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Liu Z, Liu W, Shen X, Jiang T, Li X, Liu H, Zheng Z. Molecular mechanism of type ib MET inhibitors and their potential for CNS tumors. Sci Rep 2025; 15:6926. [PMID: 40011494 PMCID: PMC11865562 DOI: 10.1038/s41598-025-85631-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 01/06/2025] [Indexed: 02/28/2025] Open
Abstract
The emergence of targeted therapies for MET exon 14 (METex14) skipping mutations has significantly changed the treatment landscape for NSCLC and other solid tumors. The skipping of METex14 results in activating the MET-HGF pathway and promoting tumor cell proliferation, migration, and preventing apoptosis. Type Ib MET inhibitors, designed to selectively target the "DFG-in" conformation of MET, characteristically bind to the ATP-binding pocket of MET in a U-shaped conformation, extending into the solvent-accessible region and interact strongly with residue Y1230 through π-π interactions, have shown remarkable efficacy in treating METex14-altered NSCLC, including cases with brain metastases (BMs). Notably, vebreltinib and capmatinib have demonstrated superior blood-brain barrier (BBB) permeability in both computational and experimental models, highlighting their potential for treating the central nervous system (CNS) metastases. P-glycoprotein (P-gp) is highly expressed in the BBB, which limits the brain uptake of many highly lipophilic drugs. Despite challenges posed by P-gp mediated efflux, vebreltinib has emerged as a promising candidate for CNS treatment due to its favorable pharmacokinetic profile and minimal susceptibility to P-gp efflux. This study underscores the importance of molecular dynamics simulations in predicting drug efficacy and BBB penetration, providing valuable insights for the development of CNS-targeted metastases therapies.
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Affiliation(s)
- Zhenhao Liu
- Divamics Inc., Suzhou, 215000, People's Republic of China
| | - Wenlang Liu
- Divamics Inc., Suzhou, 215000, People's Republic of China
| | - Xinyi Shen
- Divamics Inc., Suzhou, 215000, People's Republic of China
| | - Tao Jiang
- Divamics Inc., Suzhou, 215000, People's Republic of China
| | - Xionghao Li
- Divamics Inc., Suzhou, 215000, People's Republic of China
| | - Hao Liu
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, Hubei, People's Republic of China.
| | - Zheng Zheng
- School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, Wuhan, 430070, Hubei, People's Republic of China.
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2
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Wang M, Zhang S, Yi D, Ou Y, Xie S, Zeng C, Qin X, Zhao L, Wang Z, Kong F, Chen L. Advances in clinical research of MET exon 14 skipping mutations in non-small cell lung cancer. J Cancer Res Clin Oncol 2025; 151:78. [PMID: 39937291 PMCID: PMC11821758 DOI: 10.1007/s00432-025-06115-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 01/21/2025] [Indexed: 02/13/2025]
Abstract
The cellular-mesenchymal to epithelial transition factor (MET) gene plays a crucial role in maintaining cell homeostasis, motility, and apoptosis. In cancer, MET gene alterations promote tumour cell proliferation, invasion and metastasis. In non-small cell lung cancer (NSCLC), MET gene alterations include MET exon 14 (METex14) skipping mutation (METΔ14ex), MET amplification (METamp), MET fusion, and MET tyrosine kinase domain missense mutations (MET-TKD) and MET protein overexpression. Among them, the METΔ14ex is an independent driver gene of NSCLC. Three to four per cent of NSCLC patients carry METΔ14ex, and these patients have a poor prognosis and respond poorly to conventional chemotherapy. Small molecule highly selective MET inhibitors such as carmatinib, tepotinib, and cervotinib have shown promising efficacy and safety in clinical trials. Monoclonal antibodies, bispecific antibodies, antibody conjugate drugs, and immune checkpoint inhibitors provide more treatment space for patients with METΔ14ex. In this review, we summarize the current application and research of MET inhibitors and immune checkpoint inhibitors in NSCLC with METΔ14ex and provide recommendations for precise treatment of NSCLC patients with MET gene changes mutations. It also provides new ideas for solving the problems of synergistic effect and drug resistance in targeted therapy and immunotherapy.
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Affiliation(s)
- Mengchao Wang
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Shao Zhang
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Dan Yi
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Yan Ou
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Shuqi Xie
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Chuanxiu Zeng
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Xueqian Qin
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Lu Zhao
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Zhen Wang
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Fanming Kong
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China
| | - Liwei Chen
- Oncology Department, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.
- National Clinical Research Center of Chinese Acupuncture and Moxibustion, Tianjin, China.
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3
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Zhang D, Zhang W, Liu H, Liu P, Li C, Liu Y, Han J, Zhu G. Recent advances in the treatment of non-small cell lung cancer with MET inhibitors. Front Chem 2024; 12:1501844. [PMID: 39720556 PMCID: PMC11666382 DOI: 10.3389/fchem.2024.1501844] [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: 09/25/2024] [Accepted: 11/22/2024] [Indexed: 12/26/2024] Open
Abstract
Recently, research into the oncogenic driver genes associated with non-small cell lung cancer (NSCLC) has advanced significantly, leading to the development and clinical application of an increasing number of approved therapeutic agents. Among these, small molecule inhibitors that target mesenchymal-epithelial transition (MET) have demonstrated successful application in clinical settings. Currently, three categories of small molecule MET inhibitors, characterized by distinct binding patterns to the MET kinase region, have been developed: types Ia/Ib, II, and III. This review thoroughly examines MET's structure and its crucial role in NSCLC initiation and progression, explores discovery strategies for MET inhibitors, and discusses advancements in understanding resistance mechanisms. These insights are anticipated to enhance the development of a new generation of MET inhibitors characterized by high efficiency, selectivity, and low toxicity, thereby offering additional therapeutic alternatives for patients diagnosed with NSCLC.
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Affiliation(s)
- Dongna Zhang
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Wenying Zhang
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - He Liu
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Pan Liu
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Chunxin Li
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Yangyang Liu
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
| | - Jicheng Han
- Key Laboratory of Jilin Province for Traditional Chinese Medicine Prevention and Treatment of Infectious Diseases, College of integrative medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Guangze Zhu
- Department of Clinical Laboratory Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China
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Chilamakuri R, Agarwal S. Repurposing of c-MET Inhibitor Tivantinib Inhibits Pediatric Neuroblastoma Cellular Growth. Pharmaceuticals (Basel) 2024; 17:1350. [PMID: 39458991 PMCID: PMC11510580 DOI: 10.3390/ph17101350] [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: 08/28/2024] [Revised: 09/22/2024] [Accepted: 10/01/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Dysregulation of receptor tyrosine kinase c-MET is known to promote tumor development by stimulating oncogenic signaling pathways in different cancers, including pediatric neuroblastoma (NB). NB is an extracranial solid pediatric cancer that accounts for almost 15% of all pediatric cancer-related deaths, with less than a 50% long-term survival rate. Results: In this study, we analyzed a large cohort of primary NB patient data and revealed that high MET expression strongly correlates with poor overall survival, disease progression, relapse, and high MYCN levels in NB patients. To determine the effects of c-MET in NB, we repurposed a small molecule inhibitor, tivantinib, and found that c-MET inhibition significantly inhibits NB cellular growth. Tivantinib significantly blocks NB cell proliferation and 3D spheroid tumor formation and growth in different MYCN-amplified and MYCN-non-amplified NB cell lines. Furthermore, tivantinib blocks the cell cycle at the G2/M phase transition and induces apoptosis in different NB cell lines. As expected, c-MET inhibition by tivantinib inhibits the expression of multiple genes in PI3K, STAT, and Ras cell signaling pathways. Conclusions: Overall, our data indicate that c-MET directly regulates NB growth and 3D spheroid growth, and c-MET inhibition by tivantinib may be an effective therapeutic approach for high-risk NB. Further developing c-MET targeted therapeutic approaches and combining them with current therapies may pave the way for effectively translating novel therapies for NB and other c-MET-driven cancers.
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Affiliation(s)
| | - Saurabh Agarwal
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, New York, NY 11439, USA
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5
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Albadari N, Xie Y, Li W. Deciphering treatment resistance in metastatic colorectal cancer: roles of drug transports, EGFR mutations, and HGF/c-MET signaling. Front Pharmacol 2024; 14:1340401. [PMID: 38269272 PMCID: PMC10806212 DOI: 10.3389/fphar.2023.1340401] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 12/27/2023] [Indexed: 01/26/2024] Open
Abstract
In 2023, colorectal cancer (CRC) is the third most diagnosed malignancy and the third leading cause of cancer death worldwide. At the time of the initial visit, 20% of patients diagnosed with CRC have metastatic CRC (mCRC), and another 25% who present with localized disease will later develop metastases. Despite the improvement in response rates with various modulation strategies such as chemotherapy combined with targeted therapy, radiotherapy, and immunotherapy, the prognosis of mCRC is poor, with a 5-year survival rate of 14%, and the primary reason for treatment failure is believed to be the development of resistance to therapies. Herein, we provide an overview of the main mechanisms of resistance in mCRC and specifically highlight the role of drug transports, EGFR, and HGF/c-MET signaling pathway in mediating mCRC resistance, as well as discuss recent therapeutic approaches to reverse resistance caused by drug transports and resistance to anti-EGFR blockade caused by mutations in EGFR and alteration in HGF/c-MET signaling pathway.
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Affiliation(s)
| | | | - Wei Li
- College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, United States
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6
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Altintas DM, Comoglio PM. An Observatory for the MET Oncogene: A Guide for Targeted Therapies. Cancers (Basel) 2023; 15:4672. [PMID: 37760640 PMCID: PMC10526818 DOI: 10.3390/cancers15184672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
The MET proto-oncogene encodes a pivotal tyrosine kinase receptor, binding the hepatocyte growth factor (HGF, also known as scatter factor, SF) and governing essential biological processes such as organogenesis, tissue repair, and angiogenesis. The pleiotropic physiological functions of MET explain its diverse role in cancer progression in a broad range of tumors; genetic/epigenetic alterations of MET drive tumor cell dissemination, metastasis, and acquired resistance to conventional and targeted therapies. Therefore, targeting MET emerged as a promising strategy, and many efforts were devoted to identifying the optimal way of hampering MET signaling. Despite encouraging results, however, the complexity of MET's functions in oncogenesis yields intriguing observations, fostering a humbler stance on our comprehension. This review explores recent discoveries concerning MET alterations in cancer, elucidating their biological repercussions, discussing therapeutic avenues, and outlining future directions. By contextualizing the research question and articulating the study's purpose, this work navigates MET biology's intricacies in cancer, offering a comprehensive perspective.
