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Buti S, Olivari A, Masini C, Bimbatti D, Sartori D, Ermacora P, Cattrini C, Vitale MG, Rossi E, Mucciarini C, Rizzo M, Sisani M, Santoni M, Roviello G, Mollica V, Conteduca V, Grillone F, Cinausero M, Prati G, Atzori F, Stellato M, Massari F, Bersanelli M. Assessing the effectiveness and safety of lenvatinib and everolimus in advanced renal cell carcinoma: insights from the RELIEVE study's analysis of heavily pretreated patients. Ther Adv Urol 2024; 16:17562872241244574. [PMID: 38638242 PMCID: PMC11025417 DOI: 10.1177/17562872241244574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Accepted: 03/08/2024] [Indexed: 04/20/2024] Open
Abstract
BACKGROUND The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging. OBJECTIVES The primary objective was to assess the effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination. DESIGN We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy. METHODS The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters. RESULTS In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1-2 and. 63% received ⩾ 3 prior lines of therapy. 62% were 'intermediate risk' according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were 'poor risk'. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8-19.9), median PFS was 6.7 months (95% CI 0.6-30.8), and median TTF was 6.7 months (95% CI 4.8-16.6). A shorter OS was significantly associated with lymph node metastases (p = 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 (p = 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant (p = 0.03) while a shorter PFS was associated with lung (p = 0.048) and brain metastases (p = 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3. CONCLUSION Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC.
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Affiliation(s)
- Sebastiano Buti
- Department of Medicine and Surgery, University Hospital of Parma, Parma, Italy Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Alessandro Olivari
- Department of Medicine and Surgery, University Hospital of Parma, 14 Gramsci Street, Parma, 43125, Italy Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Cristina Masini
- Oncology Unit, Clinical Cancer Centre AUSL-IRCCS di Reggio, Emilia, Italy
| | - Davide Bimbatti
- Oncology Unit 1, Department of Oncology, Istituto Oncologico Veneto IOV – IRCCS, Padova, Italy
| | | | - Paola Ermacora
- Department of Oncology, ASUFC Santa Maria Della Misericordia, Udine, Italy
| | - Carlo Cattrini
- Azienda Ospedaliero-Universitaria ‘Maggiore della Carità’ – Università del Piemonte Orientale, Novara, Italy
| | | | - Ernesto Rossi
- Medical Oncology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | | | - Mimma Rizzo
- Azienda Ospedaliera Universitaria Consorziale, Policlinico di Bari, Bari, Italy
| | - Michele Sisani
- U.O.C. Oncologia Medica, USL Toscana sudest, Arezzo, Italy
| | - Matteo Santoni
- UOC Oncologia, Ospedale Generale Provinciale di Macerata, Macerata, Italy
| | - Giandomenico Roviello
- Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Firenze, Italy
| | - Veronica Mollica
- Medical Oncology, IRCCS - Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Vincenza Conteduca
- Department of Medical and Surgical Sciences, Unit of Medical Oncology and Biomolecular Therapy, University of Foggia, Policlinico Riuniti, Foggia, Italy
| | - Francesco Grillone
- Medical Oncology Unit, Azienda Ospedaliera Universitaria “Mater-Domini” Policlinico di Catanzaro, Catanzaro, Italy
| | - Marika Cinausero
- Department of Medicine (DAME), University of Udine, Udine, Italy
| | - Giuseppe Prati
- Azienda Unità Sanitaria Locale – IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Francesco Atzori
- Unità di Oncologia Medica, Azienda Ospedaliero Universitaria di Cagliari, Cagliari, Italy
| | - Marco Stellato
- Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Francesco Massari
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
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Patil D, Akolkar D, Nagarkar R, Srivastava N, Datta V, Patil S, Apurwa S, Srinivasan A, Datar R. Multi-analyte liquid biopsies for molecular pathway guided personalized treatment selection in advanced refractory cancers: A clinical utility pilot study. Front Oncol 2022; 12:972322. [PMID: 36620556 PMCID: PMC9822573 DOI: 10.3389/fonc.2022.972322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 12/01/2022] [Indexed: 12/24/2022] Open
Abstract
Purpose The selection of safe and efficacious anticancer regimens for treatment of patients with broadly refractory metastatic cancers remains a clinical challenge. Such patients are often fatigued by toxicities of prior failed treatments and may have no further viable standard of care treatment options. Liquid Biopsy-based multi-analyte profiling in peripheral blood can identify a majority of drug targets that can guide the selection of efficacious combination regimens. Patients and methods LIQUID IMPACT was a pilot clinical study where patients with advanced refractory cancers received combination anticancer treatment regimens based on multi-analyte liquid biopsy (MLB) profiling of circulating tumor biomarkers; this study design was based on the findings of prior feasibility analysis to determine the abundance of targetable variants in blood specimens from 1299 real-world cases of advanced refractory cancers. Results Among the 29 patients in the intent to treat (ITT) cohort of the trial, 26 were finally evaluable as per study criteria out of whom 12 patients showed Partial Response (PR) indicating an Objective Response Rate (ORR) of 46.2% and 11 patients showed Stable Disease (SD) indicating the Disease Control Rate (DCR) to be 88.5%. The median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 4.3 months (95% CI: 3.0 - 5.6 months) and 8.8 months (95% CI: 7.0 - 10.7 months), respectively. Toxicities were manageable and there were no treatment-related deaths. Conclusion The study findings suggest that MLB could be used to assist treatment selection in heavily pretreated patients with advanced refractory cancers.
