spain
| | - Ana Fernández Montes
- Medical Oncology Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain
| | - Carlos Gómez Martín
- Gastrointestinal Cancer and Early Clinical-Translational Research Units, Medical Oncology Division, 12 de Octubre University Hospital, Madrid, Spain
| | - Paula Jiménez Fonseca
- Department of Medical Oncology, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - Carolina Martínez Ciarpaglini
- Pathology Department, Hospital Clínico Universitario de Valencia, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
| | - Fernando Rivera Herrero
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - Mar Iglesias Coma
- Pathology Department, Hospital del Mar, Pompeu Fabra University, Hospital del Mar Research Institute, Barcelona, Spain.
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He L, Liu B, Wang Z, Han Q, Chen H. Evolving Landscape of HER2-Targeted Therapies for Gastric Cancer Patients. Curr Treat Options Oncol 2025:10.1007/s11864-025-01300-0. [PMID: 40056280 DOI: 10.1007/s11864-025-01300-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2025] [Indexed: 03/10/2025]
Abstract
OPINION STATEMENT Gastric cancer (GC) is a deadly disease worldwide, and trastuzumab in combination with chemotherapy has been the standard first-line treatment for HER2-positive GC following the TOGA trial. Besides adjuvant therapy, HER2-directed therapy is widely used as neoadjuvant or translational therapy, and survival benefit even surgical opportunities is seen in these patients. However, resistance is not rare in recent years, and the second-line treatment for trastuzumab beyond progression has received widespread attention in GC. Moreover, current evidence cannot recommend trastuzumab for patients with IHC1+ HER2 low expression GC yet. Researchers are currently investigating whether GC patients with low HER2 expression could also benefit from HER2-directed therapies. In addition to using HER2 as a target for targeted therapy, HER2-mediated targeted delivery of cytotoxic drugs and targeted immunity have made important contributions to overcoming trastuzumab resistance in recent trials. HER2/neu-derived peptide epitopes vaccination and HER2-specific chimeric antigen receptor (CAR) therapy focus on reestablishing anti-tumor immunity in different ways and show significant anti-tumor activity. Other antibodies that target different regions of the HER2 receptor or block key downstream pathways such as AKT or PI3K also offer potential anti-tumor activity against HER2. HER2 use in GC will not be hampered by resistance or low expression and will play a bigger role. We review the current efforts to enable GC patients with trastuzumab-resistant and HER2 low-expressing accessible to HER2 targeted therapy and present our consideration for future HER2 in GC.
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Affiliation(s)
- Lijuan He
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Ben Liu
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Zhuanfang Wang
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Qinying Han
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Hao Chen
- Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Gansu Provincial Key Laboratory of Environmental Oncology, Lanzhou, 730030, China.
- Humanized animal model laboratory, Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 201620, China.
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7
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Liao D, Zhang J, Yan T, Chen Y, Fu Y, Xie N, Long M. A Systematic Review of Mechanisms, Incidence, and Management of Trastuzumab Deruxtecan Induced ILD/Pneumonitis in Solid Tumors. Drug Des Devel Ther 2025; 19:1655-1668. [PMID: 40083848 PMCID: PMC11904318 DOI: 10.2147/dddt.s508773] [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: 02/28/2025] [Indexed: 03/16/2025] Open
Abstract
Trastuzumab deruxtecan (T-DXd) has been approved to treat various tumors. While most adverse events (AEs) associated with T-DXd are manageable, interstitial lung disease (ILD)/pneumonitis is a notable AE of special concern. This review describes the incidence, severity, and management of T-DXd-induced ILD/pneumonitis across different tumors. We conducted a systematic search of PubMed, Embase, Cochrane Library, and Web of Science for literature published up to 13 September 2024, regarding the use of T-DXd in the treatment of HER2-positive tumors. Studies included were clinical trials involving HER2-positive tumors with reported ILD/pneumonitis cases.The main data extracted from the full-text articles included the incidence and severity of T-DXd-induced ILD. 18 studies involving 3380 patients with various advanced solid malignancies were included in our review. The overall incidence of adjudicated drug-related ILD/pneumonitis was 12.40%. Although most ILD/pneumonitis cases were low-grade, the risk of ILD/pneumonitis-related death should not be overlooked. Given the prolonged exposure to the drug, careful monitoring and management of T-DXd-induced ILD/pneumonitis are critical. Management strategies include dose reduction, treatment interruption, discontinuation, corticosteroids, and supportive care. Further research is needed to clarify the risk factors and mechanisms underlying T-DXd-induced ILD/pneumonitis. This review highlights critical gaps in understanding the risk factors and mechanisms of T-DXd-induced ILD, underscoring the need for further research.
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Affiliation(s)
- Dehua Liao
- Department of Pharmacy, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
| | - Jiwen Zhang
- Department of Pharmacy, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
- School of Pharmacy, University of South China, Hengyang, People’s Republic of China
| | - Ting Yan
- Department of Pharmacy, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
| | - Yun Chen
- Department of Pharmacy, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
| | - Yilan Fu
- Department of Pharmacy, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
| | - Ning Xie
- Medical Department of Breast Cancer, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
| | - Minghui Long
- Department of Pharmacy, Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
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8
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Cammarota A, Woodford R, Smyth EC. Targeting HER2 in Gastroesophageal Cancer: A New Appetite for an Old Plight. Drugs 2025; 85:361-383. [PMID: 39843758 DOI: 10.1007/s40265-024-02132-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/21/2024] [Indexed: 01/24/2025]
Abstract
The incidence of gastroesophageal cancers is rising, driven, in part, by an increasing burden of risk factors of obesity and gastroesophageal reflux. Despite efforts to address these risk factors, and a growing interest in methods of population screening, the bulk of these tumours are unresectable at diagnosis. In this setting, effective systemic treatments are paramount to improve survival and quality of life. Early and accurate identification of oncogenic drivers, such as human epidermal growth factor receptor 2 (HER2), present in 5-30% of gastroesophageal adenocarcinomas (GEAs), is integral to guide choice of therapies due to the clear predictive implications that arise from overexpression of this receptor. After trastuzumab, the first anti-HER2 agent with approved use in HER2-positive GEA, the addition of pembrolizumab to first-line trastuzumab-chemotherapy and trastuzumab deruxtecan in the refractory space have more recently changed practice. Yet, the response to these agents has been vastly different across patients with HER2-positive disease, underpinning the need for reliable biomarkers of response. Emergent data have suggested that levels of HER2 expression on tissue or liquid biopsies may predict response to first-generation HER2 therapies while HER2 heterogeneity, receptor changes, co-occurring molecular alterations and oncogenic genomic and metabolic reprogramming may be implicated in resistance. A robust knowledge of the mechanisms of resistance and response to HER2-directed therapies is necessary to inform novel strategies of HER2-targeting and guide choice combinations with other biomarker-directed therapies, to improve outcomes from a new generation of clinical trials in HER2-positive GEA. Understanding and close examination of previous failures in this space form an important part of this assessment, as does correlative biomarker and translational work pertaining to the role of HER2 and dynamic changes that result through treatment exposure. In this review, we aim to provide an overview of strategies for HER2 targeting, summarising both the successes and disappointments in this therapeutic landscape and discuss existing challenges and future perspectives on development in this highly morbid tumour type.
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Affiliation(s)
- Antonella Cammarota
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- Department of Medical Sciences, Humanitas University, Via Rita Levi Montalcini, Pieve Emanuele, Milan, Italy
| | - Rachel Woodford
- Sarah Cannon Research Institute UK, 93 Harley St, London, UK
- National Health and Medical Research Council Clinical Trials Centre (NHMRC CTC), University of Sydney, Parramatta Road, Camperdown, Australia
| | - Elizabeth C Smyth
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
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9
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Jiang W, Zhang B, Xu J, Xue L, Wang L. Current status and perspectives of esophageal cancer: a comprehensive review. Cancer Commun (Lond) 2025; 45:281-331. [PMID: 39723635 PMCID: PMC11947622 DOI: 10.1002/cac2.12645] [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: 07/01/2024] [Revised: 12/08/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024] Open
Abstract
Esophageal cancer (EC) continues to be a significant global health concern, with two main subtypes: esophageal squamous cell carcinoma and esophageal adenocarcinoma. Prevention and changes in etiology, improvements in early detection, and refinements in the treatment have led to remarkable progress in the outcomes of EC patients in the past two decades. This seminar provides an in-depth analysis of advances in the epidemiology, disease biology, screening, diagnosis, and treatment landscape of esophageal cancer, focusing on the ongoing debate surrounding multimodality therapy. Despite significant advancements, EC remains a deadly disease, underscoring the need for continued research into early detection methods, understanding the molecular mechanisms, and developing effective treatments.
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Affiliation(s)
- Wei Jiang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenGuangdongP. R. China
| | - Bo Zhang
- Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Jiaqi Xu
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Liyan Xue
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Luhua Wang
- Department of Radiation OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeShenzhenGuangdongP. R. China
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10
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Markides DM, Hita AG, Merlin J, Reyes-Gibby C, Yeung SCJ. Antibody-Drug Conjugates: The Toxicities and Adverse Effects That Emergency Physicians Must Know. Ann Emerg Med 2025; 85:214-229. [PMID: 39641680 DOI: 10.1016/j.annemergmed.2024.10.015] [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: 05/23/2024] [Revised: 10/03/2024] [Accepted: 10/15/2024] [Indexed: 12/07/2024]
Abstract
Antibody-drug conjugates are novel antineoplastic agents whose use is expanding, both in terms of the number of drugs and the number of patients being treated. This article reviews the known toxicities and complications of antibody-drug conjugates that are currently approved for the treatment of cancer in the United States, with a focus on their emergency presentation and management. Similar to many other cancer therapies, most antibody-drug conjugates can cause diarrhea, nausea/vomiting, rash, peripheral neuropathy, and cytopenia, which are generally treated following standard-of-care. Interstitial lung disease, which may mimic pneumonia and cause respiratory failure and death, has been seen with trastuzumab deruxtecan and mirvetuximab soravtansine; emergency treatment of this condition includes oxygenation, ventilatory support, and corticosteroids. Inotuzumab ozogamicin and gemtuzumab ozogamicin are both associated with sinusoidal obstruction syndrome, a potentially fatal liver dysfunction that presents with weight gain, fluid overload, and jaundice. Abnormal liver function tests in patients who have been recently treated with these agents should be cautiously evaluated. Cardiac adverse events with antibody-drug conjugates are rare, but trastuzumab emtansine and trastuzumab deruxtecan may cause a decrease in cardiac contractility, and heart rate corrected QT interval prolongation is a rare effect of trastuzumab deruxtecan. Ocular adverse events, especially blurred vision, and keratopathy, are common with mirvetuximab soravtansine and tisotumab vedotin. Progressive multifocal leukoencephalopathy has been reported with brentuximab vedotin and polatuzumab vedotin. Tumor lysis syndrome may occur after treatment with gemtuzumab ozogamicin, polatuzumab vedotin, and brentuximab vedotin. Patients receiving enfortumab vedotin or brentuximab vedotin may develop hyperglycemia, sometimes presenting as diabetic ketoacidosis. Tisotumab vedotin and trastuzumab emtansine are associated with bleeding; although it is minor in most cases, severe bleeding and intracranial hemorrhage have occurred. Several antibody-drug conjugates can cause an anaphylactoid infusion-related reaction, which occurs most commonly during or soon after infusion but may be delayed up to 24 hours. Further research is needed to establish the real-world incidence of rare complications and how often patients with these complications present to the emergency department.
