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Yip D, Zalcberg J, Blay JY, Eriksson M, Espinoza D, Price T, Marreaud S, Italiano A, Steeghs N, Boye K, Underhill C, Gebski V, Simes J, Gelderblom H, Joensuu H. Imatinib alternating with regorafenib compared to imatinib alone for the first-line treatment of advanced gastrointestinal stromal tumor: The AGITG ALT-GIST intergroup randomized phase II trial. Br J Cancer 2025; 132:897-904. [PMID: 40133509 DOI: 10.1038/s41416-025-02983-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/14/2025] [Accepted: 03/11/2025] [Indexed: 03/27/2025] Open
Abstract
BACKGROUND To determine if an alternating regimen of the tyrosine kinase inhibitors imatinib and regorafenib improved outcomes in patients with advanced gastrointestinal stromal tumors. METHODS ALTGIST (NCT02365441) was a randomized phase II study of standard treatment of imatinib (Arm A) compared with an experimental alternating regimen of imatinib and regorafenib (Arm B). Primary outcome was best objective tumor response (OTR) at nine months. RESULTS Seventy-six eligible patients (Arm A 36, Arm B 40) enrolled were evaluable. Median follow-up was 46.0 months (range 6.5-64.6). Best responses and OTR were similar at 9 months. Eighteen (50.0%) Arm A patients and twelve (30.0%) Arm B patients discontinued treatment due to progressive disease. No Arm A patients stopped protocol therapy due to unacceptable toxicity, with 12 (30.0%) stopping in Arm B. Twelve (33.2%) Arm A patients and 12 (30.0%) Arm B patients experienced at least one serious adverse event, mostly grade 3. Secondary endpoints of PFS at 1 and OS at 1 year were not statistically different. CONCLUSIONS Alternation of imatinib and regorafenib did not impact on 9 months objective response nor on the secondary objectives of PFS and OS. Patients in the alternating arm experienced more toxicity and protocol discontinuations. CLINICAL TRIAL REGISTRATION NCT02365441.
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Affiliation(s)
- Desmond Yip
- The Canberra Hospital and Australian National University, Canberra, ACT, Australia.
| | - John Zalcberg
- School of Public Health, Monash University, Melbourne, VIC, Australia
| | | | | | - David Espinoza
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia
| | - Timothy Price
- Queen Elizabeth Hospital, University of Adelaide, Adelaide, SA, Australia
| | - Sandrine Marreaud
- European Organisation for Research and Treatment of Cancer (EORTC), Brussels, Belgium
| | | | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
| | | | - Craig Underhill
- Albury-Wodonga Regional Cancer Centre, Albury-Wodonga, NSW, Australia
| | - Val Gebski
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia
| | - John Simes
- NHMRC Clinical Trials Centre, The University of Sydney, Sydney, NSW, Australia
| | - Hans Gelderblom
- Leiden University Medical Centre, Department of Medical Oncology, Leiden, The Netherlands
| | - Heikki Joensuu
- Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
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Jeong JH, Kim S, Min SC, Kim E, Song M, Shin E. Regorafenib as a potential drug for severe COVID-19: inhibition of inflammasome activation in mice. FEBS Open Bio 2025; 15:427-435. [PMID: 39895416 PMCID: PMC11891780 DOI: 10.1002/2211-5463.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 12/31/2024] [Accepted: 01/23/2025] [Indexed: 02/04/2025] Open
Abstract
SARS-CoV-2 infection can lead to severe COVID-19, particularly in elderly individuals and those with compromised immunity. Cellular senescence has been implicated as a key pathogenic mechanism. This study investigated the therapeutic potential of regorafenib, a previously characterized senomorphic drug, for severe COVID-19. SARS-CoV-2 virus-infected K18-hACE2 mice, overexpressing the human ACE2 receptor, exhibited 100% mortality by 10 days post infection. Regorafenib treatment significantly improved survival rates, approximately 43% remaining alive. Mechanistically, regorafenib effectively suppressed type I and II interferon and cytokine signaling. Notably, regorafenib inhibited NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, a key driver of the cytokine storm associated with severe COVID-19. Our findings elucidate the molecular mechanisms underlying therapeutic effects of regorafenib and suggest its potential use as a promising treatment option for severe COVID-19.