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Affiliation(s)
- Darshana Patil
- Department of Research and Innovation, Datar Cancer Genetics, Nasik, India
| | - Dadasaheb Akolkar
- Department of Research and Innovation, Datar Cancer Genetics, Nasik, India
| | - Rajnish Nagarkar
- Department of Surgical Oncology, HCG Manavata Cancer Centre, Nasik, India
| | - Navin Srivastava
- Department of Research and Innovation, Datar Cancer Genetics, Nasik, India
| | - Vineet Datta
- Department of Research and Innovation, Datar Cancer Genetics, Nasik, India
| | - Sanket Patil
- Department of Research and Innovation, Datar Cancer Genetics, Nasik, India
| | - Sachin Apurwa
- Department of Research and Innovation, Datar Cancer Genetics, Nasik, India
| | - Ajay Srinivasan
- Department of Research and Innovation, Datar Cancer Genetics, Nasik, India,*Correspondence: Ajay Srinivasan,
| | - Rajan Datar
- Department of Research and Innovation, Datar Cancer Genetics, Nasik, India
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Ged Y, Lee CH. Lenvatinib plus pembrolizumab combination therapy for adult patients with advanced renal cell carcinoma. Expert Rev Anticancer Ther 2022; 22:1049-1059. [PMID: 36154355 DOI: 10.1080/14737140.2022.2128336] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION : The treatment landscape of metastatic RCC has significantly evolved in recent years with the advent and approval of multiple combinations of anti-angiogenic agents with immune checkpoint inhibitors, of which the combination of lenvatinib plus pembrolizumab is the most recent to be incorporated into clinical practice. AREAS COVERED Herein, we provide an overview of the combination of lenvatinib plus pembrolizumab in metastatic RCC, including the mechanism of action, pharmacokinetics, efficacy, and safety profile. EXPERT OPINION Lenvatinib plus pembrolizumab has demonstrated substantial efficacy in patients with metastatic RCC in the first-line and refractory treatment setting with the highest reported results of radiological responses, complete responses, and progression free survival compared to all other RCC treatments. However, the field is currently still limited with the limited availability of biomarkers to inform on treatment selection and the lack of head-to-head studies across the effective RCC treatments. Ongoing and future studies are eagerly anticipated to uncover multiple unmet needs in RCC.
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Affiliation(s)
- Yasser Ged
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Chung-Han Lee
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
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Ansari MJ, Bokov D, Markov A, Jalil AT, Shalaby MN, Suksatan W, Chupradit S, AL-Ghamdi HS, Shomali N, Zamani A, Mohammadi A, Dadashpour M. Cancer combination therapies by angiogenesis inhibitors; a comprehensive review. Cell Commun Signal 2022; 20:49. [PMID: 35392964 PMCID: PMC8991477 DOI: 10.1186/s12964-022-00838-y] [Citation(s) in RCA: 109] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/03/2022] [Indexed: 02/06/2023] Open
Abstract
Abnormal vasculature is one of the most conspicuous traits of tumor tissue, largely contributing to tumor immune evasion. The deregulation mainly arises from the potentiated pro-angiogenic factors secretion and can also target immune cells' biological events, such as migration and activation. Owing to this fact, angiogenesis blockade therapy was established to fight cancer by eliminating the nutrient and oxygen supply to the malignant cells by impairing the vascular network. Given the dominant role of vascular-endothelium growth factor (VEGF) in the angiogenesis process, the well-known anti-angiogenic agents mainly depend on the targeting of its actions. However, cancer cells mainly show resistance to anti-angiogenic agents by several mechanisms, and also potentiated local invasiveness and also distant metastasis have been observed following their administration. Herein, we will focus on clinical developments of angiogenesis blockade therapy, more particular, in combination with other conventional treatments, such as immunotherapy, chemoradiotherapy, targeted therapy, and also cancer vaccines. Video abstract.