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Affiliation(s)
| | - Angel Guido Hita
- Department of Emergency Medicine, MD Anderson Cancer Center, Houston, TX
| | - Jeffrey Merlin
- Department of Emergency Medicine, MD Anderson Cancer Center, Houston, TX
| | - Cielto Reyes-Gibby
- Department of Emergency Medicine, MD Anderson Cancer Center, Houston, TX
| | - Sai-Ching J Yeung
- Department of Emergency Medicine, MD Anderson Cancer Center, Houston, TX
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11
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Dienstmann R, Ruiz-García E, Alsina M, Ruiz-Pace F, Groen-van Schooten TS, Martínez-Ciarpaglini C, Fernández-Figueroa EA, Herrera-Goepfert R, Díaz-Romero C, Lino-Silva L, Hernandez-Guerrero AI, Valdez-Reyes NM, León-Takahashi A, Falcón-Martínez JC, Pouw RE, Romero S, Villagrasa R, Cabeza-Segura M, Alarcón-Molero L, Jimenez-Martí E, Miralles A, Boggino H, Gauna C, Pereira R, Lezcano H, Cantero D, Vivancos A, Matito J, Martin A, Gómez M, Castillo E, Vila M, Ferreira RM, Barros R, Santos-Antunes J, Mendes-Rocha M, Costa A, Riquelme E, Roa JC, Latorre G, Freile B, Caro L, Esteso F, O'Connor J, Riquelme A, Owen G, Garrido M, Diez-García M, Figueiredo C, Caballero C, Lordick F, Farrés J, Derks S, Carneiro F, Cervantes A, Fleitas T. Integrated clinico-molecular analysis of gastric cancer in European and Latin American populations: LEGACY project. ESMO Open 2025; 10:104482. [PMID: 40036904 PMCID: PMC11926697 DOI: 10.1016/j.esmoop.2025.104482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2024] [Revised: 01/27/2025] [Accepted: 02/04/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is recognized for intrinsic heterogeneity, although it is similarly approached in Europe and Latin America (LATAM). The LEGACY project aimed to deepen GC molecular understanding through multi-omics analysis in Europe and LATAM GC samples. PATIENTS AND METHODS Tumor samples were centrally reviewed for histology, human epidermal growth factor receptor 2 (HER2) expression, and mismatch repair-deficient (dMMR)/microsatellite instability (MSI) status. In addition, we assessed Epstein-Barr virus (EBV) status, programmed death-ligand 1 (PD-L1) combined positive score (CPS), and carried out tissue genomic profiling including tumor mutation burden (TMB) quantification plus targeted transcriptomics for immune microenvironment and cancer cell signaling scores. RESULTS In total, 328 GC patients were enrolled. HER2-positive GC and high PD-L1 CPS were more frequent in Europe than in LATAM (9% versus 3% and 15% versus 3%, respectively), whereas EBV was mainly found in LATAM (7%, versus 3% in Europe), and dMMR/MSI tumors were equally distributed (16%). High TMB was enriched in dMMR/MSI and EBV tumors. Mutations in homologous recombination repair (HRR) genes were frequent in both cohorts (24.8% and 14.7% in Europe and LATAM, respectively), and mostly found in dMMR/MSI (63.6%) and intestinal HER2-negative (18.7%) tumors. The prognosis was poor in diffuse HER2-negative GC patients, whose tumors presented an immunosuppressive microenvironment and other distinct pathway activation signatures. CONCLUSIONS Our findings relate specific molecular alterations of GC tumors from Europe and LATAM to actionable biomarkers for precision cancer therapies. The proposed GC stratification can be implemented in routine care and guide drug development strategies.
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Affiliation(s)
- R Dienstmann
- Oncology Data Science, Vall d´Hebron Institute of Oncology, Barcelona, Spain; OC Precision Medicine, Oncoclínicas & Co, São Paulo, Brazil; University of Vic-Central University of Catalonia, Barcelona, Spain. https://twitter.com/rdienstmann
| | - E Ruiz-García
- Departamento de Tumores de Tubo Digestivo, Instituto Nacional de Cancerología, Mexico City, Mexico; Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/Ruiz-García
| | - M Alsina
- Medical Oncology Department, Vall d`Hebron Institute of Oncology, Barcelona, Spain; Hospital Universitario de Navarra, Navarrabiomed-IdiSNA, Pamplona, Spain. https://twitter.com/Alsina
| | - F Ruiz-Pace
- Oncology Data Science, Vall d´Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Ruiz-Pace
| | - T S Groen-van Schooten
- Department of Medical Oncology, Amsterdam University Medical Center (UMC), location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - C Martínez-Ciarpaglini
- Department of Pathology, Hospital Clínico Universitario de Valencia, Valencia, Spain. https://twitter.com/Martínez-Ciarpaglini
| | - E A Fernández-Figueroa
- Núcleo B de Innovación en Medicina de Precisión, Instituto Nacional de Medicina Genómica, Mexico City, Mexico
| | - R Herrera-Goepfert
- Department of Pathology, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/Herrera-Goepfert
| | - C Díaz-Romero
- Department of Medical Oncology, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/Díaz-Romero
| | - L Lino-Silva
- Department of Head of Division, Surgical Pathology, National Cancer Institute (INCan), Mexico City, Mexico. https://twitter.com/Lino-Silva
| | - A I Hernandez-Guerrero
- Department of Gastrointestinal Endoscopy, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/Hernandez-Guerrero
| | - N M Valdez-Reyes
- Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - A León-Takahashi
- Departamento de Gastroenterología, Instituto Nacional de Cancerología, Mexico City, Mexico. https://twitter.com/León-Takahashi
| | - J C Falcón-Martínez
- Laboratorio de Medicina Traslacional, Instituto Nacional de Cancerología, Mexico City, Mexico
| | - R E Pouw
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center (UMC), location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - S Romero
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain. https://twitter.com/Romero
| | - R Villagrasa
- Department of Gastroenterology, Hospital Clínico Universitario de Valencia, Valencia, Spain. https://twitter.com/Villagrasa
| | - M Cabeza-Segura
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain. https://twitter.com/Cabeza-Segura
| | - L Alarcón-Molero
- Department of Pathology, Hospital Clínico Universitario de Valencia, Valencia, Spain; Department of Pathology, Hospital General de Valdepeñas, Valdepeñas, Spain. https://twitter.com/Alarcón-Molero
| | - E Jimenez-Martí
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain. https://twitter.com/Jimenez-Martí
| | - A Miralles
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - H Boggino
- Department of Pathology, GENPAT, Asunción, Paraguay
| | - C Gauna
- Department of Medical Oncology, Instituto de Previsión Social, Asunción, Paraguay
| | - R Pereira
- Department of Medical Oncology, Instituto de Previsión Social, Asunción, Paraguay
| | - H Lezcano
- Department of Pathology, Instituto de Previsión Social, Asunción, Paraguay
| | - D Cantero
- Department of Gastroenterology, Instituto de Previsión Social, Asunción, Paraguay
| | - A Vivancos
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Vivancos
| | - J Matito
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Matito
| | - A Martin
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Martin
| | - M Gómez
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Gómez
| | - E Castillo
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Castillo
| | - M Vila
- Cancer Genomics Lab, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Vila
| | - R M Ferreira
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. https://twitter.com/Ferreira
| | - R Barros
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal; Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal
| | - J Santos-Antunes
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal; Department of Gastroenterology, Unidade Local de Saúde São João, Porto, Portugal. https://twitter.com/Santos-Antunes
| | - M Mendes-Rocha
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal. https://twitter.com/Mendes-Rocha
| | - A Costa
- Department of Oncology, Unidade Local de Saúde São João, Porto, Portugal
| | - E Riquelme
- Department of Respiratory Diseases, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - J C Roa
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - G Latorre
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - B Freile
- Department of Medical Oncology Department, Instituto Alexander Fleming, Buenos Aires, Argentina
| | - L Caro
- Department of Gastroenterology, Instituto Alexander Fleming, GEDYT (Gastroenterologia diagnostica y terapeutica), Buenos Aires, Argentina
| | - F Esteso
- Department of Medical Oncology Department, Instituto Alexander Fleming, Buenos Aires, Argentina. https://twitter.com/federico_esteso
| | - J O'Connor
- Department of Medical Oncology Department, Instituto Alexander Fleming, Buenos Aires, Argentina. https://twitter.com/juanmaoconnor
| | - A Riquelme
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Center for Prevention and Control of Cancer (CECAN), Santiago, Chile
| | - G Owen
- Faculty of Biological Sciences & Faculty of Medicine, Pontificia Universidad Católica de Chile, Millennium Institute for Immunology and Immunotherapy, Center for Prevention and Control of Cancer (CECAN), Advance Center for Chronic Disease (ACCDIS), Santiago, Chile
| | - M Garrido
- Facultad de Medicina y Ciencia de la Salud, Centro de Oncología de Precision, Universidad Mayor, Santiago, Chile. https://twitter.com/DrGarridoOncoGI
| | - M Diez-García
- Medical Oncology Department, Vall d`Hebron Institute of Oncology, Barcelona, Spain. https://twitter.com/Diez-García
| | - C Figueiredo
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal. https://twitter.com/FigeuiredoCeu
| | - C Caballero
- Department of Pathology, GENPAT, Asunción, Paraguay
| | - F Lordick
- Department of Oncology and University Cancer Center Leipzig, University of Leipzig Medical Center, Leipzig, Germany. https://twitter.com/FlorianLordick
| | - J Farrés
- Anaxomics Biotech S.L., Barcelona, Spain
| | - S Derks
- Department of Medical Oncology, Amsterdam University Medical Center (UMC), location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. https://twitter.com/derks_s
| | - F Carneiro
- IPATIMUP-Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal; i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal; Faculty of Medicine of the University of Porto, Porto, Portugal; Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal. https://twitter.com/Carneiro
| | - A Cervantes
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain; Ciberonc, Instituto Carlos III, Madrid, Spain.
| | - T Fleitas
- Department of Medical Oncology, Hospital Clinico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain; Ciberonc, Instituto Carlos III, Madrid, Spain.
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12
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Farhat J, Sakai H, Tsurutani J. Management of nausea and vomiting induced by antibody-drug conjugates. Breast Cancer 2025; 32:278-285. [PMID: 39878905 PMCID: PMC11842424 DOI: 10.1007/s12282-025-01670-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 01/18/2025] [Indexed: 01/31/2025]
Abstract
Antibody-drug conjugates (ADCs) are an emerging class of anticancer therapy that combines the specificity and long circulation half-life of monoclonal antibodies with the cytotoxic potency of the payload connected through a chemical linker. The optimal management of toxicities is crucial for improving quality of life in patients undergoing ADCs and for avoiding improper dose reductions or discontinuations. This article focuses on the characteristics and management of nausea and vomiting (NV) induced by three ADCs: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan (SG), and datopotamab deruxtecan (Dato-DXd). We summarize the proposed mechanism of NV, clinical study data on NV, and recommendations from clinical guidelines. We also discuss three prospective studies evaluating prophylactic antiemetic therapy in patients receiving T-DXd, along with future perspectives.
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Affiliation(s)
| | - Hitomi Sakai
- Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
| | - Junji Tsurutani
- Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
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13
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Rogers JE, Ajani JA. Contemporary management of advanced gastric and gastroesophageal adenocarcinomas. Expert Rev Anticancer Ther 2025:1-7. [PMID: 39918299 DOI: 10.1080/14737140.2025.2463493] [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: 12/04/2024] [Accepted: 02/03/2025] [Indexed: 02/09/2025]
Abstract
INTRODUCTION Gastric and gastroesophageal adenocarcinomas (GEACs) continue to carry a poor prognosis in most patients. New and exciting therapies have entered the treatment landscape in recent years. Prior to these recent approvals, treatment advances had been limited. AREAS COVERED Important treatment decision biomarkers for metastatic GEAC are microsatellite instability-high/deficient mismatch repair, human epidermal growth factor receptor-2, programmed-death ligand 1, and claudin 18.2 expression among others (such as Epstein Barr Virus (EBV) and agnostic biomarkers). Results of these biomarkers drive therapy decisions. Second-line treatment in most cases is less biomarker driven and needs further progress. EXPERT OPINION Studies of molecular subsets in GEAC has led to the understanding that these are heterogenous diseases that need to be treated differently. Other biomarkers with targeted therapies are being studied including fibroblast growth factor receptor, trophoblast cell surface antigen-2, and epidermal growth factor receptor. Additionally, epidemiological distinctions are starting to drive therapy such as in EBV in GAC.
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Affiliation(s)
- Jane E Rogers
- Department of Pharmacy Clinical Programs, U.T. M.D. Anderson Cancer Center Pharmacy Clinical Programs, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, U.T. M.D. Anderson Cancer Center Department of Gastrointestinal Medical Oncology, Houston, TX, USA
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14
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Jiang X, Nik Nabil WN, Ze Y, Dai R, Xi Z, Xu H. Unlocking Natural Potential: Antibody-Drug Conjugates With Naturally Derived Payloads for Cancer Therapy. Phytother Res 2025; 39:789-874. [PMID: 39688127 DOI: 10.1002/ptr.8407] [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: 08/15/2024] [Revised: 11/06/2024] [Accepted: 11/19/2024] [Indexed: 12/18/2024]
Abstract
Natural compound-derived chemotherapies remain central to cancer treatment, however, they often cause off-target side effects that negatively impact patients' quality of life. In contrast, antibody-drug conjugates (ADCs) combine cytotoxic payloads with antibodies to specifically target cancer cells. Most approved and clinically investigated ADCs utilize naturally derived payloads, while those with conventional synthetic molecular payloads remain limited. This review focuses on approved ADCs that enhance the efficacy of naturally derived payloads by linking them with antibodies. We provide an overview of the core components of ADCs, their working mechanisms, and FDA-approved ADCs featuring naturally derived payloads, such as calicheamicin, camptothecin, dolastatin 10, maytansine, pyrrolbenzodiazepine (PBD), and the immunotoxin Pseudomonas exotoxin A. This review also explores recent clinical advancements aimed at broadening the therapeutic potential of ADCs, their applicability in treating heterogeneously composed tumors and their potential use beyond oncology. Additionally, this review highlights naturally derived payloads that are currently being clinically investigated but have not yet received approval. By summarizing the current landscape, this review provides insights into promising avenues for exploration and contributes to the refinement of treatment protocols for improved patient outcomes.