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Affiliation(s)
| | - Paolo M. Comoglio
- IFOM ETS—The AIRC Institute of Molecular Oncology, 20139 Milano, Italy;
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7
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Hsu R, Benjamin DJ, Nagasaka M. The Development and Role of Capmatinib in the Treatment of MET-Dysregulated Non-Small Cell Lung Cancer-A Narrative Review. Cancers (Basel) 2023; 15:3561. [PMID: 37509224 PMCID: PMC10377299 DOI: 10.3390/cancers15143561] [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: 05/24/2023] [Revised: 07/04/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) is a leading cause of death, but over the past decade, there has been tremendous progress in the field with new targeted therapies. The mesenchymal-epithelial transition factor (MET) proto-oncogene has been implicated in multiple solid tumors, including NSCLC, and dysregulation in NSCLC from MET can present most notably as MET exon 14 skipping mutation and amplification. From this, MET tyrosine kinase inhibitors (TKIs) have been developed to treat this dysregulation despite challenges with efficacy and reliable biomarkers. Capmatinib is a Type Ib MET TKI first discovered in 2011 and was FDA approved in August 2022 for advanced NSCLC with MET exon 14 skipping mutation. In this narrative review, we discuss preclinical and early-phase studies that led to the GEOMETRY mono-1 study, which showed beneficial efficacy in MET exon 14 skipping mutations, leading to FDA approval of capmatinib along with Foundation One CDx assay as its companion diagnostic assay. Current and future directions of capmatinib are focused on improving the efficacy, overcoming the resistance of capmatinib, and finding approaches for new indications of capmatinib such as acquired MET amplification from epidermal growth factor receptor (EGFR) TKI resistance. Clinical trials now involve combination therapy with capmatinib, including amivantamab, trametinib, and immunotherapy. Furthermore, new drug agents, particularly antibody-drug conjugates, are being developed to help treat patients with acquired resistance from capmatinib and other TKIs.
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Affiliation(s)
- Robert Hsu
- Division of Medical Oncology, Department of Internal Medicine, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033, USA
| | | | - Misako Nagasaka
- Division of Hematology and Oncology, Department of Medicine, Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA 92868, USA
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8
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Wang C, Lu X. Targeting MET: Discovery of Small Molecule Inhibitors as Non-Small Cell Lung Cancer Therapy. J Med Chem 2023. [PMID: 37262349 DOI: 10.1021/acs.jmedchem.3c00028] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types of binding modes (Ia/Ib, II, and III) have been developed. In this Review, we provide an overview of the structural features, activation mechanism, and dysregulation pathway of MET and summarize progress on the development and discovery strategies utilized for MET inhibitors as well as mechanisms of acquired resistance to current approved inhibitors. The insights will accelerate discovery of new generation MET inhibitors to overcome clinical acquired resistance.
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Affiliation(s)
- Chaofan Wang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou, 510632, China
| | - Xiaoyun Lu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, China
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou, 510632, China
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9
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Jiang L, Li L, Liu Y, Zhan M, Lu L, Yuan S, Liu Y. Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma. Front Pharmacol 2023; 14:1097277. [PMID: 36891274 PMCID: PMC9987615 DOI: 10.3389/fphar.2023.1097277] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 02/01/2023] [Indexed: 02/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and it usually occurs following chronic liver disease. Although some progress has been made in the treatment of HCC, the prognosis of patients with advanced HCC is not optimistic, mainly because of the inevitable development of drug resistance. Therefore, multi-target kinase inhibitors for the treatment of HCC, such as sorafenib, lenvatinib, cabozantinib, and regorafenib, produce small clinical benefits for patients with HCC. It is necessary to study the mechanism of kinase inhibitor resistance and explore possible solutions to overcome this resistance to improve clinical benefits. In this study, we reviewed the mechanisms of resistance to multi-target kinase inhibitors in HCC and discussed strategies that can be used to improve treatment outcomes.
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Affiliation(s)
- Lei Jiang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital AffiliatedWith Jinan University), Zhuhai, Guangdong, China
| | - Luan Li
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Yongzhuang Liu
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Liaoning Province, China
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital AffiliatedWith Jinan University), Zhuhai, Guangdong, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital AffiliatedWith Jinan University), Zhuhai, Guangdong, China
| | - Shengtao Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Liaoning Province, China
| | - Yanyan Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital AffiliatedWith Jinan University), Zhuhai, Guangdong, China
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10
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Wang Z, Xing Y, Li B, Li X, Liu B, Wang Y. Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer. MOLECULAR BIOMEDICINE 2022; 3:42. [PMID: 36508072 PMCID: PMC9743956 DOI: 10.1186/s43556-022-00107-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 11/03/2022] [Indexed: 12/14/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide. The discovery of tyrosine kinase inhibitors effectively targeting EGFR mutations in lung cancer patients in 2004 represented the beginning of the precision medicine era for this refractory disease. This great progress benefits from the identification of driver gene mutations, and after that, conventional and new technologies such as NGS further illustrated part of the complex molecular pathways of NSCLC. More targetable driver gene mutation identification in NSCLC patients greatly promoted the development of targeted therapy and provided great help for patient outcomes including significantly improved survival time and quality of life. Herein, we review the literature and ongoing clinical trials of NSCLC targeted therapy to address the molecular pathways and targeted intervention progress in NSCLC. In addition, the mutations in EGFR gene, ALK rearrangements, and KRAS mutations in the main sections, and the less common molecular alterations in MET, HER2, BRAF, ROS1, RET, and NTRK are discussed. The main resistance mechanisms of each targeted oncogene are highlighted to demonstrate the current dilemma of targeted therapy in NSCLC. Moreover, we discuss potential therapies to overcome the challenges of drug resistance. In this review, we manage to display the current landscape of targetable therapeutic patterns in NSCLC in this era of precision medicine.
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Affiliation(s)
- Zixi Wang
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Yurou Xing
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Bingjie Li
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Xiaoyu Li
- grid.412901.f0000 0004 1770 1022Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan China ,grid.412901.f0000 0004 1770 1022State Key Laboratory Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Bin Liu
- grid.54549.390000 0004 0369 4060Department of Medical Oncology, School of Medicine, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, Sichuan China
| | - Yongsheng Wang
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China ,grid.412901.f0000 0004 1770 1022State Key Laboratory Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
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11
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Terlecka P, Krawczyk P, Grenda A, Milanowski J. MET Gene Dysregulation as a Promising Therapeutic Target in Lung Cancer-A Review. J Pers Med 2021; 11:1370. [PMID: 34945842 PMCID: PMC8705301 DOI: 10.3390/jpm11121370] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/20/2021] [Accepted: 12/13/2021] [Indexed: 11/23/2022] Open
Abstract
Several molecular abnormalities in the MET gene have been identified, including overexpression, amplification, point mutations, and "skipping mutation" in exon 14. Even though deregulated MET signaling occurs rarely in non-small cell lung cancer (NSCLC), it possesses tumorigenic activity. Since the discovery of the significant role played by MET dysregulations in resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), many clinical trials have been focused on mechanisms underlying this acquired resistance. Therefore, new therapeutic strategies are being considered in the personalized therapy of NSCLC patients carrying MET abnormalities. First, MET kinase inhibitors (tepotinib and capmatinib) have been shown to be effective in the first and subsequent lines of treatment in NSCLC patients with "skipping mutations" in exon 14 of MET gene. In this article, the authors show the role of MET signaling pathway alterations and describe the results of clinical trials with MET inhibitors in NSCLC patients.
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Affiliation(s)
- Paulina Terlecka
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-090 Lublin, Poland; (P.K.); (A.G.); (J.M.)
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12
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Zhao S, Wu W, Jiang H, Ma L, Pan C, Jin C, Mo J, Wang L, Wang K. Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib? Front Immunol 2021; 12:731527. [PMID: 34804015 PMCID: PMC8600564 DOI: 10.3389/fimmu.2021.731527] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the "ClinicalTrials.gov" for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.
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Affiliation(s)
- Shankun Zhao
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Weizhou Wu
- Department of Urology, Maoming People's Hospital, Maoming, China
| | - Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Lei Ma
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chengyi Pan
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Liezhi Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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13
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Moosavi F, Giovannetti E, Peters GJ, Firuzi O. Combination of HGF/MET-targeting agents and other therapeutic strategies in cancer. Crit Rev Oncol Hematol 2021; 160:103234. [PMID: 33497758 DOI: 10.1016/j.critrevonc.2021.103234] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Revised: 12/29/2020] [Accepted: 01/16/2021] [Indexed: 02/06/2023] Open
Abstract
MET receptor has emerged as a druggable target across several human cancers. Agents targeting MET and its ligand hepatocyte growth factor (HGF) including small molecules such as crizotinib, tivantinib and cabozantinib or antibodies including rilotumumab and onartuzumab have proven their values in different tumors. Recently, capmatinib was approved for treatment of metastatic lung cancer with MET exon 14 skipping. In this review, we critically examine the current evidence on how HGF/MET combination therapies may take advantage of synergistic effects, overcome primary or acquired drug resistance, target tumor microenvironment, modulate drug metabolism or tackle pharmacokinetic issues. Preclinical and clinical studies on the combination of HGF/MET-targeted agents with conventional chemotherapeutics or molecularly targeted treatments (including EGFR, VEGFR, HER2, RAF/MEK, and PI3K/Akt targeting agents) and also the value of biomarkers are examined. Our deeper understanding of molecular mechanisms underlying successful pharmacological combinations is crucial to find the best personalized treatment regimens for cancer patients.
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Affiliation(s)
- Fatemeh Moosavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, the Netherlands; Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza, Pisa, Italy
| | - Godefridus J Peters
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), Amsterdam, the Netherlands; Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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14
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Hong L, Zhang J, Heymach JV, Le X. Current and future treatment options for MET exon 14 skipping alterations in non-small cell lung cancer. Ther Adv Med Oncol 2021; 13:1758835921992976. [PMID: 33643443 PMCID: PMC7890719 DOI: 10.1177/1758835921992976] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 01/13/2021] [Indexed: 12/13/2022] Open
Abstract
It has been over three decades since the hepatocyte growth factor (HGF) ligand and its receptor MET proto-oncogene (MET) pathway was established as promoting cancer growth and metastasis. MET exon 14 skipping (METex14) alterations occur in 3-4% of all non-small cell lung cancer (NSCLC) patients, typically in elderly patients (older than 70 years), and result in constitutive activation of the MET receptor by altering a region required for receptor degradation. Multi-kinase inhibitor of MET, such as crizotinib, and more recently selective MET inhibitors, such as capmatinib and tepotinib, have demonstrated clinical efficacy and safety in METex14 NSCLC patients in clinical trials. These results have led to the approval of MET inhibitors by regulatory agencies across the globe. The success also fueled the excitement of further development of therapeutic strategies to target METex14 in lung cancers. This article provides an overview of the clinical development program targeting METex14 in NSCLC, including small molecular tyrosine kinase inhibitors and anti-MET antibodies. Furthermore, combination therapy immune checkpoint inhibitors or other targeted therapies are also under development in various patient populations, with acquired resistance immune or targeted therapy. Clinical trials in different development stages are ongoing and more drugs targeted to c-MET will be available for NSCLC patients with METex14 skipping mutations in the future.