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Affiliation(s)
- Mohammad Javed Ansari
- Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia
| | - Dmitry Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., bldg. 2, Moscow, 119991 Russian Federation
- Laboratory of Food Chemistry, Federal Research Center of Nutrition, Biotechnology and Food Safety, 2/14 Ustyinsky pr., Moscow, 109240 Russian Federation
| | - Alexander Markov
- Tyumen State Medical University, Tyumen, Russian Federation
- Industrial University, Tyumen, Russian Federation
| | - Abduladheem Turki Jalil
- Faculty of Biology and Ecology, Yanka Kupala State University of Grodno, 230023 Grodno, Belarus
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- Department of Dentistry, Kut University College, Kut, Wasit 52001 Iraq
| | - Mohammed Nader Shalaby
- Biological Sciences and Sports Health Department, Faculty of Physical Education, Suez Canal University, Ismailia, Egypt
| | - Wanich Suksatan
- Faculty of Nursing, HRH Princess Chulabhorn College of Medical Science, Chulabhorn Royal Academy, Bangkok, Thailand
| | - Supat Chupradit
- Department of Occupational Therapy, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200 Thailand
| | - Hasan S. AL-Ghamdi
- Internal Medicine Department, Division of Dermatology, Albaha University, Al Bahah, Kingdom of Saudi Arabia
| | - Navid Shomali
- Immunology Research Center (IRC), Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Zamani
- Shiraz Transplant Center, Abu Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammadi
- Department of Neurology, Imam Khomeini Hospital, Urmia University of Medical Sciences, Urmia, Iran
| | - Mehdi Dadashpour
- Department of Medical Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, Iran
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Motzer RJ, Taylor MH, Evans TRJ, Okusaka T, Glen H, Lubiniecki GM, Dutcus C, Smith AD, Okpara CE, Hussein Z, Hayato S, Tamai T, Makker V. Lenvatinib dose, efficacy, and safety in the treatment of multiple malignancies. Expert Rev Anticancer Ther 2022; 22:383-400. [PMID: 35260027 PMCID: PMC9484451 DOI: 10.1080/14737140.2022.2039123] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/03/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Lenvatinib is an oral multitargeted tyrosine kinase inhibitor that has shown efficacy and manageable safety across multiple cancer types. The recommended starting doses for lenvatinib differ across cancer types and indications based on whether it is used as monotherapy or as combination therapy. AREAS COVERED This review covers clinical trials that established the dosing paradigm and efficacy of lenvatinib and defined its adverse-event profile as a monotherapy; or in combination with the mTOR inhibitor, everolimus; or the anti-PD-1 antibody, pembrolizumab; and/or chemotherapy. EXPERT OPINION Lenvatinib has been established as standard-of-care either as a monotherapy or in combination with other anticancer agents for the treatment of radioiodine-refractory differentiated thyroid carcinoma, hepatocellular carcinoma, renal cell carcinoma, and endometrial carcinoma, and is being investigated further across several other tumor types. The dosing and adverse-event management strategies for lenvatinib have been developed through extensive clinical trial experience. Collectively, the data provide the rationale to start lenvatinib at the recommended doses and then interrupt or dose reduce as necessary to achieve required dose intensity for maximized patient benefit. The adverse-event profile of lenvatinib is consistent with that of other tyrosine kinase inhibitors, and clinicians are encouraged to review and adopt relevant symptom-management strategies.