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Affiliation(s)
- Xue Jiang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Wan Najbah Nik Nabil
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- National Pharmaceutical Regulatory Agency, Ministry of Health, Selangor, Malaysia
| | - Yufei Ze
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Rongchen Dai
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Zhichao Xi
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Engineering Research Center of Shanghai Colleges for TCM New Drug Discovery, Shanghai, China
| | - Hongxi Xu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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15
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Ji P, Chen T, Li C, Zhang J, Li X, Zhu H. Comprehensive review of signaling pathways and therapeutic targets in gastrointestinal cancers. Crit Rev Oncol Hematol 2025; 206:104586. [PMID: 39653094 DOI: 10.1016/j.critrevonc.2024.104586] [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: 05/31/2024] [Revised: 11/27/2024] [Accepted: 12/04/2024] [Indexed: 12/13/2024] Open
Abstract
Targeted therapy, the milestone in the development of human medicine, originated in 2004 when the FDA approved the first targeted agent bevacizumab for colorectal cancer treatment. This new development has resulted from drug developers moving beyond traditional chemotherapy, and several trials have popped up in the last two decades with an unprecedented speed. Specifically, EGF/EGFR, VEGF/VEGFR, HGF/c-MET, and Claudin 18.2 therapeutic targets have been developed in recent years. Some targets previously thought to be undruggable are now being newly explored, such as the RAS site. However, the efficacy of targeted therapy is extremely variable, especially with the emergence of new drugs and the innovative use of traditional targets for other tumors in recent years. Accordingly, this review provides an overview of the major signaling pathway mechanisms and recent advances in targeted therapy for gastrointestinal cancers, as well as future perspectives.
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Affiliation(s)
- Pengfei Ji
- Department of Thoracic Surgery, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China
| | - Tingting Chen
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Chao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Jinyuan Zhang
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Xiao Li
- The Second Clinical Medical College, Lanzhou University, No. 199 DongGang West Road, Lanzhou, Gansu 730000, China
| | - Hong Zhu
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 GuoXue Xiang, Chengdu, Sichuan 610041, China.
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16
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Belluzzi L, Martinelli G, Medici B, Farina A, Martinelli E, Canino F, Caggia F, Molinaro A, Barbolini M, Tamburrano F, Moscetti L, Piacentini F, Dominici M, Omarini C. Update on Pulmonary Toxicity Induced by New Breast Cancer Treatments. BREAST CANCER (DOVE MEDICAL PRESS) 2025; 17:53-66. [PMID: 39867812 PMCID: PMC11762262 DOI: 10.2147/bctt.s489419] [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: 08/23/2024] [Accepted: 12/03/2024] [Indexed: 01/28/2025]
Abstract
In recent years, new anticancer drugs have been investigated and approved for the treatment of breast cancer based on improved survival outcomes. However, these new treatments have specific class-related side effects. Pulmonary toxicity has been identified as an adverse event of special interest with everolimus, and is becoming an increasingly significant clinical challenge with the recent approval of trastuzumab deruxtecan. Overall, the risk of pulmonary toxicity is quite low but in some cases lung damage can be fatal. We conducted an update including the available published data regarding the incidence, mechanisms of pathogenesis, clinical presentations, and treatment of lung toxicity induced by new anticancer drugs. A literature search was performed between January and June 2024, considering papers, clinical trials, case reports, case series, meta-analyses, and systematic reviews published from January 2014 to June 2024. We also provide an algorithm for diagnosis and treatment, along with real-life cases managed at the Modena Cancer Center. Data provided here show that pulmonary toxicity is a quite frequent side effect and underline that early recognition and prompt treatment are crucial for the best outcome of patients, whose overall prognosis is being improved by the availability of these new anticancer agents.
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Affiliation(s)
- Lorenzo Belluzzi
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Giulio Martinelli
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Bianca Medici
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Alessandro Farina
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Enrica Martinelli
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Fabio Canino
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Federica Caggia
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
- Department of Training, Research and Innovation, University Hospital of Modena, Modena, Italy
| | - Alessia Molinaro
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Monica Barbolini
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
- Department of Medical Oncology, University Hospital of Modena, Modena, Italy
| | - Fabio Tamburrano
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Luca Moscetti
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
- Department of Medical Oncology, University Hospital of Modena, Modena, Italy
| | - Federico Piacentini
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
| | - Massimo Dominici
- Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena, Modena, Italy
| | - Claudia Omarini
- GOIRC (Gruppo Oncologico Italiano di Ricerca Clinica), Parma, Italy
- Department of Medical Oncology, University Hospital of Modena, Modena, Italy
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17
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Korpan M, Puhr HC, Berger JM, Friedrich A, Prager GW, Preusser M, Ilhan-Mutlu A. Current Landscape of Molecular Biomarkers in Gastroesophageal Tumors and Potential Strategies for Co-Expression Patterns. Cancers (Basel) 2025; 17:340. [PMID: 39941712 PMCID: PMC11816248 DOI: 10.3390/cancers17030340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/14/2025] [Accepted: 01/18/2025] [Indexed: 02/16/2025] Open
Abstract
The treatment of metastasized gastroesophageal adenocarcinoma largely depends on molecular profiling based on immunohistochemical procedures. Therefore, the examination of HER2, PD-L1, and dMMR/MSI is recommended by the majority of clinical practice guidelines, as positive expression leads to different treatment approaches. Data from large phase-III trials and consequent approvals in various countries enable physicians to offer their patients several therapy options including immunotherapy, targeted therapy, or both combined with chemotherapy. The introduction of novel therapeutic targets such as CLDN18.2 leads to a more complex decision-making process as a significant number of patients show positive results for the co-expression of other biomarkers besides CLDN18.2. The aim of this review is to summarize the current biomarker landscape of patients with metastatic gastroesophageal tumors, its direct clinical impact on daily decision-making, and to evaluate current findings on biomarker co-expression. Furthermore, possible treatment strategies with multiple biomarker expression are discussed.
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Affiliation(s)
- Martin Korpan
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Hannah Christina Puhr
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Julia M. Berger
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Alexander Friedrich
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Gerald W. Prager
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Aysegül Ilhan-Mutlu
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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18
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Piha-Paul S, Olwill SA, Hamilton E, Tolcher A, Pohlmann P, Liu SV, Wurzenberger C, Hasenkamp LC, Hansbauer EM, Shroff R, Hurvitz S, Krishnamurthy A, Patnaik A, Hahn N, Kumar R, Duerr M, Zettl M, Aviano K, Matis L, Bruns I, Ku G. A First-in-Human Study of Cinrebafusp Alfa, a HER2/4-1BB Bispecific Molecule, in Patients with HER2-Positive Advanced Solid Malignancies. Clin Cancer Res 2025; 31:288-298. [PMID: 39235868 PMCID: PMC11739778 DOI: 10.1158/1078-0432.ccr-24-1552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/10/2024] [Accepted: 09/03/2024] [Indexed: 09/07/2024]
Abstract
PURPOSE 4-1BB (CD137) is a costimulatory immune receptor expressed on activated T cells, activated B cells, NK cells, and tumor-infiltrating lymphocytes, making it a promising target for cancer immunotherapy. Cinrebafusp alfa, a monoclonal antibody-like bispecific protein targeting HER2 and 4-1BB, aims to localize 4-1BB activation to HER2-positive tumors. This study evaluated the safety, tolerability, and preliminary efficacy of cinrebafusp alfa in patients with previously treated HER2-positive malignancies. PATIENTS AND METHODS This was a multicenter dose-escalation study involving patients with HER2-positive malignancies who received prior treatment. The study assessed the safety and efficacy of cinrebafusp alfa across various dose levels. Patients were assigned to different cohorts, and antitumor responses were evaluated. The study aimed to determine the MTD and to observe any clinical activity at different dose levels. RESULTS Of 40 evaluable patients in the "active dose" efficacy cohorts, five showed an antitumor response, resulting in an overall response rate of 12.5% and a disease-control rate of 52.5%. Clinical activity was observed at the 8 and 18 mg/kg dose levels, with confirmed objective response rates of 28.6% and 25.0%, respectively. Cinrebafusp alfa was safe and tolerable, with grade ≤2 infusion-related reactions being the most frequent treatment-related adverse event. MTD was not reached during the study. CONCLUSIONS Cinrebafusp alfa demonstrates promising activity in patients with HER2-positive malignancies who have progressed on prior HER2-targeting regimens. Its acceptable safety profile suggests it could be a treatment option for patients not responding to existing HER2-directed therapies. See related commentary by Eguren-Santamaría et al., p. 231.
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Affiliation(s)
- Sarina Piha-Paul
- Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shane A. Olwill
- Department of Research and Development, Pieris Pharmaceuticals GmbH, Bavaria, Germany
| | - Erika Hamilton
- Department of Oncology, Sarah Cannon Research Institute/Tennessee Oncology, LLC, Nashville, Tennessee
| | | | - Paula Pohlmann
- Department of Medicine, Georgetown University Lombardi Comprehensive Cancer Center, Washington, District of Columbia
| | - Stephen V. Liu
- Department of Medicine, Georgetown University Lombardi Comprehensive Cancer Center, Washington, District of Columbia
| | - Cornelia Wurzenberger
- Department of Research and Development, Pieris Pharmaceuticals GmbH, Bavaria, Germany
| | | | - Eva-Maria Hansbauer
- Department of Research and Development, Pieris Pharmaceuticals GmbH, Bavaria, Germany
| | - Rachna Shroff
- Department of Medicine, University of Arizona Cancer Center, Tucson, Arizona
| | - Sara Hurvitz
- Department of Medicine, University of California Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, California
| | | | - Amita Patnaik
- Department of Phase I Research, The START Center for Cancer Research, San Antonio, Texas
| | - Noah Hahn
- Department of Oncology and Urology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Raman Kumar
- Department of Research and Development, Pieris Pharmaceuticals GmbH, Bavaria, Germany
| | - Manuela Duerr
- Department of Research and Development, Pieris Pharmaceuticals GmbH, Bavaria, Germany
| | - Markus Zettl
- Department of Research and Development, Pieris Pharmaceuticals GmbH, Bavaria, Germany
| | - Kayti Aviano
- Department of Research and Development, Pieris Pharmaceuticals, Inc., Boston, Massachusetts
| | - Louis Matis
- Department of Research and Development, Pieris Pharmaceuticals, Inc., Boston, Massachusetts
| | - Ingmar Bruns
- Department of Research and Development, Pieris Pharmaceuticals, Inc., Boston, Massachusetts
| | - Geoffrey Ku
- Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
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19
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Wang L, Wen S, Zhu W, Zhang Z, Cheng Y. Response to trastuzumab deruxtecan and delayed immune-related events in a patient with metastatic HER2-positive NSCLC: a case report and literature review. Front Oncol 2025; 14:1469438. [PMID: 39896189 PMCID: PMC11782023 DOI: 10.3389/fonc.2024.1469438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 12/24/2024] [Indexed: 02/04/2025] Open
Abstract
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate (ADC) designed to target HER2 mutations. We reported a case study demonstrating a favorable response to DS-8201 in a patient with HER2 mutation-positive non-small cell lung cancer (NSCLC) who exhibited resistance to initial immunotherapy, along with delayed immune-related events of hypoadrenocorticism occurring five months after discontinuation of immune checkpoint inhibitors. After reviewing the relevant literature, we discussed the mechanism of ADC agents underlying their anti-tumor activity and the potential impact of DS-8201 on the tumor microenvironment. This case highlights the efficacy of DS-8201 in NSCLC, particularly in individuals who have failed first-line immunotherapy, and provide valuable insights for clinicians exploring innovative strategies for the management of patients with lung cancer.
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Affiliation(s)
- Lu Wang
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shidi Wen
- Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Wenjia Zhu
- Department of Nuclear Medicine, Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhiyang Zhang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yuejuan Cheng
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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20
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Dong S, Wei C, Wang X, Yang X, Shen W, Li S, Xu J, Ma Y, Bie L, Yu W, Li N. A retrospective multicenter study on the efficacy and safety of disitamab vedotin monotherapy versus combination with anti-PD-1 immunotherapy in advanced gastric cancer. Sci Rep 2025; 15:2232. [PMID: 39825061 PMCID: PMC11742410 DOI: 10.1038/s41598-025-86504-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: 10/01/2024] [Accepted: 01/10/2025] [Indexed: 01/20/2025] Open
Abstract
Novel therapeutic agents including disitamab vedotin (RC48, an antibody-drug conjugate) and immune-checkpoint inhibitors (e.g., PD-1 inhibitors) have provided new hope as an advanced gastric-cancer (GC) treatment. This multicenter retrospective study studied RC48 monotherapy (MT)'s efficacy and safety against its combination with anti-PD-1 immunotherapy (IT) in advanced GC. Patients treated with RC48 MT or RC48 combined with anti-PD-1 IT from July 2021 to April 2023 were recruited for the study. The progression-free survival (PFS), overall survival (OS), objective-response rate (ORR), disease-control rate (DCR), and safety were studied. After propensity score matching (PSM) (1:1), this study included 34 in the RC48 plus anti-PD-1 IT group and 34 in the RC48 MT group. The median PFS was significantly longer in the combination-therapy (CT) group than in the MT group (5.3 versus 3.8 months, HR: 0.51, 95% CI: 0.31-0.85, p = 0.010), and the median OS was also notably increased (10.0 versus 6.8 months, HR: 0.45, 95% CI: 0.27-0.77, p = 0.003). The ORR and DCR were higher in the combination group (41.18% versus 14.71%, p = 0.031; 61.76% versus 35.30%, p = 0.052). Moreover, subgroup analyses further revealed that those in the CT group experienced a longer PFS and OS, particularly those with high HER2 expression or a PD-L1 CPS score of 1 or higher. The combination therapy (CT) achieved acceptable tolerability and manageable adverse events. Furthermore, the most common grade 3-5 treatment-related adverse events (TRAEs) included decreased white-blood-cell (WBC) count, decreased neutrophil count, and anemia. No new safety risks were observed. In sum, the RC48 and anti-PD-1 IT combination showed good efficacy and a manageable safety profile, indicating its strong potential as an advanced GC therapeutic option.