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Affiliation(s)
- Lingzhi Hong
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Jianjun Zhang
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John V. Heymach
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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15
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McCoach CE, Yu A, Gandara DR, Riess JW, Vang DP, Li T, Lara PN, Gubens M, Lara F, Mack PC, Beckett LA, Kelly K. Phase I/II Study of Capmatinib Plus Erlotinib in Patients With MET-Positive Non-Small-Cell Lung Cancer. JCO Precis Oncol 2021; 1:PO.20.00279. [PMID: 34036220 PMCID: PMC8140807 DOI: 10.1200/po.20.00279] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2020] [Indexed: 11/24/2022] Open
Abstract
PURPOSE MET dysregulation is an oncogenic driver in non-small-cell lung cancer (NSCLC), as well as a mechanism of TKI (tyrosine kinase inhibitor) resistance in patients with epidermal growth factor receptor (EGFR)-mutated disease. This study was conducted to determine safety and preliminary efficacy of the combination EGFR and MET inhibitors as a strategy to overcome and/or delay EGFR-TKI resistance. METHODS A standard 3 + 3 dose-escalation trial of capmatinib in combination with erlotinib in patients with MET-positive NSCLC was used. Eighteen patients in the dose-escalation cohort received 100-600 mg twice daily of capmatinib with 100-150 mg daily of erlotinib. There were two dose-expansion cohorts. Cohort A included 12 patients with EGFR-mutant tumors resistant to TKIs. Cohort B included five patients with EGFR wild-type tumors. The primary outcome was to assess safety and determine the recommended phase II dose (RP2D) of the combination. RESULTS The most common adverse events of any grade were rash (62.9%), fatigue (51%), and nausea (45.7%). Capmatinib exhibited nonlinear pharmacokinetics combined with erlotinib, while showing no significant drug interactions. The RP2D was 400 mg twice daily capmatinib tablets with 150 mg daily erlotinib. The overall response rate (ORR) and DCR in dose-expansion cohort A was 50% and 50%, respectively. In cohort B, the ORR and disease control rate were 75% and 75%. CONCLUSION Capmatinib in combination with erlotinib demonstrated safety profiles consistent with prior studies. We observed efficacy in specific patient populations. Continued evaluation of capmatinib plus EGFR-TKIs is warranted in patients with EGFR activating mutations.
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Affiliation(s)
- Caroline E. McCoach
- Helen Diller Family Comprehensive Cancer
Center, University of California, San Francisco, CA
| | - Aiming Yu
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
| | - David R. Gandara
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
| | - Jonathan W. Riess
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
| | - Daniel P. Vang
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
| | - Tiahong Li
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
| | - Primo N. Lara
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
| | - Matthew Gubens
- Helen Diller Family Comprehensive Cancer
Center, University of California, San Francisco, CA
| | - Frances Lara
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
| | - Philip C. Mack
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
- Mount Sinai Tisch Cancer Institute, New
York, NY
| | - Laurel A. Beckett
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
| | - Karen Kelly
- University of California Davis
Comprehensive Cancer Center, Sacramento, CA
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16
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Yılmaz Y, Batur T, Korhan P, Öztürk M, Atabey N. Targeting c-Met and AXL Crosstalk for the Treatment of Hepatocellular Carcinoma. LIVER CANCER IN THE MIDDLE EAST 2021:333-364. [DOI: 10.1007/978-3-030-78737-0_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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17
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Yoshimatsu Y, Noguchi R, Tsuchiya R, Sei A, Sugaya J, Fukushima S, Yoshida A, Kawai A, Kondo T. Establishment and characterization of NCC-ASPS1-C1: a novel patient-derived cell line of alveolar soft-part sarcoma. Hum Cell 2020; 33:1302-1310. [PMID: 32648033 DOI: 10.1007/s13577-020-00382-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 05/25/2020] [Indexed: 02/06/2023]
Abstract
Alveolar soft-part sarcoma is a mesenchymal malignancy characterized by the rearrangement of ASPSCR1 and TFE3 and a histologically distinctive pseudoalveolar pattern. Although alveolar soft-part sarcoma takes an indolent course, its long-term prognosis is poor because of late distant metastases. Currently, curative treatments have not been found for alveolar soft-part sarcoma, and hence, a novel therapeutic strategy has long been required. Patient-derived cell lines comprise an important tool for basic and preclinical research. However, few cell lines from alveolar soft-part sarcoma have been reported in the literature because it is an extremely rare malignancy, accounting for less than 1% of all soft-tissue sarcomas. This study aimed to establish a novel alveolar soft-part sarcoma cell line. Using surgically-resected tumor tissue of alveolar soft-part sarcoma, we successfully established a cell line and named it NCC-ASPS1-C1. The NCC-ASPS1-C1 cells harbored an ASPSCR1-TFE3 fusion gene and exhibited slow growth, and spheroid formation. On the other hand, NCC-ASPS1-C1 did not show the capability of invasion. We screened the antiproliferative effects of 195 anticancer agents, including Food and Drug Administration-approved anticancer drugs. We found that the MET inhibitor tivantinib and multi-kinase inhibitor orantinib inhibited the proliferation of NCC-ASPS1-C1 cells. The clinical utility and molecular mechanisms of antitumor effects of these drugs are worth investigating in the further studies, and NCC-ASPS1-C1 cells will be a useful tool for the in vitro study of alveolar soft-part sarcoma.
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Affiliation(s)
- Yuki Yoshimatsu
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Rei Noguchi
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Ryuto Tsuchiya
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.,Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Akane Sei
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Jun Sugaya
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Suguru Fukushima
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akihiko Yoshida
- Department of Diagnosis Pathology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Akira Kawai
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tadashi Kondo
- Division of Rare Cancer Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
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18
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De Mello RA, Neves NM, Amaral GA, Lippo EG, Castelo-Branco P, Pozza DH, Tajima CC, Antoniou G. The Role of MET Inhibitor Therapies in the Treatment of Advanced Non-Small Cell Lung Cancer. J Clin Med 2020; 9:1918. [PMID: 32575417 PMCID: PMC7356188 DOI: 10.3390/jcm9061918] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/04/2020] [Accepted: 06/10/2020] [Indexed: 12/28/2022] Open
Abstract
Introduction: Non-small cell lung cancer (NSCLC) is the second most common cancer globally. The mesenchymal-epithelial transition (MET) proto-oncogene can be targeted in NSCLC patients. Methods: We performed a literature search on PubMed in December 2019 for studies on MET inhibitors and NSCLC. Phase II and III clinical trials published in English between 2014 and 2019 were selected. Results: Data on MET inhibitors (tivantinib, cabozantinib, and crizotinib) and anti-MET antibodies (emibetuzumab and onartuzumab) are reported in the text. Conclusion: Emibetuzumab could be used for NSCLC cases with high MET expression. Further, studies on onartuzumab failed to prove its efficacy, while the results of tivantinib trials were clinically but not statistically significant. Additionally, cabozantinib was effective, but adverse reactions were common, and crizotinib was generally well-tolerated.
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Affiliation(s)
- Ramon Andrade De Mello
- Algarve Biomedical Centre, Department of Biomedical Sciences and Medicine University of Algarve (DCBM UALG), 8005-139 Faro, Portugal;
- Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil; (N.M.N.); (G.A.A.)
- Precision Oncology and Health Economics Group (ONCOPRECH), Post-Graduation Program in Medicine, Nine of July University (UNINOVE), São Paulo 01525-000, Brazil
| | - Nathália Moisés Neves
- Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil; (N.M.N.); (G.A.A.)
| | - Giovanna Araújo Amaral
- Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil; (N.M.N.); (G.A.A.)
| | - Estela Gudin Lippo
- School of Biomedical Sciences, Santo Amaro University, São Paulo 01525-000, Brazil;
| | - Pedro Castelo-Branco
- Algarve Biomedical Centre, Department of Biomedical Sciences and Medicine University of Algarve (DCBM UALG), 8005-139 Faro, Portugal;
| | - Daniel Humberto Pozza
- Department of Biomedicine & I3S, Faculty of Medicine, University of Porto (FMUP), 4200-317 Porto, Portugal;
| | - Carla Chizuru Tajima
- Hospital São José & Hospital São Joaquim, A Beneficência Portuguesa de São Paulo, São Paulo 01323-001, Brazil;
| | - Georgios Antoniou
- Division of Medical Oncology, Mount Vernon Cancer Center, London HA6 2RN, UK;
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19
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Kim BJ, Kim YJ, Sohn SH, Kim B, Sul HJ, Kim HS, Zang DY. Tivantinib inhibits the VEGF signaling pathway and induces apoptosis in gastric cancer cells with c-MET or VEGFA amplification. Invest New Drugs 2020; 38:1633-1640. [PMID: 32361789 DOI: 10.1007/s10637-020-00940-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 04/15/2020] [Indexed: 12/25/2022]
Abstract
Tivantinib has been described as a selective inhibitor of c-Met and is being studied in various types of cancer. In this study, we evaluated the effects of tivantinib on the suppression of gastric cancer (GC) cell migration and apoptosis. We also examined the mechanism of action of tivantinib by oncogenic pathway analysis. We applied an RNA-sequencing approach in 34 GC patients to identify oncogenes that are differentially expressed in GC tissues. To examine the inhibitory effect of tivantinib on GC cells, we conducted apoptosis analysis using an annexin V-APC/PI apoptosis detection kit and trans-well migration assay with human GC cell lines. For oncogenic pathway analysis, Western blot and quantitative real-time PCR analysis were used to detect the expression of proteins and genes before and after tivantinib exposure. In the RNA-sequencing analysis of 34 GC patients, c-Met and VEGFA genes were expressed and positively correlated with each other. Cell migration and apoptosis analysis demonstrated that tivantinib induced the best inhibition effect in SNU620, MKN45 (carries VEGFB mutation), AGS, and MKN28 cells, but not in KATO III (carries VEGFB and VEGFC mutations) cells. Oncogenic pathway analysis showed that tivantinib, in addition to c-Met signaling pathway inhibition, also inhibits VEGF signaling and MYC expression in VEGFA-expressing GC cells. We found that tivantinib has anti-cancer activity not only in GC cells overexpressing c-Met but also in non-c-Met GC cells by inhibition of the VEGF signaling pathway.
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Affiliation(s)
- Bum Jun Kim
- Division of Internal Medicine, National Army Capital Hospital, The Armed Forces Medical Command, Sungnam, 13574, Republic of Korea
| | - Yoo Jin Kim
- Hallym Translational Research Institute, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea
| | - Sung-Hwa Sohn
- Hallym Translational Research Institute, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea
| | - Bohyun Kim
- Hallym Translational Research Institute, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea
| | - Hee Jung Sul
- Hallym Translational Research Institute, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea
| | - Hyeong Su Kim
- Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea
| | - Dae Young Zang
- Hallym Translational Research Institute, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea. .,Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea.
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20
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Zaky MY, Liu X, Wang T, Wang S, Liu F, Wang D, Wu Y, Zhang Y, Guo D, Sun Q, Li Q, Zhang J, Zhang Y, Dong W, Liu Z, Liu S, Liu H. Dynasore potentiates c-Met inhibitors against hepatocellular carcinoma through destabilizing c-Met. Arch Biochem Biophys 2019; 680:108239. [PMID: 31881189 DOI: 10.1016/j.abb.2019.108239] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/19/2019] [Accepted: 12/22/2019] [Indexed: 12/22/2022]
Abstract
c-Met receptor is frequently overexpressed in hepatocellular carcinoma and thus considered as an attractive target for pharmacological intervention with small molecule tyrosine kinase inhibitors. Albeit with the development of multiple c-Met inhibitors, none reached clinical application in the treatment of hepatoma so far. To improve the efficacy of c-Met inhibitors towards hepatocellular carcinoma, we investigated the combined effects of the dynamin inhibitor dynasore with several c-Met inhibitors, including tivantinib, PHA-665752, and JNJ-38877605. We provide several lines of evidence that dynasore enhanced the inhibitory effects of these inhibitors on hepatoma cell proliferation and migration, accompanied with increased cell cycle arrest and apoptosis. Mechanically, the combinatorial treatments decreased c-Met levels and hence markedly disrupted downstream signaling, as revealed by the dramatically declined phosphorylation of AKT and MEK. Taken together, our findings demonstrate that the candidate agent dynasore potentiated the inhibitory effects of c-Met inhibitors against hepatoma cells and will shed light on the development of novel therapeutic strategies to target c-Met in the clinical management of hepatocellular carcinoma patients.