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Affiliation(s)
- Robert J. Motzer
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY, USA
| | - Matthew H. Taylor
- Division of Hematology and Oncology, Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, USA
| | - Thomas R. Jeffry Evans
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
- Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hilary Glen
- Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, UK
| | - Gregory M. Lubiniecki
- Global Clinical Development, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
| | | | | | | | - Ziad Hussein
- Clinical Pharmacology Science, Eisai Europe Ltd., Hatfield, UK
| | - Seiichi Hayato
- Clinical Pharmacology Science, Eisai Co., Ltd., Tokyo, Japan
| | | | - Vicky Makker
- Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY, USA
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Guo J, Zhu P, Ye Z, Wang M, Yang H, Huang S, Shu Y, Zhang W, Zhou H, Li Q. YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS. Front Pharmacol 2021; 12:744578. [PMID: 34658879 PMCID: PMC8517968 DOI: 10.3389/fphar.2021.744578] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Lenvatinib is the latest and promising agent that has demonstrated a significant improvement of progression-free survival in advanced hepatocellular carcinoma (HCC). However, resistance emerges soon after initial treatment, limiting the clinical benefits of lenvatinib. Therefore, understanding the mechanism of resistance is necessary for improving lenvatinib efficacy. YRDC promotes the proliferation of hepatocarcinoma cells via regulating the activity of the RAS/RAF/MEK/ERK pathway, which was the primary pathway of the anticancer effect of lenvatinib. The purpose of this study is to investigate whether YRDC modulates the sensitivity of lenvatinib in hepatocarcinoma cells. Using the CCK-8 cell viability assay, wound-healing assay and clone formation assay in cell models, and xenograft assay in null mouse, we demonstrated that Huh7 cells with YRDC knockdown showed decreased susceptibility to lenvatinib than their control cells. Furthermore, we found that lenvatinib inhibited the expression of YRDC in a time-dependent manner. This effect may aggravate resistance to lenvatinib in hepatocarcinoma cells and may be an underlying cause of resistance, which emerges soon after lenvatinib initial treatment. To investigate how YRDC modulates the sensitivity of lenvatinib, we assessed the effect of tRNA with different t6A levels on the translation of the KRAS gene by in vitro rabbit reticulocyte translation system and measured the expression levels of the KRAS gene by western blot together with qPCR. We found that YRDC regulates the protein translation of KRAS in cell models, and the tRNA with low t6A modification level reduces the translation of the KRAS in the in vitro translation system. These results suggested that YRDC mediates the resistance of lenvatinib in hepatocarcinoma cells via modulating the translation of the KRAS. In this study, YRDC was confirmed to be a potential novel predictive biomarker of lenvatinib sensitivity in HCC.
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Affiliation(s)
- Jun Guo
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Peng Zhu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Zhi Ye
- Department of Anesthesiology, Xiangya Hospital, Central South University, Changsha, China
| | - Mengke Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Haijun Yang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Shiqiong Huang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Yan Shu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China.,Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Baltimore, MD, United States
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Honghao Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
| | - Qing Li
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.,Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China.,National Clinical Research Center for Geriatric Disorders, Changsha, China
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Li Y, Gao S, Du X, Ji J, Xi Y, Zhai G. Advances in autophagy as a target in the treatment of tumours. J Drug Target 2021; 30:166-187. [PMID: 34319838 DOI: 10.1080/1061186x.2021.1961792] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Autophagy is a multi-step lysosomal degradation process, which regulates energy and material metabolism and has been used to maintain homeostasis. Autophagy has been shown to be involved in the regulation of health and disease. But at present, there is no consensus on the relationship between autophagy and tumour, and we consider that it plays a dual role in the occurrence and development of tumour. That is to say, under certain conditions, it can inhibit the occurrence of tumour, but it can also promote the process of tumour. Therefore, autophagy could be used as a target for tumour treatment. The regulation of autophagy plays a synergistic role in the radiotherapy, chemotherapy, phototherapy and immunotherapy of tumour, and nano drug delivery system provides a promising strategy for improving the efficacy of autophagy regulation. This review summarised the progress in the regulatory pathways and factors of autophagy as well as nanoformulations as carriers for the delivery of autophagy modulators.
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Affiliation(s)
- Yingying Li
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Shan Gao
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Xiyou Du
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Jianbo Ji
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Yanwei Xi
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
| | - Guangxi Zhai
- Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, PR China
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Crook T, Patil D, Gaya A, Plowman N, Limaye S, Ranade A, Bhatt A, Page R, Akolkar D. Improved Treatment Outcomes by Using Patient Specific Drug Combinations in Mammalian Target of Rapamycin Activated Advanced Metastatic Cancers. Front Pharmacol 2021; 12:631135. [PMID: 33935721 PMCID: PMC8085687 DOI: 10.3389/fphar.2021.631135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 02/25/2021] [Indexed: 12/15/2022] Open
Abstract
Background: Activation of the mTOR signaling pathway is ubiquitous in cancers and a favourable therapeutic target. However, presently approved mTOR inhibitor monotherapies have modest benefits in labeled indications while poor outcomes have been reported for mTOR inhibitor monotherapy when administered in a label-agnostic setting based on univariate molecular indications. The present study aimed to determine whether patient-specific combination regimens with mTOR inhibitors and other anticancer agents selected based on multi-analyte molecular and functional tumor interrogation (ETA: Encyclopedic Tumor Analysis) yields significant treatment response and survival benefits in advanced or refractory solid organ cancers. Methods: We evaluated treatment outcomes in 49 patients diagnosed with unresectable or metastatic solid organ cancers, of whom 3 were therapy naïve and 46 were pre-treated in whom the cancer had progressed on 2 or more prior systemic lines. All patients received mTOR inhibitor in combination with other targeted, endocrine or cytotoxic agents as guided by ETA. Patients were followed-up to determine Objective Response Rate (ORR), Progression Free Survival (PFS) and Overall Survival (OS). Results: The Objective Response Rate (ORR) was 57.1%, the disease Control rate (DCR) was 91.8%, median Progression Free Survival (mPFS) was 4.9 months and median Overall Survival (mOS) was 9.4 months. There were no Grade IV treatment related adverse events (AEs) or any treatment related deaths. Conclusion: Patient-specific combination regimens with mTOR inhibition and other anti-neoplastic agents, when selected based on multi-analyte molecular and functional profiling of the tumor can yield meaningful outcomes in advanced or refractory solid organ cancers. Trial Registration: Details of all trials are available at WHO-ICTRP: https://apps.who.int/trialsearch/. RESILIENT ID CTRI/2018/02/011808. ACTPRO ID CTRI/2018/05/014178. LIQUID IMPACT ID CTRI/2019/02/017548.