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Affiliation(s)
- Shuailei Dong
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Chen Wei
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xueting Wang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xinyi Yang
- Phase I Clinical Research Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Wei Shen
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, Henan, China
| | - Shuyi Li
- Department of Medical Oncology, Anyang Tumor Hospital & The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang, 455100, China
| | - Jiye Xu
- Department of Oncology, Zhoukou Central Hospital, Zhoukou, 466000, China
| | - Yijie Ma
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Liangyu Bie
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Wenyue Yu
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Ning Li
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
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21
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Aoki Y, Nakayama I, Shitara K. Human Epidermal Growth Factor Receptor 2 Positive Advanced Gastric or Esophagogastric Adenocarcinoma: Reflecting on the Past to Gain a New Insights. Curr Oncol Rep 2025; 27:15-29. [PMID: 39753814 DOI: 10.1007/s11912-024-01626-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/18/2024] [Indexed: 01/30/2025]
Abstract
PURPOSE OF REVIEW Human epidermal growth factor receptor 2 (HER2) is a critical target in advanced gastric cancer (AGC). This review highlights the current treatment landscape, lessons learned from past clinical trials, and prospects for future treatment strategies for HER2-positive AGC. RECENT FINDINGS Trastuzumab had been the standard treatment for HER2-positive AGC for a decade, and subsequently, trastuzumab deruxtecan, an antibody-drug conjugate (ADC), emerged with an impressive response. Recently, the addition of pembrolizumab to first-line chemotherapy plus trastuzumab has become a novel standard treatment. Past clinical trials of HER2-targeted therapies, which succeeded in HER2-positive breast cancer but failed in AGC, have deepened our understanding of resistance mechanisms. Based on these results, several clinical trials of novel HER2-targeted therapies, including immunologic approaches such as CAR-T cells and vaccines, are currently ongoing. Circulating tumor DNA is also expected to be a tool for real-time biomarker analysis. Additionally, ADCs with a bystander effect have the potential to expand the scope of HER2-targeted therapies to HER2-expressing, including HER2-low AGC. Learning from past trials, further development of novel HER2-targeted therapies is underway, expanding their scope to HER2-expressing AGC. Meanwhile, selecting optimal treatment is a challenging issue in cases with HER2-low AGC overlapping with other biomarkers like CLDN18.2.
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Affiliation(s)
- Yu Aoki
- Department of Medical Oncology, Tokyo Saiseikai Central Hospital, Minato-Ku, Tokyo, Japan
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Chiba, Japan
| | - Izuma Nakayama
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Chiba, Japan.
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Chiba, Japan
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22
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Jubashi A, Nakayama I, Koganemaru S, Sakamoto N, Oda S, Matsubara Y, Miyashita Y, Sato S, Ushiyama S, Kobayashi A, Okazaki U, Okemoto D, Yamamoto K, Mishima S, Kotani D, Kawazoe A, Hashimoto T, Nakamura Y, Kuboki Y, Bando H, Kojima T, Yoshino T, Miyaaki H, Nakao K, Shitara K. Prognostic and predictive factors for the efficacy and safety of trastuzumab deruxtecan in HER2-positive gastric or gastroesophageal junction cancer. Gastric Cancer 2025; 28:63-73. [PMID: 39487862 PMCID: PMC11706866 DOI: 10.1007/s10120-024-01560-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 10/08/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting HER2-positive gastric cancer or gastroesophageal junction cancer (GC/GEJC). Although effective, T-DXd has notable toxicities, including interstitial lung disease (ILD). This study evaluated the efficacy, safety, and prognostic factors associated with T-DXd for GC/GEJC. METHODS A retrospective observational study was conducted at our institution by reviewing medical records of patients treated with T-DXd until September 2023. Eligible patients had unresectable advanced or recurrent GC/GEJC, HER2 status of IHC 3 + or IHC 2 + /ISH-positive, and prior treatment with trastuzumab-containing regimen. RESULTS Among the 101 patients analyzed, the initial T-DXd dose was 6.4 mg/kg in 77 patients and 5.4 mg/kg in 24 patients. The objective response rate was 54.3%, with a median PFS of 5.4 months and a median OS of 11.4 months. The significant prognostic factors for shorter PFS and OS included ECOG PS ≥ 1, presence of primary lesion, and peritoneal metastasis but not the initial T-DXd dose. ILD occurred in 14.9% of patients. Notably, higher T-DXd dose and smaller tumor burden were associated with a higher incidence of ILD. CONCLUSIONS Several factors were associated with prognosis after T-DXd treatment in patients with GC/GEJC. Tumor burden is a potential risk factor for T-DXd-related ILD. Further studies are needed to optimize dosing based on tumor burden and to improve the therapeutic index.
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Affiliation(s)
- Amane Jubashi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki City, Nagasaki, 852-8501, Japan
| | - Izuma Nakayama
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
| | - Shigehiro Koganemaru
- Department of Experimental Therapeutics, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Naoya Sakamoto
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, 277-8577, Japan
| | - Shioto Oda
- Department of Diagnostic Radiology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yuki Matsubara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yu Miyashita
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Seiya Sato
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Shinpei Ushiyama
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Akinori Kobayashi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Ukyo Okazaki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Dai Okemoto
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Kazumasa Yamamoto
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Saori Mishima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Daisuke Kotani
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Tadayoshi Hashimoto
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Translational Research Support Section, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Translational Research Support Section, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yasutoshi Kuboki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Experimental Therapeutics, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki City, Nagasaki, 852-8501, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki City, Nagasaki, 852-8501, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
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23
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Matsutoka K, Shoda K, Higuchi Y, Nakayama T, Saito R, Maruyama S, Takiguchi K, Nakata Y, Furuya S, Shiraishi K, Kawaguchi Y, Amemiya H, Masuda K, Ichikawa D. Enhancing Preoperative Diagnosis Accuracy of Stage III Gastric Cancer with Circulating circRNAs. Ann Surg Oncol 2025; 32:333-341. [PMID: 39433719 DOI: 10.1245/s10434-024-16387-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 10/07/2024] [Indexed: 10/23/2024]
Abstract
BACKGROUND The prognosis remains poor for stage III gastric cancer, and neoadjuvant chemotherapy is increasingly used to improve outcomes. Accurate diagnosis prior to treatment is essential to develop appropriate treatment strategies for poor prognosis subgroups. This study aims to enhance the accuracy of pre-treatment gastric cancer diagnosis using a biological approach centered on circulating circular RNA (circRNA). MATERIALS AND METHODS We conducted a comprehensive analysis of circRNA expression profiles using two Gene Expression Omnibus datasets to identify circRNA candidates associated with stage III gastric cancer. Subsequently, we validated these circRNA biomarkers in two independent clinical cohorts comprising a total of 174 patients with gastric cancer and non-disease controls through real-time polymerase chain reaction (PCR). RESULTS Genome-wide circRNA analysis identified a panel of four biomarkers capable of diagnosing pathologically confirmed stage III (pStage III) gastric cancer. In a training cohort (n = 83), a clinically applicable panel of four circRNAs was developed (AUC 0.81), which was successfully validated in an independent clinical cohort (n = 82; AUC 0.76). To assess clinical utility, we combined clinical imaging (cStage) with the circRNA panel. Among those initially diagnosed as cStage III but later confirmed as pStage I/II, 86% were accurately diagnosed using the molecular biological approach with circRNAs. CONCLUSIONS We have developed a circRNA-based non-invasive liquid biopsy that can improve the diagnostic performance of pStage III gastric cancer before treatment. Our circRNA model could provide a sophisticated and personalized approach to assist in treatment planning for patients with advanced gastric cancer.
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Affiliation(s)
- Koichi Matsutoka
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Katsutoshi Shoda
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan.
| | - Yudai Higuchi
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Takashi Nakayama
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Ryo Saito
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Suguru Maruyama
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Koichi Takiguchi
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Yuki Nakata
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Shinji Furuya
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Kensuke Shiraishi
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Yoshihiko Kawaguchi
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | - Hidetake Amemiya
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
| | | | - Daisuke Ichikawa
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
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24
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Kim IH, Kang SJ, Choi W, Seo AN, Eom BW, Kang B, Kim BJ, Min BH, Tae CH, Choi CI, Lee CK, An HJ, Byun HK, Im HS, Kim HD, Cho JH, Pak K, Kim JJ, Bae JS, Yu JI, Lee JW, Choi J, Kim JH, Choi M, Jung MR, Seo N, Eom SS, Ahn S, Kim SJ, Lee SH, Lim SH, Kim TH, Han HS. Korean Practice Guidelines for Gastric Cancer 2024: An Evidence-based, Multidisciplinary Approach (Update of 2022 Guideline). J Gastric Cancer 2025; 25:5-114. [PMID: 39822170 PMCID: PMC11739648 DOI: 10.5230/jgc.2025.25.e11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025] Open
Abstract
Gastric cancer is one of the most common cancers in both Korea and worldwide. Since 2004, the Korean Practice Guidelines for Gastric Cancer have been regularly updated, with the 4th edition published in 2022. The 4th edition was the result of a collaborative work by an interdisciplinary team, including experts in gastric surgery, gastroenterology, endoscopy, medical oncology, abdominal radiology, pathology, nuclear medicine, radiation oncology, and guideline development methodology. The current guideline is the 5th version, an updated version of the 4th edition. In this guideline, 6 key questions (KQs) were updated or proposed after a collaborative review by the working group, and 7 statements were developed, or revised, or discussed based on a systematic review using the MEDLINE, Embase, Cochrane Library, and KoreaMed database. Over the past 2 years, there have been significant changes in systemic treatment, leading to major updates and revisions focused on this area. Additionally, minor modifications have been made in other sections, incorporating recent research findings. The level of evidence and grading of recommendations were categorized according to the Grading of Recommendations, Assessment, Development and Evaluation system. Key factors for recommendation included the level of evidence, benefit, harm, and clinical applicability. The working group reviewed and discussed the recommendations to reach a consensus. The structure of this guideline remains similar to the 2022 version. Earlier sections cover general considerations, such as screening, diagnosis, and staging of endoscopy, pathology, radiology, and nuclear medicine. In the latter sections, statements are provided for each KQ based on clinical evidence, with flowcharts supporting these statements through meta-analysis and references. This multidisciplinary, evidence-based gastric cancer guideline aims to support clinicians in providing optimal care for gastric cancer patients.
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Affiliation(s)
- In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Joo Kang
- Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Wonyoung Choi
- Center for Gastric Cancer, National Cancer Center, Goyang, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Bang Wool Eom
- Center for Gastric Cancer, National Cancer Center, Goyang, Korea
| | - Beodeul Kang
- Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Bum Jun Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Anyang, Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Chung Hyun Tae
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | - Chang In Choi
- Department of Surgery, Pusan National University Hospital, Busan, Korea
| | - Choong-Kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Ho Jung An
- Division of Oncology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Hwa Kyung Byun
- Department of Radiation Oncology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Hyeon-Su Im
- Department of Hematology and Oncology, Ulsan University Hospital, Ulsan University College of Medicine, Ulsan, Korea
| | - Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jang Ho Cho
- Division of Medical Oncology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Kyoungjune Pak
- Department of Nuclear Medicine and Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Jae-Joon Kim
- Division of Hematology and Oncology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Jae Seok Bae
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Korea
| | - Jeong Il Yu
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
| | - Jeong Won Lee
- Department of Nuclear Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Jungyoon Choi
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Jwa Hoon Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Miyoung Choi
- National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, Korea
| | - Mi Ran Jung
- Department of Surgery, Chonnam National University Medical School, Gwangju, Korea
| | - Nieun Seo
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Soo Eom
- Department of Surgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Jin Kim
- Department of Radiology, National Cancer Center, Goyang, Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung Hee Lim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul, Korea
| | - Tae-Han Kim
- Department of Surgery, Gyeongsang National University Changwon Hospital, Changwon, Korea.
| | - Hye Sook Han
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea.
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25
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Koganemaru S, Koyama S, Suto F, Koga M, Inaki K, Kuwahara Y, Arita T, Hirata T, Goto H, Wada N, Kobayashi M, Shibutani T, Okabayashi T, Nakamaru K, Kawazoe A, Togashi Y, Nishikawa H, Shitara K. The Tumor Immune Microenvironment and Therapeutic Efficacy of Trastuzumab Deruxtecan in Gastric Cancer. CANCER RESEARCH COMMUNICATIONS 2025; 5:84-93. [PMID: 39679910 PMCID: PMC11729160 DOI: 10.1158/2767-9764.crc-24-0302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 08/01/2024] [Accepted: 12/11/2024] [Indexed: 12/17/2024]
Abstract
SIGNIFICANCE This biomarker study explored HER2 expression levels and immune cell characteristics that may affect response to T-DXd using tumor tissue samples collected from clinical trial participants. The results suggest that HER2 expression levels and tumor characteristics before the initiation of T-DXd may correlate with the efficacy of the drug.