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Affiliation(s)
- Mohamed Y Zaky
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China; Molecular Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Egypt
| | - Xiuxiu Liu
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Taishu Wang
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Shanshan Wang
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Fang Liu
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Duchuang Wang
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Yueguang Wu
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Yang Zhang
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Dong Guo
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Qianhui Sun
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Qiong Li
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Jinrui Zhang
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Yingqiu Zhang
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Weijie Dong
- College of Basic Medical Sciences, Dalian Medical University, Dalian, China
| | - Zhenhua Liu
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China; Department of General Surgery, Second Affiliated Hospital, Dalian Medical University, Dalian, China.
| | - Shuyan Liu
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
| | - Han Liu
- Institute of Cancer Stem Cell & The Second Affiliated Hospital, Dalian Medical University, Dalian, China.
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21
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MET Inhibitors in Small Cell Lung Cancer: From the Bench to the Bedside. Cancers (Basel) 2019; 11:cancers11101404. [PMID: 31547040 PMCID: PMC6827355 DOI: 10.3390/cancers11101404] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 09/14/2019] [Accepted: 09/18/2019] [Indexed: 02/06/2023] Open
Abstract
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The different systemic treatment approaches attempted in the last 35 years have not improved overall survival in the advanced stage. Targeted therapies assessed in clinical trials have failed to show efficacy against SCLC. Within the potentially interesting targets, the hepatocyte growth factor (HGF)/mesenchymal-epithelial transition (MET) pathway activation is associated with worse survival and chemoresistance in SCLC. Preclinical data suggest that the inhibition of the MET pathway can revert chemoresistance and prevent tumor growth. Recently, immunotherapy has shown modest but relevant activity in SCLC. Interestingly, MET modulation seems to be involved in increasing the efficacy of standard checkpoint inhibitors. Here, we review the preclinical and clinical data of MET inhibition in SCLC, and the role of this pathway in the immune response.
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22
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De Mattia E, Cecchin E, Guardascione M, Foltran L, Di Raimo T, Angelini F, D’Andrea M, Toffoli G. Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma. World J Gastroenterol 2019; 25:3870-3896. [PMID: 31413525 PMCID: PMC6689804 DOI: 10.3748/wjg.v25.i29.3870] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 05/23/2019] [Accepted: 07/03/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies (i.e., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors (e.g., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (e.g., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.
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Affiliation(s)
- Elena De Mattia
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Erika Cecchin
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Michela Guardascione
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Luisa Foltran
- Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
| | - Tania Di Raimo
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Francesco Angelini
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
- Medical Oncology and Anatomic Pathology Unit, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Mario D’Andrea
- Department of Oncology, “San Filippo Neri Hospital”, Rome 00135, Italy
| | - Giuseppe Toffoli
- Clinical and Experimental Pharmacology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano (PN) 33081, Italy
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23
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Fendiline Enhances the Cytotoxic Effects of Therapeutic Agents on PDAC Cells by Inhibiting Tumor-Promoting Signaling Events: A Potential Strategy to Combat PDAC. Int J Mol Sci 2019; 20:ijms20102423. [PMID: 31100813 PMCID: PMC6567171 DOI: 10.3390/ijms20102423] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Revised: 05/10/2019] [Accepted: 05/12/2019] [Indexed: 02/07/2023] Open
Abstract
The L-type calcium channel blocker fendiline has been shown to interfere with Ras-dependent signaling in K-Ras mutant cancer cells. Earlier studies from our lab had shown that treatment of pancreatic cancer cells with fendiline causes significant cytotoxicity and interferes with proliferation, survival, migration, invasion and anchorage independent growth. Currently there are no effective therapies to manage PDACs. As fendiline has been approved for treatment of patients with angina, we hypothesized that, if proven effective, combinatorial therapies using this agent would be easily translatable to clinic for testing in PDAC patients. Here we tested combinations of fendiline with gemcitabine, visudyne (a YAP1 inhibitor) or tivantinib (ARQ197, a c-Met inhibitor) for their effectiveness in overcoming growth and oncogenic characteristics of PDAC cells. The Hippo pathway component YAP1 has been shown to bypass K-Ras addiction, and allow tumor growth, in a Ras-null mouse model. Similarly, c-Met expression has been associated with poor prognosis and metastasis in PDAC patients. Our results presented here show that combinations of fendiline with these inhibitors show enhanced anti-tumor activity in Panc1, MiaPaCa2 and CD18/HPAF PDAC cells, as evident from the reduced viability, migration, anchorage-independent growth and self-renewal. Biochemical analysis shows that these agents interfere with various signaling cascades such as the activation of Akt and ERK, as well as the expression of c-Myc and CD44 that are altered in PDACs. These results imply that inclusion of fendiline may improve the efficacy of various chemotherapeutic agents that could potentially benefit PDAC patients.
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Kumar SR, Gajagowni S, Bryan JN, Bodenhausen HM. Molecular targets for tivantinib (ARQ 197) and vasculogenic mimicry in human melanoma cells. Eur J Pharmacol 2019; 853:316-324. [PMID: 30954563 DOI: 10.1016/j.ejphar.2019.04.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/27/2019] [Accepted: 04/02/2019] [Indexed: 11/25/2022]
Abstract
Tivantinib (TivB) was reported previously to target MET and microtubule assembly in different cells resulting in cytotoxicity. However, its other cellular targets remain unknown, especially the proteins involved in focal adhesion and cytoskeletal organization. We studied the effect of TivB on vinculin a focal adhesion protein, and RhoC, a GTPase which promote the reorganization of cytoskeleton. Biomolecules involved in vasculogenic mimicry (VM) previously not reported in melanoma, and their susceptibility to TivB was also evaluated. TivB affects the viability and apoptosis of human melanoma cells depending on the cell type. Vinculin and RhoC were increased in the presence of TivB and affected the integrity of actin filaments and altered the cellular morphology. TivB disrupts the VM exhibited by melanoma cells in 3D matrix. Roundabout Guidance Receptor 4 (Robo4), a receptor protein implicated in axonal guidance and angiogenesis and its ligand Slit2 are expressed in human C8161 and WM793 melanoma cells, but absent in other melanoma cells including normal melanocytes. VM is more prominent in C8161 cells and could be blocked by siRNA mediated silencing of Robo4 mRNA, but TivB does not affect Robo4 in C8161 cells. Immunoblot analysis indicated no changes in Robo4 and Slit2 protein expression, however, both vinculin and RhoC protein increased in TivB treated melanoma cells. These results suggest that TivB affects cell cytoskeleton and morphology by altering proteins such as vinculin and RhoC. Our studies indicate TivB could target molecules other than MET in melanoma cells, which may provide insight into its alternate mechanism of action.
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Affiliation(s)
- Senthil R Kumar
- Comparative Oncology, Radiobiology and Epigenetics Laboratory, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA; Department of Surgery, Ellis Fischel Cancer Centre, School of Medicine, University of Missouri, Columbia, MO, 65201, USA; Harry S. Truman Veterans Medical Center, Columbia, MO, 65201, USA.
| | - Saivaroon Gajagowni
- Comparative Oncology, Radiobiology and Epigenetics Laboratory, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA
| | - Jeffrey N Bryan
- Comparative Oncology, Radiobiology and Epigenetics Laboratory, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA
| | - Hannah M Bodenhausen
- Comparative Oncology, Radiobiology and Epigenetics Laboratory, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA
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Bahcall M, Awad MM, Sholl LM, Wilson FH, Xu M, Wang S, Palakurthi S, Choi J, Ivanova EV, Leonardi GC, Ulrich BC, Paweletz CP, Kirschmeier PT, Watanabe M, Baba H, Nishino M, Nagy RJ, Lanman RB, Capelletti M, Chambers ES, Redig AJ, VanderLaan PA, Costa DB, Imamura Y, Jänne PA. Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non-Small Cell Lung Cancer. Clin Cancer Res 2018; 24:5963-5976. [PMID: 30072474 PMCID: PMC6279568 DOI: 10.1158/1078-0432.ccr-18-0876] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/19/2018] [Accepted: 07/23/2018] [Indexed: 01/06/2023]
Abstract
PURPOSE MET inhibitors can be effective therapies in patients with MET exon 14 (METex14) mutant non-small cell lung cancer (NSCLC). However, long-term efficacy is limited by the development of drug resistance. In this study, we characterize acquired amplification of wild-type (WT) KRAS as a molecular mechanism behind crizotinib resistance in three cases of METex14-mutant NSCLC and propose a combination therapy to target it. EXPERIMENTAL DESIGN The patient-derived cell line and xenograft (PDX) DFCI358 were established from a crizotinib-resistant METex14-mutant patient tumor with massive focal amplification of WT KRAS. To characterize the mechanism of KRAS-mediated resistance, molecular signaling was analyzed in the parental cell line and its KRAS siRNA-transfected derivative. Sensitivity of the cell line to ligand stimulation was assessed and KRAS-dependent expression of EGFR ligands was quantified. Drug combinations were screened for efficacy in vivo and in vitro using viability and apoptotic assays. RESULTS KRAS amplification is a recurrent genetic event in crizotinib-resistant METex14-mutant NSCLC. The key characteristics of this genetic signature include uncoupling MET from downstream effectors, relative insensitivity to dual MET/MEK inhibition due to compensatory induction of PI3K signaling, KRAS-induced expression of EGFR ligands and hypersensitivity to ligand-dependent and independent activation, and reliance on PI3K signaling upon MET inhibition. CONCLUSIONS Using patient-derived cell line and xenografts, we characterize the mechanism of crizotinib resistance mediated by KRAS amplification in METex14-mutant NSCLC and demonstrate the superior efficacy of the dual MET/PI3K inhibition as a therapeutic strategy addressing this resistance mechanism.
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Affiliation(s)
- Magda Bahcall
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Mark M Awad
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Lynette M Sholl
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Frederick H Wilson
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Man Xu
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Stephen Wang
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Sangeetha Palakurthi
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jihyun Choi
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Elena V Ivanova
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Giulia C Leonardi
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Bryan C Ulrich
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Cloud P Paweletz
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Paul T Kirschmeier
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Mizuki Nishino
- Department of Radiology, Brigham And Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | | | | | - Marzia Capelletti
- Center for Hematologic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Emily S Chambers
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
| | - Amanda J Redig
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Paul A VanderLaan
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Daniel B Costa
- Thoracic Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
- Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Yu Imamura
- Department of Gastroenterological Surgery, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Pasi A Jänne
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Wu YL, Zhang L, Kim DW, Liu X, Lee DH, Yang JCH, Ahn MJ, Vansteenkiste JF, Su WC, Felip E, Chia V, Glaser S, Pultar P, Zhao S, Peng B, Akimov M, Tan DSW. Phase Ib/II Study of Capmatinib (INC280) Plus Gefitinib After Failure of Epidermal Growth Factor Receptor (EGFR) Inhibitor Therapy in Patients With EGFR-Mutated, MET Factor-Dysregulated Non-Small-Cell Lung Cancer. J Clin Oncol 2018; 36:3101-3109. [PMID: 30156984 DOI: 10.1200/jco.2018.77.7326] [Citation(s) in RCA: 255] [Impact Index Per Article: 36.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
PURPOSE MET dysregulation occurs in up to 26% of non-small-cell lung cancers (NSCLCs) after epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) treatment. Capmatinib (INC280) is a potent and selective MET inhibitor with preclinical activity in combination with gefitinib in EGFR-mutant, MET-amplified/overexpressing models of acquired EGFR-TKI resistance. This phase Ib/II study investigated the safety and efficacy of capmatinib plus gefitinib in patients with EGFR-mutated, MET-dysregulated (amplified/overexpressing) NSCLC who experienced disease progression while receiving EGFR-TKI treatment. METHODS Patients in phase Ib received capmatinib 100- to 800-mg capsules once per day or 200- to 600-mg capsules or tablets twice per day, plus gefitinib 250 mg once per day. Patients in phase II received the recommended phase II dose. The primary end point was the overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS Sixty-one patients were treated in phase Ib, and 100 were treated in phase II. The recommended phase II dose was capmatinib 400 mg twice per day plus gefitinib 250 mg once per day. Preliminary clinical activity was observed, with an ORR across phase Ib/II of 27%. Increased activity was seen in patients with high MET-amplified tumors, with a phase II ORR of 47% in patients with a MET gene copy number ≥ 6. Across phases Ib and II, the most common drug-related adverse events were nausea (28%), peripheral edema (22%), decreased appetite (21%), and rash (20%); the most common drug-related grade 3/4 adverse events were increased amylase and lipase levels (both 6%). No significant drug-drug interactions between capmatinib and gefitinib were evident. CONCLUSION This study, focused on a predominant EGFR-TKI resistance mechanism in patients with EGFR-mutated NSCLC, shows that the combination of capmatinib with gefitinib is a promising treatment for patients with EGFR-mutated, MET-dysregulated NSCLC, particularly MET-amplified disease.