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Affiliation(s)
| | | | - Andrew Gaya
- HCA Healthcare United Kingdom, London, United Kingdom
| | | | | | | | | | - Raymond Page
- Worcester Polytechnic Institute, Worcester, India
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Hutson TE, Michaelson MD, Kuzel TM, Agarwal N, Molina AM, Hsieh JJ, Vaishampayan UN, Xie R, Bapat U, Ye W, Jain RK, Fishman MN. A Single-arm, Multicenter, Phase 2 Study of Lenvatinib Plus Everolimus in Patients with Advanced Non-Clear Cell Renal Cell Carcinoma. Eur Urol 2021; 80:162-170. [PMID: 33867192 DOI: 10.1016/j.eururo.2021.03.015] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 03/15/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Non-clear cell renal cell carcinoma (nccRCC) accounts for ≤20% of RCC cases. Lenvatinib (a multitargeted tyrosine kinase inhibitor) in combination with everolimus (an mTOR inhibitor) is approved for the treatment of advanced RCC after one prior antiangiogenic therapy. OBJECTIVE To determine the safety and efficacy of lenvatinib plus everolimus as a first-line treatment for patients with advanced nccRCC. DESIGN, SETTING, AND PARTICIPANTS This open-label, single-arm, multicenter, phase 2 study enrolled patients with unresectable advanced or metastatic nccRCC and no prior anticancer therapy for advanced disease. INTERVENTION Lenvatinib (18 mg) plus everolimus (5 mg) orally once daily. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary endpoint was the objective response rate (ORR) as assessed by investigators according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety assessments. The 95% confidence intervals (CIs) for ORRs were calculated using the two-sided Clopper-Pearson method. Median PFS and median OS were estimated using the Kaplan-Meier product-limit method and their 95% CIs were estimated via a generalized Brookmeyer and Crowley method. RESULTS AND LIMITATIONS The study (start date: February 20, 2017) enrolled 31 patients with nccRCC (papillary, n = 20; chromophobe, n = 9; unclassified, n = 2). At the data cutoff date (July 17, 2019), the best overall response was a partial response (eight patients: papillary, n = 3; chromophobe, n = 4; unclassified, n = 1) for an overall ORR of 26% (95% CI 12-45). Median PFS was 9.2 mo (95% CI 5.5-not estimable), and median OS was 15.6 mo (95% CI 9.2-not estimable). The most common treatment-emergent adverse events were fatigue (71%), diarrhea (58%), decreased appetite (55%), nausea (55%), and vomiting (52%). Limitations include the small sample size and single-arm design. CONCLUSIONS Lenvatinib plus everolimus showed promising anticancer activity in patients with advanced nccRCC with an ORR of 26% and is worthy of further study. The safety profile was consistent with the established profile of the study-drug combination. PATIENT SUMMARY We examined the combination of lenvatinib plus everolimus as the first therapy for 31 patients who had advanced nccRCC. We found that this treatment seemed effective, because most patients had a decrease in tumor size and manageable treatment-related side effects. CLINICAL REGISTRATION This trial is registered at ClinicalTrials.Gov as NCT02915783.
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Affiliation(s)
- Thomas E Hutson
- Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA.
| | | | | | - Neeraj Agarwal
- Huntsman Cancer Center, (NCI-CCC), University of Utah, Salt Lake City, UT, USA
| | | | - James J Hsieh
- Washington University School of Medicine, St. Louis, MO, USA
| | | | - Ran Xie
- Eisai Inc., Woodcliff Lake, NJ, USA
| | | | - Weifei Ye
- Green Key Resources, LLC, New York, NY USA
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10
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Zielli T, Gnetti L, Buti S. Activity of lenvatinib plus everolimus combination in a heavily pretreated patient with papillary renal cell carcinoma: a case report. TUMORI JOURNAL 2020; 106:NP79-NP83. [PMID: 32458743 DOI: 10.1177/0300891620924472] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND Papillary renal cell carcinoma (pRCC) represents the second most common histologic subtype of renal cell carcinoma and comprises 2 subtypes. Prognosis for type 2 is associated with poor clinical outcome. Current guidelines are based on phase II trials, phase III trials in patients with clear cell histology, or retrospective data. CASE DESCRIPTION To our knowledge, we describe for the first time a case of a patient with heavily pretreated metastatic pRCC who benefited from the combination of lenvatinib plus everolimus for more than 2 years. CONCLUSION According to immunohistologic and biological findings in our patient both on primary tumor and liver metastasis, we hypothesize that selected patients with metastatic pRCC, progressed to standard/available treatments (including angiogenic drugs, mTOR inhibitors, and immunotherapy) and dissociated response to everolimus, could benefit from adding lenvatinib to everolimus.