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Affiliation(s)
- Shigehiro Koganemaru
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shohei Koyama
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Chiba, Japan
- Department of Immunogenomic Medicine, Research Institute, National Cancer Center, Tokyo, Japan
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Fumitaka Suto
- Translational Science Department, Precision Medicine Function, Daiichi Sankyo, Inc., Basking Ridge, New Jersey
| | - Makito Koga
- Translational Science Department I, Precision Medicine Function, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Koichiro Inaki
- Oncology Medical Science Department, Medical Affairs Division, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Yusuke Kuwahara
- Translational Science Department, Precision Medicine Function, Daiichi Sankyo, Inc., Basking Ridge, New Jersey
| | - Takeo Arita
- Translational Science Department I, Precision Medicine Function, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Tsuyoshi Hirata
- Translational Science Department, Precision Medicine Function, Daiichi Sankyo, Inc., Basking Ridge, New Jersey
| | - Hiroki Goto
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Naoya Wada
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Maki Kobayashi
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Tomoko Shibutani
- Translational Research Department, Daiichi Sankyo RD Novare Co., Ltd., Tokyo, Japan
| | - Tatsuya Okabayashi
- Clinical Development Department I, Development Function, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Kenji Nakamaru
- Translational Science Department I, Precision Medicine Function, Daiichi Sankyo, Co., Ltd., Tokyo, Japan
| | - Akihito Kawazoe
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yousuke Togashi
- Department of Tumor Microenvironment, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hiroyoshi Nishikawa
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tokyo/Chiba, Japan
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kohei Shitara
- Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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26
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Eom SS, Ryu KW, Han HS, Kong SH. A Comprehensive and Comparative Review of Global Gastric Cancer Treatment Guidelines: 2024 Update. J Gastric Cancer 2025; 25:153-176. [PMID: 39822173 PMCID: PMC11739642 DOI: 10.5230/jgc.2025.25.e10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 01/19/2025] Open
Abstract
Differences in demographics, medical expertise, and patient healthcare resources across countries have led to significant variations in guidelines. In light of these differences, in this review, we aimed to explore and compare the most recent updates to gastric cancer treatment from five guidelines that are available in English. These English-version guidelines, which have been recently published and updated for journal publication, include those published in South Korea in 2024, Japan in 2021, China in 2023, the United States in 2024, and Europe in 2024. The South Korean and Japanese guidelines provide a higher proportion of content to endoscopic and surgical treatments, reflecting their focus on minimally invasive techniques, function-preserving surgeries, and systemic therapy. The Chinese guidelines provide recommendations addressing not only surgical approaches but also perioperative chemotherapy and palliative systemic therapy. Meanwhile, in the United States and European guidelines, a higher proportion of the content is dedicated to perioperative and palliative systemic therapy, aligning with their approaches to advanced-stage disease management. All guidelines address surgical and systemic chemotherapy treatments; however, the proportion and emphasis of content vary based on the patient distribution and treatment approaches specific to each country. With emerging research findings on gastric cancer treatment worldwide, the national guidelines are being progressively revised and updated. Understanding the commonalities and differences among national guidelines, along with the underlying evidence, can provide valuable insights into the treatment of gastric cancer.
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Affiliation(s)
- Sang Soo Eom
- Department of Surgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Keun Won Ryu
- Center for Gastric Cancer, National Cancer Center, Goyang, Korea
| | - Hye Sook Han
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea.
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University Hospital and Seoul National University College of Medicine Cancer Research Institute, Seoul, Korea.
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27
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Guo M, Zhao W, Chen Y, Zou D, Peng W, Sha H, Zhou G, Fang Y, Shen B. Efficacy of rechallenge after first-line immunotherapy for advanced gastric cancer: A retrospective real-world study. Hum Vaccin Immunother 2024; 20:2423479. [PMID: 39494935 PMCID: PMC11540071 DOI: 10.1080/21645515.2024.2423479] [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: 07/19/2024] [Revised: 10/15/2024] [Accepted: 10/28/2024] [Indexed: 11/05/2024] Open
Abstract
We aimed to explore the efficacy of rechallenge after first-line immunotherapy in advanced gastric cancer (AGC) and to analyze the factors affecting prognosis based on clinical characteristics. Eighty-five AGC patients who underwent rechallenged after the failure of first-line treatment with immune checkpoint inhibitors (ICIs) were retrospectively collected from July 2019 to December 2022 in Jiangsu Cancer Hospital. Potential factors affecting prognosis were analyzed by univariate and multivariate Cox analysis. Survival analysis was performed by Kaplan-Meier method and Log rank test. Stratified factors included human epidermal growth factor receptor 2 (HER-2) and programmed cell death-ligand 1 combined positive score (PD-L1 CPS). The objective response rate (ORR) was 15.3%, and the disease control rate (DCR) was 74.1%. The median progression-free survival (PFS) was 4.8 months. Results showed that patients in the I + C group had the best response. The ORR was 20.0% VS 8.7% in the I + C group and I + C + AAD group. The DCR was 78.0% VS 65.2%, and the median PFS was 6.7 VS 4.7 months [hazard ratio (HR): 0.55, 95% confidence interval (CI): 0.30-1.00, p = .022]. The ORR was 20.0% VS 8.3% in the I + C group and I + C + ADC group. The DCR was 78.0% VS 75.0%, and the median PFS was 6.7 VS 4.4 months (HR: 0.59, 95%CI: 0.26-1.30, p = .112). The median PFS was 4.7 VS 4.4 months in the I + C + AAD group and I + C + ADC group (HR: 1.21, 95%CI: 0.60-2.47, p = .580). Adverse events (AEs) were found in 34 patients, mainly including leukopenia 9 (10.6%), and neutropenia 8 (9.4%). The incidence of grade 3-4 AEs was 8.2%. There were no drug-related deaths and all AEs were manageable. Rechallenge after first-line immunotherapy showed good survival benefit and acceptable safety in the therapy of AGC. Especially for patients with HER-2-positive and PD-L1 CPS ≥ 1%, rechallenge may be an effective treatment modality.
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Affiliation(s)
- Mengya Guo
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wenhui Zhao
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yue Chen
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dan Zou
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weiwei Peng
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huanhuan Sha
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Guoren Zhou
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | | | - Bo Shen
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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28
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Tsutsumi C, Ohuchida K, Tsutsumi H, Shimada Y, Yamada Y, Son K, Hayashida S, Katayama N, Mochida Y, Iwamoto C, Torata N, Horioka K, Shindo K, Mizuuchi Y, Ikenaga N, Nakata K, Ota K, Iwama E, Yamamoto M, Tsukamoto T, Nomura S, Morisaki T, Oda Y, Okamoto I, Nakamura M. TIM3 on natural killer cells regulates antibody-dependent cellular cytotoxicity in HER2-positive gastric cancer. Cancer Lett 2024; 611:217412. [PMID: 39722406 DOI: 10.1016/j.canlet.2024.217412] [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: 05/10/2024] [Revised: 12/09/2024] [Accepted: 12/22/2024] [Indexed: 12/28/2024]
Abstract
Therapies targeting HER2 are the standard treatment for HER2-positive gastric cancer (GC). Trastuzumab, a monoclonal antibody against HER2, exerts anti-tumor activity through cell growth regulation and antibody-dependent cellular cytotoxicity (ADCC). ADCC is induced by the binding of trastuzumab to Fcγ receptor III (CD16) in natural killer (NK) cells. However, the relationship between immune checkpoint (IC) molecules of NK cells and trastuzumab-induced ADCC is poorly understood. We performed single-cell RNA sequencing (scRNA-seq) and immunohistochemistry to identify IC molecules associated with CD16 expression in NK cells of GC patients. Additionally, we conducted in vitro assays with HER2-transfected GC cells and in vivo experiments using a mouse HER2-positive GC model to assess expression changes in IC molecules in NK cells and their ligands during trastuzumab treatment. In GC patients, the expression of TIM3, an IC molecule, was strongly correlated with that of CD16 in NK cells. In vitro assays showed that ADCC with trastuzumab increased TIM3 expression in NK cells. scRNA-seq analysis revealed that TIM3 expression of cytotoxic NK cells was elevated in HER2-positive GC patients treated with trastuzumab. HMGB1, a TIM3 ligand, was expressed at higher levels in HER2-transfected GC cells than in controls. Furthermore, HMGB1 expression was higher in HER2-positive GC patients treated with trastuzumab compared to untreated HER2-positive GC patients. In the mouse HER2-positive GC model, anti-TIM3 antibodies and trastuzumab demonstrated synergistic anti-tumor effects without toxicity. This study suggests the combined anti-TIM3 antibody and trastuzumab therapy may have potential as a new treatment strategy for HER2-positive GC.
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Affiliation(s)
- Chikanori Tsutsumi
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Hirono Tsutsumi
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Shimada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yutaka Yamada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kiwa Son
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Sayuri Hayashida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoki Katayama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuki Mochida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Chika Iwamoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nobuhiro Torata
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohei Horioka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Koji Shindo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yusuke Mizuuchi
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoki Ikenaga
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kohei Nakata
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Keiichi Ota
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Iwama
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masami Yamamoto
- Laboratory of Physiological Pathology, Nippon Veterinary and Life Science University, Tokyo, Japan
| | - Tetsuya Tsukamoto
- Department of Pathology, Graduate School of Medicine, Fujita Health University, Toyoake, Japan
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takashi Morisaki
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Isamu Okamoto
- Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Jourdain H, Albin N, Monard A, Desplas D, Zureik M, Haddy N. Trastuzumab Deruxtecan in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Gastric Cancer in a Real-World Setting: A Nationwide Cohort Study. Clin Transl Gastroenterol 2024; 15:e00773. [PMID: 39373321 DOI: 10.14309/ctg.0000000000000773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 09/24/2024] [Indexed: 10/08/2024] Open
Abstract
INTRODUCTION Trastuzumab deruxtecan (T-DXd) has been approved for human epidermal growth factor receptor 2-positive locally advanced or metastatic gastric and gastroesophageal junction (HER2+ mG/GEJ) cancer since July 2022 in France, through an accelerated approval. The aim of this study was to evaluate its real-world use. METHODS We characterized T-DXd users treated for HER2+ mG/GEJ cancer using data from the French National Health Insurance database. RESULTS The cohort included 196 patients, mostly men (78.1%), with a median age of 65 years. Median overall survival reached 7.7 months (95% CI: 6.2-9.0). DISCUSSION Patients treated with T-DXd for HER2+ mG/GEJ cancer in the real world showed lower outcomes than those in pivotal clinical trials, consistent with previous reports on accelerated approvals.
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Affiliation(s)
- Hugo Jourdain
- EPI-PHARE, French National Agency for Medicine and Health Product Safety (ANSM) and the French National Health Insurance, Saint-Denis, France
| | - Nicolas Albin
- Department of Oncohematology, Avec Groupe Hospitalier Mutualiste, Grenoble, France
- Oncology Hematology and Cell Therapy Department, French National Agency for Medicine and Health Product Safety (ANSM), Saint-Denis, France
| | - Adrien Monard
- Department of Oncohematology, Avec Groupe Hospitalier Mutualiste, Grenoble, France
- Oncology Hematology and Cell Therapy Department, French National Agency for Medicine and Health Product Safety (ANSM), Saint-Denis, France
| | - David Desplas
- EPI-PHARE, French National Agency for Medicine and Health Product Safety (ANSM) and the French National Health Insurance, Saint-Denis, France
| | - Mahmoud Zureik
- EPI-PHARE, French National Agency for Medicine and Health Product Safety (ANSM) and the French National Health Insurance, Saint-Denis, France
- University Paris-Saclay, UVSQ, University Paris-Sud, Inserm, Anti-infective evasion and Pharmacoepidemiology Unit/Team, CESP, Montigny le Bretonneux, France
| | - Nadia Haddy
- EPI-PHARE, French National Agency for Medicine and Health Product Safety (ANSM) and the French National Health Insurance, Saint-Denis, France
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30
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Waliany S, Nagasaka M, Park L, Lam C, Jiang Z, Lin F, Neal JW. Real-World Prevalence, Treatment Patterns, and Outcomes for Patients With HER2 (ERBB2)-Mutant Metastatic Non-Small Cell Lung Cancer, From a US-Based Clinico-Genomic Database. Cancer Med 2024; 13:e70272. [PMID: 39692700 DOI: 10.1002/cam4.70272] [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: 05/16/2024] [Revised: 09/04/2024] [Accepted: 09/11/2024] [Indexed: 12/19/2024] Open
Abstract
OBJECTIVES Targeted therapies have been shown to improve outcomes in metastatic non-small cell lung cancer (mNSCLC) with driver mutations. We evaluated the real-world prevalence of human epidermal growth factor receptor 2 (HER2; ERBB2) tumor gene mutations among patients with mNSCLC and described historical treatments and outcomes in patients with HER2-mutant mNSCLC, during a period when there was no approved targeted therapy for HER2-mutant mNSCLC. MATERIALS AND METHODS This retrospective observational study used a US nationwide de-identified NSCLC clinico-genomic database. Eligible patients were adults diagnosed with HER2-mutant mNSCLC from January 2014 to July 2021 without co-occuring epidermal growth factor receptor (EGFR) tumor mutations. Descriptive statistics were used to summarize prevalence, baseline characteristics and treatment patterns. Clinical outcomes were estimated with Kaplan-Meier analyses. RESULTS Among 9206 patients with mNSCLC, 164 (1.78%) met the eligibility criteria (mean age: 67.3 years, 63.4% White, 56.7% female, and 53.0% with a smoking history). 132/164 (80.5%) had at least one line of treatment. Platinum-based chemotherapy (45.5%) and immune checkpoint inhibitor (ICI) with chemotherapy (28.0%) were the most frequently used first-line treatments. The median (95% confidence interval [CI]) real-world (rw) progression-free survival in first-line was 5.5 (4.8, 6.2) months and 3.0 (2.3, 4.2) months in second-line. The median rw overall survival in first-line was 13.2 (10.6, 18.4) months and 8.2 (6.6, 13.2) months in second-line. CONCLUSION During this study period, the most common regimens were platinum-based chemotherapy with or without ICI in first and second line, and median rwOS was 13.2 and 8.2 months, respectively. These results indicate the need for more effective targeted therapies in this patient population.