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Affiliation(s)
- Ju Hwan Jeong
- Department of Microbiology, Chungbuk National University College of Medicine and Medical Research CenterChungbuk National University HospitalCheongjuRepublic of Korea
| | - Sun‐Ok Kim
- Department of Biochemistry, Chungbuk National University College of Medicine and Medical Research CenterChungbuk National University HospitalCheongjuRepublic of Korea
| | - Seong Cheol Min
- Department of Microbiology, Chungbuk National University College of Medicine and Medical Research CenterChungbuk National University HospitalCheongjuRepublic of Korea
| | - Eung‐Gook Kim
- Department of Biochemistry, Chungbuk National University College of Medicine and Medical Research CenterChungbuk National University HospitalCheongjuRepublic of Korea
| | - Min‐Suk Song
- Department of Microbiology, Chungbuk National University College of Medicine and Medical Research CenterChungbuk National University HospitalCheongjuRepublic of Korea
| | - Eun‐Young Shin
- Department of Biochemistry, Chungbuk National University College of Medicine and Medical Research CenterChungbuk National University HospitalCheongjuRepublic of Korea
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3
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Hossain MA. A comprehensive review of targeting RAF kinase in cancer. Eur J Pharmacol 2025; 986:177142. [PMID: 39577552 DOI: 10.1016/j.ejphar.2024.177142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 11/11/2024] [Accepted: 11/17/2024] [Indexed: 11/24/2024]
Abstract
RAF kinases, particularly the BRAF isoform, play a crucial role in the MAPK/ERK signaling pathway, regulating key cellular processes such as proliferation, differentiation, and survival. Dysregulation of this pathway often caused by mutations in the BRAF gene or alterations in upstream regulators like Ras and receptor tyrosine kinases contributes significantly to cancer development. Mutations, such as BRAF-V600E, are present in a variety of malignancies, with the highest prevalence in melanoma. Targeted therapies against RAF kinases have achieved substantial success, especially in BRAF-V600E-mutant melanomas, where inhibitors like vemurafenib and dabrafenib have demonstrated remarkable efficacy, leading to improved patient outcomes. These inhibitors have also shown clinical benefits in cancers such as thyroid and colorectal carcinoma, although to a lesser extent. Despite these successes, therapeutic resistance remains a major hurdle. Resistance mechanisms, including RAF dimerization, feedback reactivation of the MAPK pathway, and paradoxical activation of ERK signaling, often lead to diminished efficacy over time, resulting in disease progression or even secondary malignancies. In response, current research is focusing on novel therapeutic strategies, including combination therapies that target multiple components of the pathway simultaneously, such as MEK inhibitors used in tandem with RAF inhibitors. Additionally, next-generation RAF inhibitors are being developed to address resistance and enhance therapeutic specificity. This review discusses the clinical advancements in RAF-targeted therapies, with a focus on ongoing efforts to overcome therapeutic resistance and enhance outcomes for cancer patients. It also underscores the persistent challenges in effectively targeting RAF kinase in oncology.
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Affiliation(s)
- Md Arafat Hossain
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalganj, 8100, Bangladesh.