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Affiliation(s)
- Teresa Zielli
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
| | - Letizia Gnetti
- Department of Medicine and Surgery, Pathology Unit, University Hospital of Parma, Parma, Italy
| | - Sebastiano Buti
- Medical Oncology Unit, University Hospital of Parma, Parma, Italy
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11
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Khetani VV, Portal DE, Shah MR, Mayer T, Singer EA. Combination drug regimens for metastatic clear cell renal cell carcinoma. World J Clin Oncol 2020; 11:541-562. [PMID: 32879843 PMCID: PMC7443831 DOI: 10.5306/wjco.v11.i8.541] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 05/11/2020] [Accepted: 07/18/2020] [Indexed: 02/06/2023] Open
Abstract
Renal cell carcinomas (RCC) make up about 90% of kidney cancers, of which 80% are of the clear cell subtype. About 20% of patients are already metastatic at the time of diagnosis. Initial treatment is often cytoreductive nephrectomy, but systemic therapy is required for advanced RCC. Single agent targeted therapies are moderately toxic and only somewhat effective, leading to development of immunotherapies and combination therapies. This review identifies limitations of monotherapies for metastatic renal cell carcinoma, discusses recent advances in combination therapies, and highlights therapeutic options under development. The goal behind combining various modalities of systemic therapy is to potentiate a synergistic antitumor effect. However, combining targeted therapies may cause increased toxicity. The initial attempts to create therapeutic combinations based on inhibition of the vascular endothelial growth factor or mammalian target of rapamycin pathways were largely unsuccessful in achieving a profile of increased synergy without increased toxicity. To date, five combination therapies have been approved by the U.S. Food and Drug Administration, with the most recently approved therapies being a combination of checkpoint inhibition plus targeted therapy. Several other combination therapies are under development, including some in the phase 3 stage. The new wave of combination therapies for metastatic RCC has the potential to increase response rates and improve survival outcomes while maintaining tolerable side effect profiles.
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Affiliation(s)
- Viraj V Khetani
- Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, United States
| | - Daniella E Portal
- Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, United States
| | - Mansi R Shah
- Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, United States
| | - Tina Mayer
- Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, United States
| | - Eric A Singer
- Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, United States
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12
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The Efficacy of Lenvatinib Plus Everolimus in Patients with Metastatic Renal Cell Carcinoma Exhibiting Primary Resistance to Front-Line Targeted Therapy or Immunotherapy. Clin Genitourin Cancer 2020; 18:252-257.e2. [PMID: 32291161 DOI: 10.1016/j.clgc.2020.03.003] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/28/2020] [Accepted: 03/03/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND Patients with primary refractory metastatic renal cell carcinoma (mRCC) have a dismal prognosis and poor response to subsequent treatments. While there are several approved second-line therapies, it remains critical to choose the most effective treatment regimen. PATIENTS AND METHODS We identified 7 patients with clear cell mRCC who had primary resistance to vascular endothelial growth factor (VEGF)-targeted tyrosine kinase inhibitors (TKIs) or immune checkpoint inhibitor (ICI) combination therapy. The patients were treated with lenvatinib (a multitargeted TKI) plus everolimus (a mammalian target of rapamycin inhibitor). Among these 7 patients, 2 had prior TKI therapy, 3 had prior ICI therapy, and 2 had prior TKI and ICI therapy. We collected the patients' clinical characteristics, molecular profiles, treatment durations, and toxicity outcomes. RESULTS The median time to progression on prior therapies was 1.5 months. Lenvatinib plus everolimus was used either as a second-line (n = 4) or third-line (n = 3) therapy. As best responses, 3 patients had partial responses and 3 achieved stable disease. Patients were followed for ≥17 months; progression-free survival ranged from 3 to 15 months, and overall survival ranged from 4 to 17 months. CONCLUSION These 7 cases provide real-world data for the use of lenvatinib plus everolimus in patients with mRCC with primary resistance to first-line VEGF-targeted TKIs or ICI combination therapy.