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Affiliation(s)
- Sarah Waliany
- Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA
| | - Misako Nagasaka
- University of California Irvine School of Medicine, Orange, California, USA
| | - Leah Park
- AstraZeneca, Gaithersburg, Maryland, USA
| | - Clara Lam
- AstraZeneca, Gaithersburg, Maryland, USA
| | - Zoe Jiang
- AstraZeneca, Gaithersburg, Maryland, USA
| | - Feng Lin
- Daiichi Sankyo, Basking Ridge, New Jersey, USA
| | - Joel W Neal
- Department of Medicine, Stanford University, Stanford, California, USA
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31
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Costa M, Lopes Fernandes C, Magalhães H. Perioperative Treatment in Gastric Cancer: A Fast-Changing Field. Cancers (Basel) 2024; 16:4036. [PMID: 39682222 DOI: 10.3390/cancers16234036] [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: 10/28/2024] [Revised: 11/21/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Gastric cancer is the fifth most common cancer worldwide and its incidence is rising. Surgery is the only curative strategy and its association with perioperative chemotherapy is now standard treatment for most resectable tumors. Despite treatment advances, disease relapse is high, even in early stages, and continued improvement in curative treatment is imperative. With deeper knowledge of gastric cancer heterogeneity, molecular subtypes, and the tumor immune microenvironment, new standard treatment strategies may emerge in the near future. This paper provides a comprehensive review of the current treatment landscape in resectable gastric cancer and future perspectives for the next decade regarding new agents such as targeted therapies, immunotherapy, antibody-drug conjugates, and the combination of multiple treatment modalities.
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Affiliation(s)
- Mafalda Costa
- Medical Oncology Department, Pedro Hispano Hospital, 4464-513 Matosinhos, Portugal
| | | | - Helena Magalhães
- Medical Oncology Department, Pedro Hispano Hospital, 4464-513 Matosinhos, Portugal
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32
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Villacampa G, Cresta Morgado P, Carità L, Navarro V, Pascual T, Dienstmann R. Safety and efficacy of antibody-drug conjugates plus immunotherapy in solid tumours: A systematic review and meta-analysis. Cancer Treat Rev 2024; 131:102847. [PMID: 39454548 DOI: 10.1016/j.ctrv.2024.102847] [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: 09/18/2024] [Revised: 10/16/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND Combining antibody-drug conjugate (ADCs) with immune checkpoint inhibitors (ICIs) is emerging as a promising treatment option to increase efficacy outcomes. However, concerns arise regarding the safety of these combinations, as some toxicities may overlap. Currently, there is still limited information about the safety profiles of this strategy. METHODS A systematic review and meta-analysis was conducted to identify clinical trials investigating FDA-approved ADCs in combination with ICI drugs in the metastatic setting across all solid tumors. The primary endpoint of this study was the percentage of adverse events (AEs) of any grade and grade ≥ 3. Secondary endpoints include the percentage of patients with AEs leading to death, treatment discontinuation, proportion of complete responses (CR) and overall response rate (ORR). A parallel search was conducted to quantify the safety profile of ADCs and ICIs in monotherapy. Random effects models were used to estimate pooled outcomes. RESULTS Sixteen trials involving 1,133 patients treated with ADC plus ICI met the inclusion criteria with six different ADCs evaluated. Overall, 55.3 % of patients developed grade ≥ 3 AEs, 30.0 % of patients had treatment discontinuation, and 3.0 % experienced AEs leading to death. When compared to trials evaluating ADC or ICI as monotherapy, the combination results in similar rates of the most common AEs. However, it increases the risk of specific toxicities, such as ILD/pneumonitis (15.0 % with T-DXd plus ICI vs. 11.5 % with T-DXd alone). The pooled ORR was 48.8 % (95 %CI 39.4 % - 58.4 %) and the CR rate was 9.0 % (95 %CI 5.5 - 14.5). PD-L1-positive tumors showed numerically better efficacy outcomes. CONCLUSIONS This meta-analysis shows that the safety profile of the ADC plus ICI is comparable to that of ADC monotherapy. However, it increases the risk of certain toxicities of special interest, such as ILD/pneumonitis, highlighting the need for careful monitoring.
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Affiliation(s)
- Guillermo Villacampa
- Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain; SOLTI Cancer Research Group, Barcelona, Spain.
| | - Pablo Cresta Morgado
- Prostate Cancer Translational Research Group, VHIO, Barcelona, Spain; Oncology Data Science, VHIO, Barcelona, Spain
| | - Lorenzo Carità
- Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Victor Navarro
- Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Tomas Pascual
- SOLTI Cancer Research Group, Barcelona, Spain; Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain
| | - Rodrigo Dienstmann
- Oncology Data Science, VHIO, Barcelona, Spain; University of Vic - Central University of Catalonia, Vic, Spain
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33
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Wang W, Ye L, Li H, Mao W, Xu X. Targeting esophageal carcinoma: molecular mechanisms and clinical studies. MedComm (Beijing) 2024; 5:e782. [PMID: 39415846 PMCID: PMC11480525 DOI: 10.1002/mco2.782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Revised: 09/24/2024] [Accepted: 09/24/2024] [Indexed: 10/19/2024] Open
Abstract
Esophageal cancer (EC) is identified as a predominant health threat worldwide, with its highest incidence and mortality rates reported in China. The complex molecular mechanisms underlying EC, coupled with the differential incidence of esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) across various regions, highlight the necessity for in-depth research targeting molecular pathogenesis and innovative treatment strategies. Despite recent progress in targeted therapy and immunotherapy, challenges such as drug resistance and the lack of effective biomarkers for patient selection persist, impeding the optimization of therapeutic outcomes. Our review delves into the molecular pathology of EC, emphasizing genetic and epigenetic alterations, aberrant signaling pathways, tumor microenvironment factors, and the mechanisms of metastasis and immune evasion. We further scrutinize the current landscape of targeted therapies, including the roles of EGFR, HER2, and VEGFR, alongside the transformative impact of ICIs. The discussion extends to evaluating combination therapies, spotlighting the synergy between targeted and immune-mediated treatments, and introduces the burgeoning domain of antibody-drug conjugates, bispecific antibodies, and multitarget-directed ligands. This review lies in its holistic synthesis of EC's molecular underpinnings and therapeutic interventions, fused with an outlook on future directions including overcoming resistance mechanisms, biomarker discovery, and the potential of novel drug formulations.
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Affiliation(s)
- Wenjing Wang
- Department of Medical Thoracic OncologyZhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
| | - Lisha Ye
- Department of Medical Thoracic OncologyZhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
| | - Huihui Li
- Department of Medical Thoracic OncologyZhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of SciencesHangzhouZhejiangChina
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
| | - Weimin Mao
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
- The Cancer Hospital of the University of Chinese Academy of Sciences, Institute of Basic Medicine and Cancer (IBMC)Chinese Academy of SciencesHangzhouZhejiangChina
| | - Xiaoling Xu
- Postgraduate Training Base AllianceWenzhou Medical UniversityWenzhouZhejiangChina
- Department of Radiation OncologyShanghai Pulmonary Hospital, Tongji University School of MedicineShanghaiChina
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34
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Decker A, Quante M. [Esophageal cancer: new developments in prevention and therapy]. Dtsch Med Wochenschr 2024; 149:1329-1334. [PMID: 39437824 DOI: 10.1055/a-2255-7109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Esophageal carcinomas comprise 2 entities, squamous cell carcinoma and adenocarcinoma, which differ in pathogenesis and treatment. Elimination of inflammatory influences and risk factors, such as obesity and gastroesophageal reflux that contribute to a rising incidence of adenocarcinoma, is crucial for tumor prevention. In Germany, general endoscopic screening for upper GI tumors is not recommended, whereas endoscopic surveillance is applied in the presence of Barrett's metaplasia. In the future, better prediction models will be needed to identify patients at risk who will benefit from endoscopic surveillance. Precancerous lesions and early tumor stages can be removed endoscopically using modern resection methods. In recent years, therapeutic strategies for advanced esophageal tumors have undergone significant changes. In the multimodal treatment of locally advanced stages, radiochemotherapy remains to play a key role for squamous cell carcinoma, whereas new evidence highlights the importance of perioperative chemotherapy for the optimal management of adenocarcinoma. Systemic treatment options for both tumor entities have been significantly expanded due to the successful use of immune checkpoint inhibitors in adjuvant and palliative treatment regimen. Determination of PD-L1 and MSI status has therefore become decisive for the choice of therapy. In metastatic stages of adenocarcinoma, chemotherapy can now be supplemented by multiple antibodies directed against Her2, PD1, or claudin 18.2, and the antibody-drug conjugate trastuzumab deruxtecan has become a Her2-targeted option in second line treatment.
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Affiliation(s)
- Annegrit Decker
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie, Endokrinologie und Infektiologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
| | - Michael Quante
- Klinik für Innere Medizin II - Gastroenterologie, Hepatologie, Endokrinologie und Infektiologie, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany
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35
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Colombo R, Tarantino P, Rich JR, LoRusso PM, de Vries EGE. The Journey of Antibody-Drug Conjugates: Lessons Learned from 40 Years of Development. Cancer Discov 2024; 14:2089-2108. [PMID: 39439290 DOI: 10.1158/2159-8290.cd-24-0708] [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: 05/17/2024] [Revised: 08/16/2024] [Accepted: 09/09/2024] [Indexed: 10/25/2024]
Abstract
Antibody-drug conjugates (ADC) represent one of the most rapidly expanding treatment modalities in oncology, with 11 ADCs approved by the FDA and more than 210 currently being tested in clinical trials. Spanning over 40 years, ADC clinical development has enhanced our understanding of the multifaceted mechanisms of action for this class of therapeutics. In this article, we discuss key insights into the toxicity, efficacy, stability, distribution, and fate of ADCs. Furthermore, we highlight ongoing challenges related to their clinical optimization, the development of rational sequencing strategies, and the identification of predictive biomarkers. Significance: The development and utilization of ADCs have allowed for relevant improvements in the prognosis of multiple cancer types. Concomitantly, the rise of ADCs in oncology has produced several challenges, including the prediction of their activity, their utilization in sequence, and minimization of their side effects, that still too often resemble those of the cytotoxic molecule that they carry. In this review, we retrace 40 years of development in the field of ADCs and delve deep into the mechanisms of action of these complex therapeutics and reasons behind the many achievements and failures observed in the field to date.
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Affiliation(s)
| | - Paolo Tarantino
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Jamie R Rich
- ADC Therapeutic Development, Zymeworks Inc., Vancouver, Canada
| | - Patricia M LoRusso
- Department of Internal Medicine (Medical Oncology), Yale University School of Medicine, New Haven, Connecticut
| | - Elisabeth G E de Vries
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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36
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Rivera F, Longo F, Martín Richard M, Richart P, Alsina M, Carmona A, Custodio AB, Fernández Montes A, Gallego J, Fleitas Kanonnikoff T. SEOM-GEMCAD-TTD clinical guideline for the diagnosis and treatment of gastric cancer (2023). Clin Transl Oncol 2024; 26:2826-2840. [PMID: 39023829 PMCID: PMC11467061 DOI: 10.1007/s12094-024-03600-7] [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] [Accepted: 07/01/2024] [Indexed: 07/20/2024]
Abstract
Gastric cancer (GC) is the fifth most common cancer worldwide with a varied geographic distribution and an aggressive behavior. In Spain, the incidence is lower and GC represents the tenth most frequent tumor and the seventh cause of cancer mortality. Molecular biology knowledge allowed to better profile patients for a personalized therapeutic approach. In the localized setting, the multidisciplinary team discussion is fundamental for planning the therapeutic approach. Endoscopic resection in very early stage, perioperative chemotherapy in locally advanced tumors, and chemoradiation + surgery + adjuvant immunotherapy for the GEJ are current standards. For the metastatic setting, biomarker profiling including Her2, PD-L1, MSS status is needed. Chemotherapy in combination with checkpoint inhibitors had improved the outcomes for patients with PD-L1 expression. Her2 positive patients should receive antiHer2 therapy added to chemotherapy. We describe the different evidences and recommendations based on the literature.