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Affiliation(s)
- Yi-Long Wu
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Li Zhang
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Dong-Wan Kim
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Xiaoqing Liu
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Dae Ho Lee
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - James Chih-Hsin Yang
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Myung-Ju Ahn
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Johan F Vansteenkiste
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Wu-Chou Su
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Enriqueta Felip
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Vincent Chia
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Sabine Glaser
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Philippe Pultar
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Sylvia Zhao
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Bin Peng
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Mikhail Akimov
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
| | - Daniel S W Tan
- Yi-Long Wu, Guangdong General Hospital and Guangdong Academy of Medical Sciences; Li Zhang, Sun Yat-sen University Cancer Center, Guangdong; Xiaoqing Liu, Affiliated Hospital of the Chinese Academy of Military Medical Sciences, Beijing; Sylvia Zhao and Bin Peng, Novartis Institutes for Biomedical Research, Shanghai, People's Republic of China; Dong-Wan Kim, Seoul National University Hospital; Dae Ho Lee, University of Ulsan College of Medicine; Myung-Ju Ahn, Samsung Medical Center, Seoul, Republic of Korea; James Chih-Hsin Yang, National Taiwan University Hospital, Taipei; Wu-Chou Su, National Cheng Kung University Hospital, Tainan, Taiwan; Johan F. Vansteenkiste, University Hospital KU Leuven, Leuven, Belgium; Enriqueta Felip, Vall d'Hebron University Hospital, Barcelona, Spain; Vincent Chia and Philippe Pultar, Novartis Pharmaceuticals, East Hanover, NJ; Sabine Glaser and Mikhail Akimov, Novartis Pharma AG, Basel, Switzerland; and Daniel S.W. Tan, National Cancer Centre Singapore, Singapore
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27
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Buttigliero C, Shepherd FA, Barlesi F, Schwartz B, Orlov S, Favaretto AG, Santoro A, Hirsh V, Ramlau R, Blackler AR, Roder J, Spigel D, Novello S, Akerley W, Scagliotti GV. Retrospective Assessment of a Serum Proteomic Test in a Phase III Study Comparing Erlotinib plus Placebo with Erlotinib plus Tivantinib (MARQUEE) in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer. Oncologist 2018; 24:e251-e259. [PMID: 30139835 DOI: 10.1634/theoncologist.2018-0089] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 07/05/2018] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND The VeriStrat test provides accurate predictions of outcomes in all lines of therapy for patients with non-small cell lung cancer (NSCLC). We investigated the predictive and prognostic role of VeriStrat in patients enrolled on the MARQUEE phase III trial of tivantinib plus erlotinib (T+E) versus placebo plus erlotinib (P+E) in previously treated patients with advanced NSCLC. METHODS Pretreatment plasma samples were available for 996 patients and were analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry to generate VeriStrat labels (good, VS-G, or poor, VS-P). RESULTS Overall, no significant benefit in overall survival (OS) and progression-free survival (PFS) were observed for the addition of tivantinib to erlotinib. Regardless of treatment arm, patients who were classified as VS-G had significantly longer PFS (3.8 mo for T+E arm, 2.0 mo for P+E arm) and OS (11.6 mo for T+E, 10.2 mo for P+E arm) than patients classified as VS-P (PFS: 1.9 mo for both arms, hazard ratio [HR], 0.584; 95% confidence interval [CI], 0.468-0.733; p < .0001 for T+E, HR, 0.686; 95% CI, 0.546-0.870; p = .0015 for P+E; OS: 4.0 mo for both arms, HR, 0.333; 95% CI, 0.264-0.422; p < .0001 for T+E; HR, 0.449; 95% CI, 0.353-0.576; p < .0001 for P+E). The VS-G population had higher OS than the VS-P population within Eastern Cooperative Oncology Group (ECOG) performance score (PS) categories. VS-G patients on the T+E arm had longer PFS, but not OS, than VS-G patients on the P+E arm (p = .0108). Among EGFR mutation-positive patients, those with VS-G status had a median OS more than twice that of any other group (OS: 31.6 mo for T+E and 22.8 mo for P+E), whereas VS-P patients had similar survival rates as VS-G, EGFR-wild type patients (OS: 13.7 mo for T+E and 6.5 mo for P+E). CONCLUSION In these analyses, VeriStrat showed a prognostic role within EGOC PS categories and regardless of treatment arm and EGFR status, suggesting that VeriStrat could be used to identify EGFR mutation-positive patients who will have a poor response to EGFR tyrosine kinase inhibitors. IMPLICATIONS FOR PRACTICE This study suggests that VeriStrat testing could enhance the prognostic role of performance status and smoking status and replicates findings from other trials that showed that the VeriStrat test identifies EGFR mutation-positive patients likely to have a poor response to EGFR tyrosine kinase inhibitors (TKIs). Although these findings should be confirmed in other populations, VeriStrat use could be considered in EGFR mutation-positive patients as an additional prognostic tool, and these results suggest that EGFR mutation-positive patients with VeriStrat "poor" classification could benefit from other therapeutic agents given in conjunction with TKI monotherapy.
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Affiliation(s)
- Consuelo Buttigliero
- Division of Medical Oncology, Department of Oncology, University of Torino at San Luigi Gonzaga Hospital, Turin, Italy
| | | | | | | | - Sergey Orlov
- St. Petersburg State Medical University, St. Petersburg, Russian Federation
| | | | | | - Vera Hirsh
- McGill University Health Centre, Montreal, Canada
| | - Rodryg Ramlau
- Oncology Department, Poznan University of Medical Sciences, Poznan, Poland
| | | | | | - David Spigel
- Tennessee Oncology Associates, Nashville, Tennessee, USA
| | - Silvia Novello
- Division of Medical Oncology, Department of Oncology, University of Torino at San Luigi Gonzaga Hospital, Turin, Italy
| | | | - Giorgio V Scagliotti
- Division of Medical Oncology, Department of Oncology, University of Torino at San Luigi Gonzaga Hospital, Turin, Italy
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28
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Liu SV, Groshen SG, Kelly K, Reckamp KL, Belani C, Synold TW, Goldkorn A, Gitlitz BJ, Cristea MC, Gong IY, Semrad TJ, Xu Y, Xu T, Koczywas M, Gandara DR, Newman EM. A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors. Cancer Chemother Pharmacol 2018; 82:723-732. [PMID: 30128950 DOI: 10.1007/s00280-018-3672-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Accepted: 08/17/2018] [Indexed: 01/17/2023]
Abstract
PURPOSE Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib. METHODS Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0-1.5 mg/m2/day for five consecutive days in 21-day cycles with continuous, oral tivantinib given at escalating doses of 120-360 mg orally twice daily. Pharmacokinetic analyses of tivantinib were included. Circulating tumor cells (CTC) were collected serially to identify peripheral changes in MET phosphorylation. RESULTS The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy. CONCLUSIONS The combination of topotecan and oral tivantinib was not tolerable in this patient population.
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Affiliation(s)
- Stephen V Liu
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
| | - Susan G Groshen
- University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
| | - Karen Kelly
- University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | | | | | | | - Amir Goldkorn
- University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
| | - Barbara J Gitlitz
- University of Southern California, Keck School of Medicine, Los Angeles, CA, USA.,Genentech Inc., San Francisco, CA, USA
| | | | - I-Yeh Gong
- University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Thomas J Semrad
- University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
| | - Yucheng Xu
- University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
| | - Tong Xu
- University of Southern California, Keck School of Medicine, Los Angeles, CA, USA
| | | | - David R Gandara
- University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
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29
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The role of molecular enrichment on future therapies in hepatocellular carcinoma. J Hepatol 2018; 69:237-247. [PMID: 29505843 DOI: 10.1016/j.jhep.2018.02.016] [Citation(s) in RCA: 86] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 02/15/2018] [Accepted: 02/24/2018] [Indexed: 12/20/2022]
Abstract
Hepatocellular carcinomas (HCCs) are characterised by considerable phenotypic and molecular heterogeneity. Treating HCC and designing clinical trials are particularly challenging because co-existing liver disease, present in most patients, limits aggressive therapeutic options. Positive results in recent phase III clinical trials have confirmed the high value of anti-angiogenic therapies for HCC in both first (sorafenib and lenvatinib) and second line (regorafenib and cabozantinib) treatment modalities. However, failure of several large randomised controlled clinical trials over the last 10 years underlines the necessity for innovative treatment strategies and implementation of translational findings to overcome the unmet clinical need. Furthermore, the promising results from novel immunotherapies are likely to complement the landscape of active compounds for HCC and will require a completely different approach to patients, as well as the development of prognostic/predictive biomarkers. Given our increasing understanding of the most abundant molecular alterations in HCC, effective enrichment of patients based on clinical and molecular biomarkers, as well as adaptive clinical trials, are now feasible and should be implemented. Herein, we aim to review important aspects of precision medicine approaches in HCC that might contribute to improving the molecular subclassification of patients in a clinical trial setting and pave the way for novel therapeutic strategies.
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30
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Comoglio PM, Trusolino L, Boccaccio C. Known and novel roles of the MET oncogene in cancer: a coherent approach to targeted therapy. Nat Rev Cancer 2018; 18:341-358. [PMID: 29674709 DOI: 10.1038/s41568-018-0002-y] [Citation(s) in RCA: 245] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The MET oncogene encodes an unconventional receptor tyrosine kinase with pleiotropic functions: it initiates and sustains neoplastic transformation when genetically altered ('oncogene addiction') and fosters cancer cell survival and tumour dissemination when transcriptionally activated in the context of an adaptive response to adverse microenvironmental conditions ('oncogene expedience'). Moreover, MET is an intrinsic modulator of the self-renewal and clonogenic ability of cancer stem cells ('oncogene inherence'). Here, we provide the latest findings on MET function in cancer by focusing on newly identified genetic abnormalities in tumour cells and recently described non-mutational MET activities in stromal cells and cancer stem cells. We discuss how MET drives cancer clonal evolution and progression towards metastasis, both ab initio and under therapeutic pressure. We then elaborate on the use of MET inhibitors in the clinic with a critical appraisal of failures and successes. Ultimately, we advocate a rationale to improve the outcome of anti-MET therapies on the basis of thorough consideration of the entire spectrum of MET-mediated biological responses, which implicates adequate patient stratification, meaningful biomarkers and appropriate clinical end points.