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13
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Graham J, Shah AY, Wells JC, McKay RR, Vaishampayan U, Hansen A, Donskov F, Bjarnason GA, Beuselinck B, De Velasco G, Iafolla M, Duh MS, Huynh L, Chang R, Zanotti G, Ramaswamy K, Choueiri TK, Tannir NM, Heng DYC. Outcomes of Patients with Metastatic Renal Cell Carcinoma Treated with Targeted Therapy After Immuno-oncology Checkpoint Inhibitors. Eur Urol Oncol 2019; 4:102-111. [PMID: 31786162 DOI: 10.1016/j.euo.2019.11.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/20/2019] [Accepted: 11/09/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Immuno-oncology (IO) therapies have changed the treatment standards of metastatic renal cell carcinoma (mRCC). However, the effectiveness of targeted therapy following discontinuation of IO therapy in real-world settings has not been well studied. OBJECTIVE To describe treatment sequence and assess clinical effectiveness of targeted therapy for mRCC patients who received prior IO therapy. DESIGN, SETTING, AND PARTICIPANTS A retrospective, longitudinal cohort study using data from eight international cancer centers was conducted. Patients with mRCC were ≥18yr old, received IO therapy in any line, and initiated targeted therapy following IO therapy discontinuation. INTERVENTION Patients were treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) or mammalian target of rapamycin inhibitors (mTORIs). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Outcomes were time to treatment discontinuation (TTD), overall survival (OS), and objective response rate (ORR). Crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models. Models were adjusted for age, sex, therapy line, and International Metastatic RCC Database Consortium risk group. RESULTS AND LIMITATIONS Among 314 patients, 276 (87.9%) and 38 (12.1%) were treated with VEGFR-TKI and mTORI therapy, respectively. The most common tyrosine kinase inhibitor treatments were axitinib, cabozantinib, and sunitinib following IO therapy. In adjusted models, patients treated with VEGFR-TKI versus mTORI therapy had lower hazard of TTD after IO treatment (aHR=0.46; 95% CI: 0.30-0.71; p < 0.01). One-year OS probability (65% vs 47%, p < 0.01) and proportion of ORR (29.8% vs 3.6%, p < 0.01) were significantly greater for patients treated with VEGFR-TKIs versus those treated with mTORIs. CONCLUSIONS Targeted therapy has clinical activity following IO treatment. Patients who received VEGFR-TKIs versus mTORIs following IO therapy had improved clinical outcomes. These findings may help inform treatment guidelines and clinical practice for patients post-IO therapy. PATIENT SUMMARY Patients may continue to experience clinical benefits from targeted therapies after progression on immuno-oncology treatment.
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Affiliation(s)
- Jeffrey Graham
- CancerCare Manitoba, University of Manitoba, Winnipeg, Canada
| | | | | | - Rana R McKay
- University of California San Diego, San Diego, CA, USA
| | | | - Aaron Hansen
- Princess Margaret Cancer Centre, Toronto, Canada
| | | | | | | | | | | | - Mei S Duh
- Analysis Group, Inc., Boston, MA, USA
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14
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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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15
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Grünwald V, Powles T, Choueiri TK, Hutson TE, Porta C, Eto M, Sternberg CN, Rha SY, He CS, Dutcus CE, Smith A, Dutta L, Mody K, Motzer RJ. Lenvatinib plus everolimus or pembrolizumab versus sunitinib in advanced renal cell carcinoma: study design and rationale. Future Oncol 2019; 15:929-941. [PMID: 30689402 DOI: 10.2217/fon-2018-0745] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
AIM Lenvatinib plus everolimus is approved for the treatment of advanced renal cell carcinoma (RCC) after one prior vascular endothelial growth factor-targeted therapy. Lenvatinib plus pembrolizumab demonstrated promising antitumor activity in a Phase I/II trial of RCC. METHODS We describe the rationale and design of the CLEAR study, a three-arm Phase III trial comparing lenvatinib plus everolimus and lenvatinib plus pembrolizumab versus sunitinib monotherapy for first-line treatment of RCC. Eligible patients must have advanced clear cell RCC and must not have received any prior systemic anticancer therapy. The primary end point is progression-free survival; secondary end points include objective response rate, overall survival, safety, health-related quality of life and pharmacokinetics. Biomarker evaluations are included as exploratory end points.