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Affiliation(s)
- Fernando Rivera
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain.
| | - Federico Longo
- Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain
| | | | - Paula Richart
- Medical Oncology Department, Hospital La Fe, Valencia, Spain
| | - Maria Alsina
- Medical Oncology Department, Hospital Universitario de Navarra (HUN), Pamplona, Spain
| | - Alberto Carmona
- Medical Oncology Department, Hospital Morales Meseguer, Murcia, Spain
| | - Ana Belén Custodio
- Medical Oncology Department, Hospital Universitario La Paz, Madrid, Spain
| | - Ana Fernández Montes
- Medical Oncology Department, Complexo Hospitalario Universitario de Ourense (CHUO), Ourense, Spain
| | - Javier Gallego
- Medical Oncology Department, Hospital General Universitario de Elche, Alicante, Spain
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Hong SD, Katuwal NB, Kang MS, Ghosh M, Park SM, Kim TH, Baek YS, Lee SR, Moon YW. Trastuzumab-Mediated Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Enhances Natural Killer Cell Cytotoxicity in HER2-Overexpressing Ovarian Cancer. Int J Mol Sci 2024; 25:11733. [PMID: 39519282 PMCID: PMC11545925 DOI: 10.3390/ijms252111733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 10/27/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Ovarian cancer is the deadliest gynecologic cancer. Although human epidermal growth factor receptor-2 (HER2) overexpression, a poor prognostic molecular marker in ovarian cancer, is found in almost 30% of ovarian cancer cases, there are no established therapies for HER2-overexpressing ovarian cancer. In this study, we investigated the efficacy of combined samfenet, a biosimilar compound of trastuzumab, and natural killer (NK) cells in preclinical model of HER2-overexpressing ovarian cancer. Firstly, we screened the HER2 expression in three ovarian cancer cell lines and eight ovarian cancer patient-derived tumor xenograft (PDTX) samples. Then, immunohistochemistry and silver in situ hybridization (SISH) were performed following clinical criteria. HER2-overexpressing cells exhibited the highest sensitivity to samfenet compared with low-HER2-expressing cells. In addition, the combination of samfenet with natural killer (NK) cells resulted in significantly enhanced sensitivity to HER2-overexpressing cells and showed a significant antitumor effect on PDTX mice compared with monotherapy. It is known that anti-HER2-humanized IgG1 monoclonal antibodies, including trastuzumab, induce antibody-dependent cellular cytotoxicity (ADCC). Consequently, the combination of samfenet with NK cells demonstrated NK cell-mediated ADCC, as confirmed using an in vitro NK cytotoxicity assay and in vivo antitumor efficacy. A transferase dUTP nick end labeling (TUNEL) assay using xenografted tumors further supported the ADCC effects based on the increase in the number of apoptotic cells in the combination group. Furthermore, high HER2 expression was associated with shorter progression-free survival and overall survival based on public mRNA expression data. In this study, we demonstrated that the combination of samfenet and NK cell therapy could be a promising treatment strategy for patients with HER2-overexpressing ovarian cancer, through ADCC effects. Therefore, this study supports a rationale for further clinical studies of the combination of samfenet and NK cells as a therapy for patients with HER2-overexpressing ovarian cancer.
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Affiliation(s)
- Sa Deok Hong
- Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si 13488, Republic of Korea
| | - Nar Bahadur Katuwal
- Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si 13488, Republic of Korea
| | - Min Sil Kang
- Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si 13488, Republic of Korea
| | - Mithun Ghosh
- Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si 13488, Republic of Korea
| | - Seong Min Park
- Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si 13488, Republic of Korea
| | - Tae Hoen Kim
- Department of Pathology, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea
| | - Young Seok Baek
- Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si 13488, Republic of Korea
- Immunotherapy Team, New Biological Entity (NBE) Research, R&D Division, CHA Biotech, Seongnam-si 13488, Republic of Korea
| | - Seung Ryeol Lee
- Department of Urology, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea
| | - Yong Wha Moon
- Division of Hematology-Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam-si 13496, Republic of Korea
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Shaikh AR, Lin D. Liposomal eribulin (E7389-LF) plus nivolumab: a potential treatment option for patients with advanced gastric cancer? J Gastrointest Oncol 2024; 15:2343-2348. [PMID: 39554561 PMCID: PMC11565124 DOI: 10.21037/jgo-24-415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 09/11/2024] [Indexed: 11/19/2024] Open
Affiliation(s)
- Ali Raza Shaikh
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Thomas Jefferson University, Philadelphia, PA, USA
| | - Daniel Lin
- Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University Hospital, Thomas Jefferson University, Philadelphia, PA, USA
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Strickland MR, Klempner SJ. Dual HER2 inhibition: Is two better than one? MED 2024; 5:1191-1193. [PMID: 39395400 DOI: 10.1016/j.medj.2024.07.008] [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: 07/04/2024] [Revised: 07/05/2024] [Accepted: 07/09/2024] [Indexed: 10/14/2024]
Abstract
Li et al. present data from a randomized frontline phase II trial in HER2+ gastroesophageal cancers exploring dual targeting of HER2 with HLX22 (a novel HER2-specific antibody) with HLX02 (a trastuzumab biosimilar) and capecitabine/oxaliplatin chemotherapy. While the objective response and progression-free survival are encouraging, the future development of the combination in a crowded HER2 space remains unclear.
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Affiliation(s)
- Matthew R Strickland
- Department of Medicine, Division of Hematology-Oncology, Massachusetts General Cancer Center, Boston, MA, USA
| | - Samuel J Klempner
- Department of Medicine, Division of Hematology-Oncology, Massachusetts General Cancer Center, Boston, MA, USA.
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40
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Wong R, Anderson B, Bashir B, Bateman J, Chalchal H, Davies J, Dehmoobed A, Geller G, Ghose A, Gill S, Gordon V, Green S, Hebbard P, Iqbal M, Ji S, Karachiwala H, Kidane B, Kim C, Kosyachkova E, Krahn M, Krishnan T, Kristjanson M, Lee S, Lee-Ying R, Lelond S, Liu HW, Meyers D, Mulder K, Paul J, Planincic E. Report from the 25th Annual Western Canadian Gastrointestinal Cancer Consensus Conference on Gastric and Gastroesophageal Cancers, Winnipeg, Manitoba, 26-27 October 2023. Curr Oncol 2024; 31:5987-6006. [PMID: 39451751 PMCID: PMC11505746 DOI: 10.3390/curroncol31100447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 09/20/2024] [Accepted: 09/21/2024] [Indexed: 10/26/2024] Open
Abstract
The 25th Annual Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC) was held in Winnipeg, Manitoba, on 26-27 October 2023. The WCGCCC is an interactive multidisciplinary conference that was attended by healthcare professionals from across Western Canada (British Columbia, Alberta, and Manitoba) who are involved in the care of patients with gastrointestinal cancer. Surgical, medical, and radiation oncologists; pathologists; oncology nurses; pharmacists; and a family physician in oncology (FPO) participated in presentation and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses current issues in the management of gastroesophageal cancers.
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Affiliation(s)
- Ralph Wong
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | - Brady Anderson
- Western Manitoba Cancer Center, Brandon, MB R7A 5M8, Canada;
| | - Bashir Bashir
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | | | - Haji Chalchal
- Allan Blair Cancer Centre, Regina, SK S4T 7T1, Canada;
| | - Janine Davies
- BC Cancer Centre, Vancouver, BC V5Z 4E6, Canada; (J.D.); (S.G.); (T.K.)
| | - Anahita Dehmoobed
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | | | - Abhijit Ghose
- Chinook Regional Hospital, Lethbridge, AB T1J 1W5, Canada
| | - Sharlene Gill
- BC Cancer Centre, Vancouver, BC V5Z 4E6, Canada; (J.D.); (S.G.); (T.K.)
| | - Vallerie Gordon
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | - Susan Green
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | - Pamela Hebbard
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | | | - Shuying Ji
- Shared Health Manitoba, Winnipeg, MB R2N 0E2, Canada;
| | - Hatim Karachiwala
- Tom Baker Cancer Centre, Calgary, AB T2N 4N2, Canada; (H.K.); (R.L.-Y.)
| | - Biniam Kidane
- Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3A 1R9, Canada;
| | - Christina Kim
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | | | - Marianne Krahn
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | - Tharani Krishnan
- BC Cancer Centre, Vancouver, BC V5Z 4E6, Canada; (J.D.); (S.G.); (T.K.)
| | - Mark Kristjanson
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | - Sangjune Lee
- Department of Oncology, University of Calgary, Calgary, AB T2N 4N2, Canada;
| | - Richard Lee-Ying
- Tom Baker Cancer Centre, Calgary, AB T2N 4N2, Canada; (H.K.); (R.L.-Y.)
| | - Stephanie Lelond
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | - Hong-Wei Liu
- Central Alberta Cancer Center, Red Deer, AB T4N 6R2, Canada;
| | - Daniel Meyers
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | - Karen Mulder
- Cross Cancer Institute, Edmonton, AB T6G 1Z2, Canada;
| | - James Paul
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
| | - Elvira Planincic
- CancerCare Manitoba, Winnipeg, MB R3E 0V9, Canada; (B.B.); (A.D.); (V.G.); (S.G.); (P.H.); (M.K.); (M.K.); (S.L.); (D.M.); (E.P.); (J.P.)
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Chen R, Ren Z, Bai L, Hu X, Chen Y, Ye Q, Hu Y, Shi J. Novel antibody-drug conjugates based on DXd-ADC technology. Bioorg Chem 2024; 151:107697. [PMID: 39121594 DOI: 10.1016/j.bioorg.2024.107697] [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: 04/28/2024] [Revised: 07/27/2024] [Accepted: 08/04/2024] [Indexed: 08/12/2024]
Abstract
In recent years, antibody-drug conjugate (ADC) technology, which uses monoclonal antibodies (mAbs) to specifically deliver effective cytotoxic payloads to tumor cells, has become a promising method of tumor targeted therapy. ADCs are a powerful class of biopharmaceuticals that link antibodies targeting specific antigens and small molecule drugs with potent cytotoxicity via a linker, thus enabling selective destruction of cancer cells while minimizing systemic toxicity. DXd is a topoisomerase I inhibitor that induces DNA damage leading to cell cycle arrest, making it an option for ADC payloads. The DXd-ADC technology, developed by Daiichi Sankyo, is a cutting-edge platform that produces a new generation of ADCs with improved therapeutic metrics and has shown significant therapeutic potential in various types of cancer. This review provides a comprehensive assessment of drugs developed with DXd-ADC technology, with a focus on mechanisms of action, pharmacokinetics studies, preclinical data, and clinical outcomes for DS-8201a, U3-1402, DS-1062a, DS-7300a, DS-6157a, and DS-6000a. By integrating existing data, we aim to provide valuable insights into the current therapeutic status and future prospects of these novel agents.
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Affiliation(s)
- Rong Chen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China
| | - Zhiwen Ren
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Lan Bai
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Xuefang Hu
- Key Laboratory of Agro-Products Postharvest Handling, Ministry of Agriculture, Academy of Agricultural Planning and Engineering Mara, Beijing 100121, China
| | - Yuchen Chen
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China
| | - Qiang Ye
- School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, Sichuan, China.
| | - Yuan Hu
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
| | - Jianyou Shi
- Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
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Rogers JE, Gan Q, Waters RE, Horak AA, Ajani JA. Targeted and combination immunotherapies using biologics for gastric cancer: the state-of-the-art. Expert Opin Biol Ther 2024; 24:1005-1015. [PMID: 39315517 DOI: 10.1080/14712598.2024.2401622] [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: 04/25/2024] [Revised: 08/09/2024] [Accepted: 09/03/2024] [Indexed: 09/25/2024]
Abstract
INTRODUCTION Gastric adenocarcinoma (GAC) remains a prevalent cancer worldwide and its incidence is increasing in South America. The heterogenous nature of GAC makes advances in management challenging. AREAS COVERED Despite challenges, recent therapeutic targets are individualizing treatment. For localized disease with microsatellite-instability-high/deficient mismatch repair, immunotherapy is now an adopted practice. In the advanced unresectable setting, those harboring human epidermal growth factor receptor-2 (HER2) expression continue to be a separate entity. EXPERT OPINION Future targets are developing. Among these include claudin 18.2 (CLDN18.2), fibroblast growth factor receptor 2b (FGFR2b), and trophoblast cell surface antigen-2 (TROP-2). FDA approval of zolbetuximab's, an anti-CLDN 18.2 monoclonal antibody, is expected soon. Additionally, bemarituzumab, ananti-FGFR2b monoclonal antibody, has shown improvements in combination with chemotherapy in those with HER2 negative GAC with FGFR2 overexpression. This combination is now being investigated in a phase 3 trial. Lastly, TROP-2 has emerged as an exciting solid tumor target and study is expected in GAC. All three of these therapeutic targets have seen an abundance of drug development in recent years, and we anticipate newer targeted agents driving therapeutic decisions in GAC in the coming years.