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Affiliation(s)
- Paolo M Comoglio
- Exploratory Research and Molecular Cancer Therapy, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy.
| | - Livio Trusolino
- Translational Cancer Medicine, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Oncology, University of Torino Medical School, Candiolo, Italy
| | - Carla Boccaccio
- Cancer Stem Cell Research, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Italy
- Department of Oncology, University of Torino Medical School, Candiolo, Italy
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31
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Srivastava AK, Hollingshead MG, Govindharajulu JP, Covey JM, Liston D, Simpson MA, Peggins JO, Bottaro DP, Wright JJ, Kinders RJ, Doroshow JH, Parchment RE. Molecular Pharmacodynamics-Guided Scheduling of Biologically Effective Doses: A Drug Development Paradigm Applied to MET Tyrosine Kinase Inhibitors. Mol Cancer Ther 2018; 17:698-709. [PMID: 29444985 PMCID: PMC5935559 DOI: 10.1158/1535-7163.mct-17-0552] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2017] [Revised: 12/11/2017] [Accepted: 12/29/2017] [Indexed: 11/16/2022]
Abstract
The development of molecularly targeted agents has benefited from use of pharmacodynamic markers to identify "biologically effective doses" (BED) below MTDs, yet this knowledge remains underutilized in selecting dosage regimens and in comparing the effectiveness of targeted agents within a class. We sought to establish preclinical proof-of-concept for such pharmacodynamics-based BED regimens and effectiveness comparisons using MET kinase small-molecule inhibitors. Utilizing pharmacodynamic biomarker measurements of MET signaling (tumor pY1234/1235MET/total MET ratio) in a phase 0-like preclinical setting, we developed optimal dosage regimens for several MET kinase inhibitors and compared their antitumor efficacy in a MET-amplified gastric cancer xenograft model (SNU-5). Reductions in tumor pY1234/1235MET/total MET of 95%-99% were achievable with tolerable doses of EMD1214063/MSC2156119J (tepotinib), XL184 (cabozantinib), and XL880/GSK1363089 (foretinib), but not ARQ197 (tivantinib), which did not alter the pharmacodynamic biomarker. Duration of kinase suppression and rate of kinase recovery were specific to each agent, emphasizing the importance of developing customized dosage regimens to achieve continuous suppression of the pharmacodynamic biomarker at the required level (here, ≥90% MET kinase suppression). The customized dosage regimen of each inhibitor yielded substantial and sustained tumor regression; the equivalent effectiveness of customized dosage regimens that achieve the same level of continuous molecular target control represents preclinical proof-of-concept and illustrates the importance of proper scheduling of targeted agent BEDs. Pharmacodynamics-guided biologically effective dosage regimens (PD-BEDR) potentially offer a superior alternative to pharmacokinetic guidance (e.g., drug concentrations in surrogate tissues) for developing and making head-to-head comparisons of targeted agents. Mol Cancer Ther; 17(3); 698-709. ©2018 AACR.
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Affiliation(s)
- Apurva K Srivastava
- Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Melinda G Hollingshead
- Biological Testing Branch, Developmental Therapeutics Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Jeevan Prasaad Govindharajulu
- Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - Joseph M Covey
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
| | - Dane Liston
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
| | - Melanie A Simpson
- Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - James O Peggins
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
| | - Donald P Bottaro
- Urologic Oncology Branch, National Cancer Institute, Bethesda, Maryland
| | - John J Wright
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
| | - Robert J Kinders
- Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland
| | - James H Doroshow
- Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Ralph E Parchment
- Clinical Pharmacodynamics Biomarker Program, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.
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Tachibana M, Papadopoulos KP, Strickler JH, Puzanov I, Gajee R, Wang Y, Zahir H. Evaluation of the pharmacokinetic drug interaction potential of tivantinib (ARQ 197) using cocktail probes in patients with advanced solid tumours. Br J Clin Pharmacol 2018; 84:112-121. [PMID: 28865153 PMCID: PMC5736844 DOI: 10.1111/bcp.13424] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 07/19/2017] [Accepted: 08/14/2017] [Indexed: 12/31/2022] Open
Abstract
AIMS This phase 1, open-label, crossover study sought to evaluate drug-drug interactions between tivantinib and cytochrome P450 (CYP) substrates and tivantinib and P-glycoprotein. METHODS The effect of tivantinib doses on the pharmacokinetics of the probe drugs for CYP1A2 (caffeine), CYP2C9 (S-warfarin), CYP2C19 (omeprazole), and CYP3A4 (midazolam), and for P-glycoprotein (digoxin) was investigated in 28 patients with advanced cancer using a cocktail probe approach. Patients received single doses of probe drugs alone and, after 5 days of treatment, with tivantinib 360 mg twice daily. RESULTS The ratios of geometric least squares mean (90% confidence interval) for the area under the concentration-time curve from time zero to the last quantifiable concentration in the presence/absence of tivantinib were 0.97 (0.89-1.05) for caffeine, 0.88 (0.76-1.02) for S-warfarin, 0.89 (0.60-1.31) for omeprazole, 0.83 (0.67-1.02) for midazolam, and 0.69 (0.51-0.94) for digoxin. Similar effects were observed for maximum plasma concentrations; the ratio for digoxin in the presence/absence of tivantinib was 0.75 (0.60-0.95). CONCLUSIONS The data suggest that tivantinib 360 mg twice daily has either a minimal or no effect on the pharmacokinetics of probe drugs for CYP1A2, CYP2C9, CYP2C19 and CYP3A4 substrates, and decreases the systemic exposure of P-glycoprotein substrates when administered with tivantinib.
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33
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Geller JI, Perentesis JP, Liu X, Minard CG, Kudgus RA, Reid JM, Fox E, Blaney SM, Weigel BJ. A phase 1 study of the c-Met inhibitor, tivantinib (ARQ197) in children with relapsed or refractory solid tumors: A Children's Oncology Group study phase 1 and pilot consortium trial (ADVL1111). Pediatr Blood Cancer 2017; 64:10.1002/pbc.26565. [PMID: 28449393 PMCID: PMC5657151 DOI: 10.1002/pbc.26565] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 02/22/2017] [Accepted: 02/28/2017] [Indexed: 01/20/2023]
Abstract
BACKGROUND The c-Met receptor tyrosine kinase is dysregulated in many pediatric cancers. Tivantinib is an oral small molecule that inhibits the c-Met receptor tyrosine kinase. A phase 1 and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors. METHODS Oral tivantinib capsules were administered twice daily with food, continuously in 28-day cycles. Dose levels 170, 200, and 240 mg/m2 /dose were evaluated using a rolling-six design (Part A). In Part B, subjects received tivantinib powder sprinkled on food at the recommended phase 2 dose (RP2D) from Part A. PK, CYP2C19 genotyping, and baseline tumor tissue c-Met expression were analyzed. RESULTS Thirty-six patients were enrolled: 20 in Part A, 6 in a PK expansion cohort, and 10 in Part B. Fifteen patients had primary central nervous system tumors and 21 had solid tumors. In Part A, there were no dose-limiting toxicities. One grade 4 intracranial hemorrhage occurred in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m2 ). PK analysis showed marked interpatient variability (20-fold) in the Cmax and AUC0-8h across all dose levels. Sprinkling tivantinib powder over food did not alter exposure. Membranous and total c-Met expression was moderate (2), low (4), or not detected (26). Two patients had stable disease as the best response. CONCLUSIONS The RP2D of tivantinib given with food in children with refractory solid tumors is 240 mg/m2 /dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial.
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Affiliation(s)
- James I. Geller
- Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH
| | - John P. Perentesis
- Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH
| | | | - Charles G. Minard
- Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX
| | | | | | - Elizabeth Fox
- Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Susan M. Blaney
- Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX
| | - Brenda J. Weigel
- Masonic Children’s Hospital, University of Minnesota Medical Center, Minneapolis, MN
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Bahrami A, Shahidsales S, Khazaei M, Ghayour-Mobarhan M, Maftouh M, Hassanian SM, Avan A. C-Met as a potential target for the treatment of gastrointestinal cancer: Current status and future perspectives. J Cell Physiol 2017; 232:2657-2673. [PMID: 28075018 DOI: 10.1002/jcp.25794] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2017] [Accepted: 01/10/2017] [Indexed: 01/05/2025]
Abstract
Aberrant activation of the HGF/c-Met signalling pathways is shown to be related with cell proliferation, progression, metastasis, and worse prognosis in several tumor types, including gastrointestinal cancers, suggesting its value as a stimulating-target for cancer-therapy. Several approaches have been developed for targeting HGF and/or c-Met, and one of them, crizotinib (dual c-Met/ALK inhibitor), is recently been approved by FDA for lung-cancers with ALK-rearrangement. The main aim of current review is to give an overview on the role of c-Met/HGF pathway in gastrointestinal cancer, in preclinical and clinical trials. Although several important matters is still remained to be elucidated on the molecular pathways underlying the antitumor effects of this therapy in gastrointestinal-cancers. Further investigations are warranted to recognize the main determinants of the activity of c-Met inhibitors, for parallel targeting signalling pathway associated/activated via MET/HGF pathway or in response to the cell resistance to anti-c-Met agents. Additionally, identification of patients that might benefit from therapy could help to increase the selectivity and efficacy of the therapy.
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Affiliation(s)
- Afsane Bahrami
- Molecular Medicine Group, Department of Modern Sciences and Technology, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soodabeh Shahidsales
- Cancer Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Neurogenic Inflammatory Research Center and Department of Physiology, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mina Maftouh
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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Rothenberger NJ, Stabile LP. Hepatocyte Growth Factor/c-Met Signaling in Head and Neck Cancer and Implications for Treatment. Cancers (Basel) 2017; 9:cancers9040039. [PMID: 28441771 PMCID: PMC5406714 DOI: 10.3390/cancers9040039] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Revised: 04/14/2017] [Accepted: 04/20/2017] [Indexed: 12/11/2022] Open
Abstract
Aberrant signaling of the hepatocyte growth factor (HGF)/c-Met pathway has been identified as a promoter of tumorigenesis in several tumor types including head and neck squamous cell carcinoma (HNSCC). Despite a relatively low c-Met mutation frequency, overexpression of HGF and its receptor c-Met has been observed in more than 80% of HNSCC tumors, with preclinical and clinical studies linking overexpression with cellular proliferation, invasion, migration, and poor prognosis. c-Met is activated by HGF through a paracrine mechanism to promote cellular morphogenesis enabling cells to acquire mesenchymal phenotypes in part through the epithelial-mesenchymal transition, contributing to metastasis. The HGF/c-Met pathway may also act as a resistance mechanism against epidermal growth factor receptor (EGFR) inhibition in advanced HNSCC. Furthermore, with the identification of a biologically distinct subset of HNSCC tumors acquired from human papillomavirus (HPV) infection that generally portends a good prognosis, high expression of HGF or c-Met in HPV-negative tumors has been associated with worse prognosis. Dysregulated HGF/c-Met signaling results in an aggressive HNSCC phenotype which has led to clinical investigations for targeted inhibition of this pathway. In this review, HGF/c-Met signaling, pathway alterations, associations with clinical outcomes, and preclinical and clinical therapeutic strategies for targeting HGF/c-Met signaling in HNSCC are discussed.