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Affiliation(s)
- Viktor Grünwald
- Clinic for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
| | - Thomas Powles
- Experimental Cancer Medicine, Barts Cancer Institute, London, UK
| | - Toni K Choueiri
- Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Thomas E Hutson
- Urologic Oncology Program, Baylor University Medical Center, Dallas, TX, USA
| | - Camillo Porta
- University of Pavia & Division of Translational Oncology, IRCCS Istituti Clinici Scientifici Maugeri, Pavia, Italy
| | - Masatoshi Eto
- Department of Urology, Kyushu University, Fukuoka, Japan
| | - Cora N Sternberg
- Weill Cornell Medicine, New York-Presbyterian, New York, NY, USA
| | - Sun Young Rha
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | | | | | | | | | | | - Robert J Motzer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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16
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Zschäbitz S, Grüllich C. Lenvantinib: A Tyrosine Kinase Inhibitor of VEGFR 1-3, FGFR 1-4, PDGFRα, KIT and RET. Recent Results Cancer Res 2018; 211:187-198. [PMID: 30069768 DOI: 10.1007/978-3-319-91442-8_13] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Lenvatinib is an oral receptor tyrosine kinase inhibitor (TKI) with activity against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor receptors (FGFR) 1-4, platelet-derived growth factor receptor-alpha (PDGFRα), and RET and KIT proto-oncogenes. Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the treatment of advanced renal cell carcinoma following anti-VEGF treatment. In hepatocellular carcinoma lenvatinib was non inferior to sorafenib in first line with an improved progression-free survival and approval in this indication is expected. Lenvatinib is currently investigated for further indications as single agent and in combinations. Side effects include typical TKI induced toxicities such as hypertension, diarrhea, hypothyroidism, and fatigue.
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Affiliation(s)
- Stefanie Zschäbitz
- National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg University Medical Center, Im Neuenheimer Feld 460, D-69120, Heidelberg, Germany
| | - Carsten Grüllich
- National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg University Medical Center, Im Neuenheimer Feld 460, D-69120, Heidelberg, Germany.
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17
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Roviello G, Corona SP, Bozza G, Aieta M, Generali D, Rodriquenz MG, Mileo AM, Imperatori M, Ianza A, Conca R, Sobhani N. Lenvatinib for the treatment of renal cell carcinoma. Expert Opin Investig Drugs 2018; 27:507-512. [PMID: 29718721 DOI: 10.1080/13543784.2018.1472235] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Renal cell carcinoma (RCC) accounts for 2-3% of all solid tumors. Expression of the receptor for the vascular endothelial growth factor (VEGF) is one of the most common features of RCC. AREAS COVERED Lenvatinib is a novel multi-kinase inhibitor that has been studied in several solid tumors. It has shown promising results in the treatment of RCC, especially when combined with everolimus, In this review, we summarize the available data of lenvatinib for the treatment of advanced/metastatic renal cell carcinoma. EXPERT OPINION Lenvatinib in combination with everolimus has provided encouraging results in both clinical and laboratory investigations showing that blocking angiogenesis and the mTOR signalling pathway could be a remarkable approach for treating RCC. As an additive to this type of approach it would be interesting in future clinical settings testing also the combination of lenvatinib and everolimus with immune-therapy.
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Affiliation(s)
- Giandomenico Roviello
- a Division of Medical Oncology, Department of Onco-Hematology , IRCCS-CROB, Referral Cancer Center of Basilicata , Rionero, Vulture , Italy
| | | | - Giovanni Bozza
- a Division of Medical Oncology, Department of Onco-Hematology , IRCCS-CROB, Referral Cancer Center of Basilicata , Rionero, Vulture , Italy
| | - Michele Aieta
- a Division of Medical Oncology, Department of Onco-Hematology , IRCCS-CROB, Referral Cancer Center of Basilicata , Rionero, Vulture , Italy
| | - Daniele Generali
- c Department of Medical, Surgery and Health Sciences , University of Trieste , Trieste , Italy
- d Breast Cancer and Translational Research Unit , ASST Cremona , Cremona , Italy
| | - Maria Grazia Rodriquenz
- a Division of Medical Oncology, Department of Onco-Hematology , IRCCS-CROB, Referral Cancer Center of Basilicata , Rionero, Vulture , Italy
| | - Anna Maria Mileo
- a Division of Medical Oncology, Department of Onco-Hematology , IRCCS-CROB, Referral Cancer Center of Basilicata , Rionero, Vulture , Italy
| | - Marco Imperatori
- a Division of Medical Oncology, Department of Onco-Hematology , IRCCS-CROB, Referral Cancer Center of Basilicata , Rionero, Vulture , Italy
| | - Anna Ianza
- c Department of Medical, Surgery and Health Sciences , University of Trieste , Trieste , Italy
| | - Raffaele Conca
- a Division of Medical Oncology, Department of Onco-Hematology , IRCCS-CROB, Referral Cancer Center of Basilicata , Rionero, Vulture , Italy
| | - Navid Sobhani
- c Department of Medical, Surgery and Health Sciences , University of Trieste , Trieste , Italy
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