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Affiliation(s)
- Jane E Rogers
- Pharmacy Clinical Programs, U.T. M.D. Anderson Cancer Center, Houston, TX, USA
| | - Qiong Gan
- Department of Pathology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA
| | - Rebecca E Waters
- Department of Pathology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA
| | - Ashley A Horak
- Department of Gastrointestinal Medical Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX, USA
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Tanaka Y, Ikeda N, Niho S, Ishida K. Effectiveness of trastuzumab deruxtecan rechallenge in a patient with HER2-positive metastatic breast cancer: a case report. Int Cancer Conf J 2024; 13:353-359. [PMID: 39398901 PMCID: PMC11465017 DOI: 10.1007/s13691-024-00723-0] [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: 03/26/2024] [Accepted: 09/01/2024] [Indexed: 10/15/2024] Open
Abstract
Trastuzumab deruxtecan (T-DXd), a high-payload antibody drug conjugate, has been reported to exert potent antitumor effects and has recently shown promising efficacy against human epidermal growth factor receptor 2 (HER2)-positive adenocarcinoma. Despite its high efficacy, interstitial lung disease (ILD) is a severe adverse event (AE) associated with T-DXd. This report describes a patient who was successfully treated with a dose-reduced T-DXd challenge after recovery from ILD. Little disease progression was observed during the treatment interruption period; thus, the effect of T-DXd was considered to have been maintained. T-DXd may induce ILD, and re-administration under careful observation is considered an important option for treating patients with HER2-positive breast cancer.
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Affiliation(s)
- Yuko Tanaka
- Department of Cancer Genome, Dokkyo Medical University, 880 Kitakobayashi, Shimotsuga District, Mibu, Tochigi 321-0293 Japan
| | - Naoya Ikeda
- Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University, 880 Kitakobayashi, Shimotsuga District, Mibu, Tochigi 321-0293 Japan
| | - Seiji Niho
- Department of Pulmonary Medicine and Clinical Immunology, Dokkyo Medical University, 880 Kitakobayashi, Shimotsuga District, Mibu, Tochigi 321-0293 Japan
| | - Kazuyuki Ishida
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kitakobayashi, Shimotsuga District, Mibu, Tochigi 321-0293 Japan
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Lordick F, Rha SY, Muro K, Yong WP, Lordick Obermannová R. Systemic Therapy of Gastric Cancer-State of the Art and Future Perspectives. Cancers (Basel) 2024; 16:3337. [PMID: 39409957 PMCID: PMC11475804 DOI: 10.3390/cancers16193337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Revised: 09/27/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Background: The prognosis of patients diagnosed with locally advanced and metastatic gastric and esophago-gastric junction cancer is critical. The optimal choice of systemic therapy is essential to optimize survival outcomes. Methods: A comprehensive literature review via PubMed and analysis of major oncology congresses (European Society for Medical Oncology and American Society of Clinical Oncology websites) were conducted to ascertain the current status and latest developments in the systemic treatment of patients with localized or advanced gastric and esophago-gastric junction adenocarcinoma. Results: While neoadjuvant and perioperative chemotherapy for localized tumor stages is the preferred approach in the Western Hemisphere, adjuvant chemotherapy remains the preferred course of action in East Asia. The administration of chemotherapy, typically in the form of combinations comprising platinum and fluoropyrimidine compounds in combination with docetaxel, represents a standard of care. Investigations are underway into the potential of immunotherapy and other biologically targeted agents in the perioperative setting. To select the most appropriate therapy for advanced gastric cancer, including adenocarcinoma of the esophago-gastric junction, it is essential to determine biomarkers such as HER2 expression, PD-L1 combined positive score (CPS) (combined positive score), Claudin 18.2, and microsatellite instability (MSI). In the present clinical context, the standard first-line therapy is a combination of fluoropyrimidine and a platinum derivative. The selection of chemotherapy in combination with antibodies is contingent upon the specific biomarker under consideration. Conclusions: This article reviews the current state of the art based on recent clinical trial results and provides an outlook on the future of systemic therapy.
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Affiliation(s)
- Florian Lordick
- Department of Medicine (Oncology, Gastroenterology, Hepatology, Pulmonology), University of Leipzig Medical Center, Cancer Center Central Germany, 04103 Leipzig, Germany
| | - Sun Young Rha
- Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya 464-8681, Japan
| | - Wei Peng Yong
- Department of Haematology-Oncology, National University Cancer Institute, Singapore 119074, Singapore
| | - Radka Lordick Obermannová
- Department of Comprehensive Cancer Care, Masaryk Memorial Cancer Institute, Faculty of Medicine, Masaryk University, 656 53 Brno, Czech Republic
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Li W, Wei J, Cheng M, Liu M. Unveiling promising targets in gastric cancer therapy: A comprehensive review. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200857. [PMID: 39280587 PMCID: PMC11396074 DOI: 10.1016/j.omton.2024.200857] [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] [Indexed: 09/18/2024]
Abstract
Gastric cancer (GC) poses a significant global health challenge, ranking fifth in incidence and third in mortality among all malignancies worldwide. Its insidious onset, aggressive growth, proclivity for metastasis, and limited treatment options have contributed to its high fatality rate. Traditional approaches for GC treatment primarily involve surgery and chemotherapy. However, there is growing interest in targeted therapies and immunotherapies. This comprehensive review highlights recent advancements in GC targeted therapy and immunotherapy. It delves into the mechanisms of various strategies, underscoring their potential in GC treatment. Additionally, the review evaluates the efficacy and safety of relevant clinical trials. Despite the benefits observed in numerous advanced GC patients with targeted therapies and immunotherapies, challenges persist. We discuss pertinent strategies to overcome these challenges, thereby providing a solid foundation for enhancing the clinical effectiveness of targeted therapies and immunotherapies.
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Affiliation(s)
- Wenke Li
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Jing Wei
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Mo Cheng
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
| | - Ming Liu
- Gastric Cancer Center/Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan Province 610041, China
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46
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Hao JL, Li XY, Liu YT, Lang JX, Liu DJ, Zhang CD. Antibody-drug conjugates in gastric cancer: from molecular landscape to clinical strategies. Gastric Cancer 2024; 27:887-906. [PMID: 38963593 DOI: 10.1007/s10120-024-01529-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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 06/25/2024] [Indexed: 07/05/2024]
Abstract
Antibody-drug conjugates (ADCs) represent a crucial component of targeted therapies in gastric cancer, potentially altering traditional treatment paradigms. Many ADCs have entered rigorous clinical trials based on biological theories and preclinical experiments. Modality trials have also been conducted in combination with monoclonal antibody therapies, chemotherapies, immunotherapies, and other treatments to enhance the efficacy of drug coordination effects. However, ADCs exhibit limitations in treating gastric cancer, including resistance triggered by their structure or other factors. Ongoing intensive researches and preclinical experiments are yielding improvements, while enhancements in drug development processes and concomitant diagnostics during the therapeutic period actively boost ADC efficacy. The optimal treatment strategy for gastric cancer patients is continually evolving. This review summarizes the clinical progress of ADCs in treating gastric cancer, analyzes the mechanisms of ADC combination therapies, discusses resistance patterns, and offers a promising outlook for future applications in ADC drug development and companion diagnostics.
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Affiliation(s)
- Jia-Lin Hao
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Xin-Yun Li
- Clinical Medicine, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Yu-Tong Liu
- Department of Anesthesiology, Shengjing Hospital of China Medical University, Shenyang, 110022, China
| | - Ji-Xuan Lang
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Di-Jie Liu
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China
| | - Chun-Dong Zhang
- Central Laboratory, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.
- Department of Surgical Oncology, The Fourth Affiliated Hospital of China Medical University, Shenyang, 110032, China.
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47
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Zouein J, Karam E, Strickler JH, Kourie HR. Trastuzumab-Deruxtecan: Redefining HER2 as a Tumor Agnostic Biomarker. Target Oncol 2024; 19:705-710. [PMID: 38963654 DOI: 10.1007/s11523-024-01079-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2024] [Indexed: 07/05/2024]
Abstract
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) targeting HER2-positive malignancies across various tumor types. Through its unique composition, T-DXd achieves selective payload delivery, inducing cell death and halting tumor progression. Clinical trials initially investigated T-DXd's efficacy in HER2-positive advanced or metastatic breast, gastric, lung, and colorectal cancers; however, recent results from the DESTINY-PanTumor02 trial further underscore T-DXd's versatility, prompting T-DXd's US FDA approval for HER2-positive (immunohistochemistry [IHC] 3+) solid tumors. Moreover, in addition to T-DXd's efficacy against brain metastasis, T-DXd is showing promising results in HER2-low and HER2-ultra-low metastatic breast cancer, indicating a broader population of patients who may benefit.
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Affiliation(s)
- Joseph Zouein
- Department of Medicine, Duke University Medical Center, Durham, NC, USA.
- Hematology-Oncology Department, Faculty of Medicine, Saint-Joseph University of Beirut, Beirut, Lebanon.
| | - Elias Karam
- Départements de Médecine Oncologique, Gustave Roussy, 94805, Villejuif, France
- Hematology-Oncology Department, Faculty of Medicine, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - John H Strickler
- Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Hampig Raphael Kourie
- Hematology-Oncology Department, Faculty of Medicine, Saint-Joseph University of Beirut, Beirut, Lebanon
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48
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Booth ME, Clements HA, Helbrow J, Baxter MA, Bleaney CW, Hawkins MA, Markar SR, Peters CJ, Smyth EC, Crosby TDL. United Kingdom and Ireland Oesophagogastric Cancer Group Cancer Update 2023. Clin Oncol (R Coll Radiol) 2024; 36:e283-e291. [PMID: 38876807 DOI: 10.1016/j.clon.2024.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Revised: 04/18/2024] [Accepted: 04/29/2024] [Indexed: 06/16/2024]
Affiliation(s)
- M E Booth
- Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - H A Clements
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
| | - J Helbrow
- South West Wales Cancer Centre, Swansea Bay University Health Board, Swansea, UK
| | - M A Baxter
- Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
| | - C W Bleaney
- Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - M A Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, UK
| | - S R Markar
- Nuffield Department of Surgical Sciences, University of Oxford, UK
| | - C J Peters
- Department of Surgery and Cancer, Imperial College London, UK
| | - E C Smyth
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK
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49
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Kudo T. Advances in the treatment of human epidermal growth factor receptor 2-positive gastric cancer. Int J Clin Oncol 2024; 29:1220-1227. [PMID: 39083154 DOI: 10.1007/s10147-024-02587-z] [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: 04/13/2024] [Accepted: 07/15/2024] [Indexed: 08/27/2024]
Abstract
Human epidermal growth factor receptor 2 has been a pivotal biomarker for gastric cancer treatment strategies for many years. However, more than a decade after the ToGA trial demonstrated the efficacy of trastuzumab in improving survival, the development of treatments targeting human epidermal growth factor receptor 2 remains challenging. Several large-scale clinical trials of tyrosine kinase inhibitors, non-trastuzumab anti-human epidermal growth factor receptor 2 antibodies, and antibody-drug conjugates have failed to meet the primary endpoints. The concept of trastuzumab beyond progression and the complexity of resistance mechanisms to anti-human epidermal growth factor receptor 2 therapy after trastuzumab treatment presented significant obstacles, leading to trastuzumab being the sole therapy for human epidermal growth factor receptor 2-positive gastric cancer for some time. Nevertheless, the landscape has shifted in recent years, especially since the introduction of the antibody-drug conjugate trastuzumab deruxtecan in 2020. This has rekindled the interest in developing treatments targeting human epidermal growth factor receptor 2 in gastric cancer.
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Affiliation(s)
- Toshihiro Kudo
- Department of Medical Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.
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50
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Yoon J, Oh DY. HER2-targeted therapies beyond breast cancer - an update. Nat Rev Clin Oncol 2024; 21:675-700. [PMID: 39039196 DOI: 10.1038/s41571-024-00924-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/28/2024] [Indexed: 07/24/2024]
Abstract
The receptor tyrosine-kinase HER2 (also known as ErbB2) is a well-established therapeutic target in patients with breast or gastric cancer selected on the basis of HER2 overexpression on immunohistochemistry and/or ERBB2 amplification on in situ hybridization. With advances in cancer molecular profiling and increased implementation of precision medicine approaches into oncology practice, actionable HER2 alterations in solid tumours have expanded to include ERBB2 mutations in addition to traditional HER2 overexpression and ERBB2 amplification. These various HER2 alterations can be found in solid tumour types beyond breast and gastric cancer, although few HER2-targeted therapeutic options have been established for the other tumour types. Nevertheless, during the 5 years since our previous Review on this topic was published in this journal, obvious and fruitful progress in the development of HER2-targeted therapies has been made, including new disease indications, innovative drugs with diverse mechanisms of action and novel frameworks for approval by regulatory authorities. These advances have culminated in the recent histology-agnostic approval of the anti-HER2 antibody-drug conjugate trastuzumab deruxtecan for patients with HER2-overexpressing solid tumours. In this new Review, we provide an update on the current development landscape of HER2-targeted therapies beyond breast cancer, as well as anticipated future HER2-directed treatment strategies to overcome resistance and thereby improve efficacy and patient outcomes.
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Affiliation(s)
- Jeesun Yoon
- Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Do-Youn Oh
- Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
- Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, Republic of Korea.
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