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Affiliation(s)
- Natalie J Rothenberger
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
| | - Laura P Stabile
- Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
- University of Pittsburgh Cancer Center, Pittsburgh, PA 15213, USA.
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36
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Best J, Schotten C, Lohmann G, Gerken G, Dechêne A. Tivantinib for the treatment of hepatocellular carcinoma. Expert Opin Pharmacother 2017; 18:727-733. [DOI: 10.1080/14656566.2017.1316376] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
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Targeting c-MET in gastrointestinal tumours: rationale, opportunities and challenges. Nat Rev Clin Oncol 2017; 14:562-576. [PMID: 28374784 DOI: 10.1038/nrclinonc.2017.40] [Citation(s) in RCA: 127] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Data from many preclinical studies, including those using cellular models of colorectal, gastric, gastro-oesophageal and gastro-oesophageal junction cancers, indicate that the hepatocyte growth factor (HGF)-hepatocyte growth factor receptor (c-MET) pathway is vital for the growth, survival and invasive potential of gastrointestinal cancers. Following the availability of data from these various studies, and data on c-MET expression as a biomarker that indicates a poor prognosis in patients with gastrointestinal cancer and increased c-MET expression, inhibitors targeting this pathway have entered the clinic in the past decade. However, the design of clinical trials that incorporate the use of HGF/c-MET inhibitors in their most appropriate genetic and molecular context remains crucial. Recognizing and responding to this challenge, the European Commission funded Framework 7 MErCuRIC programme is running a biomarker-enriched clinical trial investigating the efficacy of combined c-MET/MEK inhibition in patients with RAS-mutant or RAS-wild-type metastatic colorectal cancer with aberrant c-MET expression. The design of this trial enables the continued refinement of the predictive biomarker and co-development of companion diagnostics. In this Review, we focus on advances in our understanding of inhibition of the HGF/c-MET pathway in patients with gastro-intestinal cancers, the prominent challenges facing the clinical translation and implementation of agents targeting HGF/c-MET, and discuss the various efforts, and associated obstacles to the discovery and validation of biomarkers that will enable patient stratification in this context.
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Rebouissou S, La Bella T, Rekik S, Imbeaud S, Calatayud AL, Rohr-Udilova N, Martin Y, Couchy G, Bioulac-Sage P, Grasl-Kraupp B, de Koning L, Ganne-Carrié N, Nault JC, Ziol M, Zucman-Rossi J. Proliferation Markers Are Associated with MET Expression in Hepatocellular Carcinoma and Predict Tivantinib Sensitivity In Vitro. Clin Cancer Res 2017; 23:4364-4375. [DOI: 10.1158/1078-0432.ccr-16-3118] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/05/2017] [Accepted: 02/17/2017] [Indexed: 11/16/2022]
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Bahcall M, Sim T, Paweletz CP, Patel JD, Alden RS, Kuang Y, Sacher AG, Kim ND, Lydon CA, Awad MM, Jaklitsch MT, Sholl LM, Jänne PA, Oxnard GR. Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer. Cancer Discov 2016; 6:1334-1341. [PMID: 27694386 PMCID: PMC5140694 DOI: 10.1158/2159-8290.cd-16-0686] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Revised: 09/28/2016] [Accepted: 09/28/2016] [Indexed: 12/17/2022]
Abstract
Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that METD1228V induces resistance to type I MET TKIs through impaired drug binding, while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response. SIGNIFICANCE With several structurally distinct MET inhibitors undergoing development for treatment of NSCLC, it is critical to identify mechanism-based therapies for drug resistance. We demonstrate that an acquired METD1228V mutation mediates resistance to type I, but not type II, MET inhibitors, having therapeutic implications for the clinical use of sequential MET inhibitors. Cancer Discov; 6(12); 1334-41. ©2016 AACR.See related commentary by Trusolino, p. 1306This article is highlighted in the In This Issue feature, p. 1293.
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Affiliation(s)
- Magda Bahcall
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Taebo Sim
- Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea
- KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
| | - Cloud P Paweletz
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jyoti D Patel
- Department of Medicine, University of Chicago, Chicago, Illinois
| | - Ryan S Alden
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Yanan Kuang
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Adrian G Sacher
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Nam Doo Kim
- Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
| | - Christine A Lydon
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Mark M Awad
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Michael T Jaklitsch
- Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Lynette M Sholl
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Pasi A Jänne
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Geoffrey R Oxnard
- Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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Reuther C, Heinzle V, Spampatti M, Vlotides G, de Toni E, Spöttl G, Maurer J, Nölting S, Göke B, Auernhammer CJ. Cabozantinib and Tivantinib, but Not INC280, Induce Antiproliferative and Antimigratory Effects in Human Neuroendocrine Tumor Cells in vitro: Evidence for 'Off-Target' Effects Not Mediated by c-Met Inhibition. Neuroendocrinology 2016; 103:383-401. [PMID: 26338447 DOI: 10.1159/000439431] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 08/15/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIMS The hepatocyte growth factor/transmembrane tyrosine kinase receptor c-Met has been defined as a potential target in antitumoral treatment of various carcinomas. We aimed to investigate the direct effect of c-Met inhibition on neuroendocrine tumor cells in vitro. METHODS The effects of the multi-tyrosine kinase inhibitors cabozantinib and tivantinib and of the highly specific c-Met inhibitor INC280 were investigated in human pancreatic neuroendocrine BON1, bronchopulmonary NCI-H727 and midgut GOT1 cells in vitro. RESULTS INC280, cabozantinib and tivantinib inhibited c-Met phosphorylation, respectively. However, while equimolar concentrations (10 μM) of cabozantinib and tivantinib inhibited cell viability and cell migration, INC280 had no inhibitory effect. Knockdown experiments with c-Met siRNA also did not demonstrate effects on cell viability. Cabozantinib and tivantinib caused a G2 arrest in neuroendocrine tumor cells. CONCLUSIONS Our in vitro data suggest that c-Met inhibition alone is not sufficient to exert direct antitumoral or antimigratory effects in neuroendocrine tumor cells. The multi-tyrosine kinase inhibitors cabozantinib and tivantinib show promising antitumoral and antimigratory effects in neuroendocrine tumor cells, which are most probably 'off-target' effects, not mediated by c-Met.
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Affiliation(s)
- Clemens Reuther
- Department of Internal Medicine II, Campus Grosshadern, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
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Current and Future Approaches to Target the Epidermal Growth Factor Receptor and Its Downstream Signaling in Metastatic Colorectal Cancer. Clin Colorectal Cancer 2015; 14:203-18. [DOI: 10.1016/j.clcc.2015.05.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 05/20/2015] [Accepted: 05/22/2015] [Indexed: 01/27/2023]
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Murphy AG, Lynch D, Kelly RJ. State of the art management of metastatic gastroesophageal cancer. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:236. [PMID: 26539453 DOI: 10.3978/j.issn.2305-5839.2015.09.19] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The anatomical locations of upper gastrointestinal (GI) tumors have changed remarkably in the western world and reflect the increasing impact of obesity and gastroesophageal (GE) reflux rather than infectious etiologies. Incidence rates of GE tumors are rising rapidly and survival rates for patients with metastatic disease remain poor. Traditionally, cytotoxic chemotherapy has had some survival advantages but increasingly complex combination regimens are limited by toxicities. The advent of molecularly targeted therapy has provided additional options for patients with advanced disease including trastuzumab and ramucirumab. There has also been detailed molecular characterization of upper GI tumors which hopefully will result in improved tailoring of clinical trial design accounting for the heterogeneity inherent in GE tumors. While numerous targeted therapies are currently being studied in clinical trials, there is much excitement regarding the role of immunotherapy in GE cancers. Although further investigation is warranted, it represents a promising avenue for patients with advanced GE tumors.
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Affiliation(s)
- Adrian G Murphy
- 1 Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA ; 2 Faculty of Education & Health Services, University of Limerick, Limerick, Ireland
| | - David Lynch
- 1 Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA ; 2 Faculty of Education & Health Services, University of Limerick, Limerick, Ireland
| | - Ronan J Kelly
- 1 Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA ; 2 Faculty of Education & Health Services, University of Limerick, Limerick, Ireland
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Lu S, Török HP, Gallmeier E, Kolligs FT, Rizzani A, Arena S, Göke B, Gerbes AL, De Toni EN. Tivantinib (ARQ 197) affects the apoptotic and proliferative machinery downstream of c-MET: role of Mcl-1, Bcl-xl and Cyclin B1. Oncotarget 2015; 6:22167-78. [PMID: 26259250 PMCID: PMC4673154 DOI: 10.18632/oncotarget.4240] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 05/28/2015] [Indexed: 01/11/2023] Open
Abstract
Tivantinib, a c-MET inhibitor, is investigated as a second-line treatment of HCC. It was shown that c-MET overexpression predicts its efficacy. Therefore, a phase-3 trial of tivantinib has been initiated to recruit "c-MET-high" patients only. However, recent evidence indicates that the anticancer activity of tivantinib is not due to c-MET inhibition, suggesting that c-MET is a predictor of response to this compound rather than its actual target. By assessing the mechanisms underlying the anticancer properties of tivantinib we showed that this agent causes apoptosis and cell cycle arrest by inhibiting the anti-apoptotic molecules Mcl-1 and Bcl-xl, and by increasing Cyclin B1 expression regardless of c-MET status. However, we found that tivantinib might antagonize the antiapoptotic effects of c-MET activation since HGF enhanced the expression of Mcl-1 and Bcl-xl. In summary, we show that the activity of tivantinib is independent of c-MET and describe Mcl-1, Bcl-xl and Cyclin B1 as effectors of its antineoplastic effects in HCC cells. We suggest that the predictive effect of c-MET expression in part reflects the c-MET-driven overexpression of Mcl-1 and Bcl-xl in c-MET-high patients and that these molecules are considered as possible response predictors.
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Affiliation(s)
- Shuai Lu
- Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany
| | - Helga-Paula Török
- Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany
| | - Eike Gallmeier
- Department of Gastroenterology, Endocrinology and Metabolism, University Hospital of Marburg, Philipps-University of Marburg, Marburg, Germany
| | - Frank T Kolligs
- Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany
- Department of Internal Medicine and Gastroenterology, HELIOS Klinikum Berlin-Buch, Berlin, Germany
| | - Antonia Rizzani
- Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany
| | - Sabrina Arena
- Department of Oncology, University of Torino, Candiolo, Torino, Italy
- Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy
| | - Burkhard Göke
- Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany
| | - Alexander L Gerbes
- Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany
| | - Enrico N De Toni
- Medizinische Klinik und Poliklinik 2, Klinikum der Universität München, Campus Grosshadern, Munich, Germany
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Marano L, Chiari R, Fabozzi A, De Vita F, Boccardi V, Roviello G, Petrioli R, Marrelli D, Roviello F, Patriti A. c-Met targeting in advanced gastric cancer: An open challenge. Cancer Lett 2015; 365:30-36. [PMID: 26049023 DOI: 10.1016/j.canlet.2015.05.028] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Revised: 05/21/2015] [Accepted: 05/23/2015] [Indexed: 12/14/2022]
Abstract
Despite significant improvements in systemic chemotherapy over the last two decades, the prognosis of patients with advanced gastric and gastroesophageal junction adenocarcinoma (GC) remains poor. Because of molecular heterogeneity, it is essential to classify tumors based on the underlying oncogenic pathways and to develop targeted therapies acting on individual tumors. High-quality research and advances in technology have contributed to the elucidation of molecular pathways underlying disease progression and have stimulated many clinical studies testing target therapies in an advanced disease setting. In particular, strong preclinical evidence for the aberrant activation of the HGF/c-Met signaling pathways in GC cancers exists. This review will cover the c-Met pathway, the mechanisms of c-Met activation and the different strategies of its inhibition. Next, we will focus on the current state of the art in the clinical evaluation of c-Met-targeted therapies and the description of ongoing randomized trials with the idea that in this disease, high quality translational research to identify and validate biomarkers is a priority task.
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Affiliation(s)
- Luigi Marano
- General, Minimally Invasive and Robotic Surgery, Department of Surgery, "San Matteo degli Infermi" Hospital, ASL Umbria 2, 06049 Spoleto, Italy.
| | - Rita Chiari
- Department of Medical Oncology, "Santa Maria della Misericordia" Hospital, Azienda Ospedaliera di Perugia, 06132 Perugia, Italy
| | - Alessio Fabozzi
- Division of Medical Oncology, Department of Clinical and Experimental Medicine "F. Magrassi-A. Lanzara", Second University of Naples, 80131 Naples, Italy
| | - Ferdinando De Vita
- Division of Medical Oncology, Department of Clinical and Experimental Medicine "F. Magrassi-A. Lanzara", Second University of Naples, 80131 Naples, Italy
| | - Virginia Boccardi
- Section of Gerontology and Geriatrics, Department of Medicine, University of Perugia, 06132 Perugia, Italy
| | | | | | - Daniele Marrelli
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
| | - Franco Roviello
- Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
| | - Alberto Patriti
- General, Minimally Invasive and Robotic Surgery, Department of Surgery, "San Matteo degli Infermi" Hospital, ASL Umbria 2, 06049 Spoleto, Italy
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Scagliotti G, von Pawel J, Novello S, Ramlau R, Favaretto A, Barlesi F, Akerley W, Orlov S, Santoro A, Spigel D, Hirsh V, Shepherd FA, Sequist LV, Sandler A, Ross JS, Wang Q, von Roemeling R, Shuster D, Schwartz B. Phase III Multinational, Randomized, Double-Blind, Placebo-Controlled Study of Tivantinib (ARQ 197) Plus Erlotinib Versus Erlotinib Alone in Previously Treated Patients With Locally Advanced or Metastatic Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 2015; 33:2667-74. [PMID: 26169611 DOI: 10.1200/jco.2014.60.7317] [Citation(s) in RCA: 221] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
PURPOSE Tivantinib, a MET receptor tyrosine kinase inhibitor, demonstrated increased anticancer activity in preclinical and early clinical studies when combined with erlotinib. Our study aimed to confirm efficacy and safety of the combination in previously treated patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with advanced nonsquamous NSCLC previously treated with one to two systemic regimens, including a platinum doublet, were randomly assigned at a 1:1 ratio to receive erlotinib 150 mg daily plus oral tivantinib 360 mg twice daily (E + T) or erlotinib plus placebo (E + P) until disease progression. Tumor specimens were evaluated for EGFR and KRAS mutations, MET expression, and MET gene amplification. The primary end point was overall survival (OS). Secondary and exploratory objectives included progression-free survival (PFS), OS in molecular subgroups, and safety. RESULTS The study enrolled 1,048 patients and was discontinued for futility at the interim analysis. OS did not improve with E + T versus E + P (median OS, 8.5 v 7.8 months, respectively; hazard ratio [HR], 0.98; 95% CI, 0.84 to 1.15; P = .81), even though PFS increased (median PFS, 3.6 v 1.9 months; HR, 0.74; 95% CI, 0.62 to 0.89; P < .001). Exploratory subgroup analyses suggested OS improvement in patients with high MET expression (HR, 0.70; 95% CI, 0.49 to 1.01). Most common adverse events occurring with E + T versus E + P were rash (33.1% v 37.3%, respectively), diarrhea (34.6% v 41.0%), asthenia or fatigue (43.5% v 38.1%), and neutropenia (grade 3 to 4; 8.5% v 0.8%). CONCLUSION E + T was well tolerated and increased PFS but did not improve OS in the overall nonsquamous NSCLC population.
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Affiliation(s)
- Giorgio Scagliotti
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ.
| | - Joachim von Pawel
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Silvia Novello
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Rodryg Ramlau
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Adolfo Favaretto
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Fabrice Barlesi
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Wallace Akerley
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Sergey Orlov
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Armando Santoro
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - David Spigel
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Vera Hirsh
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Frances A Shepherd
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Lecia V Sequist
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Alan Sandler
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Jeffrey S Ross
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Qiang Wang
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Reinhard von Roemeling
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Dale Shuster
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
| | - Brian Schwartz
- Giorgio Scagliotti and Silvia Novello, University of Turin, Orbassano, Torino; Adolfo Favaretto, Istituto Oncologico Veneto, Padova; Armando Santoro, Istituto Clinico Humanitas, Milan, Italy; Joachim von Pawel, Asklepios-Fachkliniken München-Gauting, Munich, Germany; Rodryg Ramlau, Poznań University of Medical Sciences, Poznań, Poland; Fabrice Barlesi, Aix Marseille University, Assistance Publique Hôpitaux de Marseille, Marseille, France; Wallace Akerley, Huntsman Cancer Institute, Salt Lake City, UT; Sergey Orlov, St Petersburg State Medical University, St Petersburg, Russian Federation; David Spigel, Clinical Locations, Nashville, TN; Vera Hirsh, McGill University Health Centre, Montreal, Quebec; Frances A. Shepherd, Princess Margaret Cancer Centre, Toronto, Ontario, Canada; Lecia V. Sequist, Massachusetts General Hospital, Boston; Jeffrey S. Ross, Foundation Medicine, Cambridge; Brian Schwartz, ArQule, Woburn, MA; Alan Sandler, Genentech, San Francisco, CA; and Qiang Wang, Reinhard von Roemeling, and Dale Shuster, Daiichi Sankyo, Edison, NJ
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Tolaney SM, Tan S, Guo H, Barry W, Van Allen E, Wagle N, Brock J, Larrabee K, Paweletz C, Ivanova E, Janne P, Overmoyer B, Wright JJ, Shapiro GI, Winer EP, Krop IE. Phase II study of tivantinib (ARQ 197) in patients with metastatic triple-negative breast cancer. Invest New Drugs 2015; 33:1108-14. [PMID: 26123926 PMCID: PMC4608248 DOI: 10.1007/s10637-015-0269-8] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 06/19/2015] [Indexed: 12/21/2022]
Abstract
Background MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer. Methods Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored. Results 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0–25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0–25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade ≥3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia). Conclusion This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy.
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Affiliation(s)
- Sara M Tolaney
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA.
| | - Sally Tan
- Harvard Medical School, Boston, MA, USA
| | - Hao Guo
- Department of Biostatistics and Computation Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - William Barry
- Department of Biostatistics and Computation Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Eliezer Van Allen
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Nikhil Wagle
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Jane Brock
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Katherine Larrabee
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA
| | - Cloud Paweletz
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA
- Belfer Institute for Applied Cancer Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Elena Ivanova
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA
- Belfer Institute for Applied Cancer Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Pasi Janne
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA
- Belfer Institute for Applied Cancer Sciences, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Beth Overmoyer
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA
| | - John J Wright
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA
| | - Geoffrey I Shapiro
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA
| | - Eric P Winer
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA
| | - Ian E Krop
- Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Yawkey 1257, Boston, MA, 02215, USA
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Abstract
Mortality owing to liver cancer has increased in the past 20 years, and the latest estimates indicate that the global health burden of this disease will continue to grow. Most patients with hepatocellular carcinoma (HCC) are still diagnosed at intermediate or advanced disease stages, where curative approaches are often not feasible. Among the treatment options available, the molecular targeted agent sorafenib is able to significantly increase overall survival in these patients. Thereafter, up to seven large, randomized phase III clinical trials investigating other molecular therapies in the first-line and second-line settings have failed to improve on the results observed with this agent. Potential reasons for this include intertumour heterogeneity, issues with trial design and a lack of predictive biomarkers of response. During the past 5 years, substantial advances in our knowledge of the human genome have provided a comprehensive picture of commonly mutated genes in patients with HCC. This knowledge has not yet influenced clinical decision-making or current clinical practice guidelines. In this Review the authors summarize the molecular concepts of progression, discuss the potential reasons for clinical trial failure and propose new concepts of drug development, which might lead to clinical implementation of emerging targeted agents.
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Rothschild SI. Targeted Therapies in Non-Small Cell Lung Cancer-Beyond EGFR and ALK. Cancers (Basel) 2015; 7:930-49. [PMID: 26018876 PMCID: PMC4491691 DOI: 10.3390/cancers7020816] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Revised: 05/07/2015] [Accepted: 05/13/2015] [Indexed: 01/30/2023] Open
Abstract
Systemic therapy for non-small cell lung cancer (NSCLC) has undergone a dramatic paradigm shift over the past decade. Advances in our understanding of the underlying biology of NSCLC have revealed distinct molecular subtypes. A substantial proportion of NSCLC depends on oncogenic molecular aberrations (so-called "driver mutations") for their malignant phenotype. Personalized therapy encompasses the strategy of matching these subtypes with effective targeted therapies. EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC. EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors. The number of molecular subgroups of NSCLC continues to grow. The scope of this review is to discuss recent data on novel molecular targets as ROS1, BRAF, KRAS, HER2, c-MET, RET, PIK3CA, FGFR1 and DDR2. Thereby the review will focus on therapeutic strategies targeting these aberrations. Moreover, the emerging challenge of acquired resistance to initially effective therapies will be discussed.
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Affiliation(s)
- Sacha I Rothschild
- Medical Oncology, University Hospital Basel, Petersgraben 4, 4031 Basel, Switzerland.
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49
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Rimassa L, Personeni N, Santoro A. Tivantinib for hepatocellular carcinoma. Expert Opin Orphan Drugs 2015. [DOI: 10.1517/21678707.2015.1009038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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50
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Murphy A, Kelly RJ. From molecular classification to targeted therapeutics: the changing face of systemic therapy in metastatic gastroesophageal cancer. Gastroenterol Res Pract 2015; 2015:896560. [PMID: 25784931 PMCID: PMC4346691 DOI: 10.1155/2015/896560] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 01/15/2015] [Indexed: 01/14/2023] Open
Abstract
Histological classification of adenocarcinoma or squamous cell carcinoma for esophageal cancer or using the Lauren classification for intestinal and diffuse type gastric cancer has limited clinical utility in the management of advanced disease. Germline mutations in E-cadherin (CDH1) or mismatch repair genes (Lynch syndrome) were identified many years ago but given their rarity, the identification of these molecular alterations does not substantially impact treatment in the advanced setting. Recent molecular profiling studies of upper GI tumors have added to our knowledge of the underlying biology but have not led to an alternative classification system which can guide clinician's therapeutic decisions. Recently the Cancer Genome Atlas Research Network has proposed four subtypes of gastric cancer dividing tumors into those positive for Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. Unfortunately to date, many phase III clinical trials involving molecularly targeted agents have failed to meet their survival endpoints due to their use in unselected populations. Future clinical trials should utilize molecular profiling of individual tumors in order to determine the optimal use of targeted therapies in preselected patients.
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Affiliation(s)
- Adrian Murphy
- Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
| | - Ronan J. Kelly
- Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
- Gastroesophageal Cancer Therapeutics Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Room G93, Baltimore, MD 21231, USA
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