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4
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Gabellone S, Vanni S, Fausti V, Miserocchi G, Liverani C, Spadazzi C, Cocchi C, Calabrese C, Cavaliere D, Pacilio CA, Ercolani G, Pieri F, Gurrieri L, Riva N, Jones R, De Vita A. Exploring nanotechnology solutions for improved outcomes in gastrointestinal stromal tumors. Heliyon 2024; 10:e40596. [PMID: 39687122 PMCID: PMC11647801 DOI: 10.1016/j.heliyon.2024.e40596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 12/18/2024] Open
Abstract
Objectives Gastrointestinal stromal tumors, the most prevalent mesenchymal tumors (80 %) of the gastrointestinal tract, comprise less than 1 % of all gastrointestinal neoplasms and about 5 % of all sarcomas. Despite their rarity, Gastrointestinal stromal tumors present diverse clinical manifestations, anatomic locations, histological subtypes, and prognostic outcomes. Methods This scoping review comprehensively explores the epidemiology, clinical characteristics, diagnostic and prognostic modalities, as well as new therapeutic options for Gastrointestinal stromal tumors. Results A particular focus is placed on the promising role of bio-nanomaterials as multifunctional agents for drug delivery and 3D tumor microenvironment modeling. Bio-nanomaterials offer promising opportunities for targeted drug delivery, overcoming treatment resistance, and improving therapeutic efficacy. Conclusion Despite significant advancements, Gastrointestinal stromal tumors remain a complex clinical entity with ongoing challenges. The integration of nanotechnology into Gastrointestinal stromal tumors management offers the potential to enhance patient outcomes. Future studies should prioritize the development and evaluation of nanomaterial-based therapies in clinical trials to facilitate the translation of laboratory discoveries into real-world clinical applications.
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Affiliation(s)
- Sofia Gabellone
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Silvia Vanni
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Valentina Fausti
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Giacomo Miserocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Chiara Liverani
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Chiara Spadazzi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Claudia Cocchi
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Chiara Calabrese
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Davide Cavaliere
- General and Oncologic Surgery, “Morgagni-Pierantoni” Hospital, 47121, Forlì, Italy
| | | | - Giorgio Ercolani
- General and Oncologic Surgery, “Morgagni-Pierantoni” Hospital, 47121, Forlì, Italy
| | - Federica Pieri
- Pathology Unit, “Morgagni-Pierantoni” Hospital, 47121, Forlì, Italy
| | - Lorena Gurrieri
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Nada Riva
- Clinical and Experimental Oncology, Immunotherapy, Rare Cancers and Biological Resource Center, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
| | - Robin Jones
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, SW3 6JJ, London, UK
| | - Alessandro De Vita
- Preclinic and Osteoncology Unit, Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014, Meldola, Italy
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Ming Y, Gong Y, Fu X, Ouyang X, Peng Y, Pu W. Small-molecule-based targeted therapy in liver cancer. Mol Ther 2024; 32:3260-3287. [PMID: 39113358 PMCID: PMC11489561 DOI: 10.1016/j.ymthe.2024.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/13/2024] [Accepted: 08/02/2024] [Indexed: 08/23/2024] Open
Abstract
Liver cancer is one of the most prevalent malignant tumors worldwide. According to the Barcelona Clinic Liver Cancer staging criteria, clinical guidelines provide tutorials to clinical management of liver cancer at their individual stages. However, most patients diagnosed with liver cancer are at advanced stage; therefore, many researchers conduct investigations on targeted therapy, aiming to improve the overall survival of these patients. To date, small-molecule-based targeted therapies are highly recommended (first line: sorafenib and lenvatinib; second line: regorafenib and cabozantinib) by current the clinical guidelines of the American Society of Clinical Oncology, European Society for Medical Oncology, and National Comprehensive Cancer Network. Herein, we summarize the small-molecule-based targeted therapies in liver cancer, including the approved and preclinical therapies as well as the therapies under clinical trials, and introduce their history of discovery, clinical trials, indications, and molecular mechanisms. For drug resistance, the revealed mechanisms of action and the combination therapies are also discussed. In fact, the known small-molecule-based therapies still have limited clinical benefits to liver cancer patients. Therefore, we analyze the current status and give our ideas for the urgent issues and future directions in this field, suggesting clues for novel techniques in liver cancer treatment.
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Affiliation(s)
- Yue Ming
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China
| | - Yanqiu Gong
- National Clinical Research Center for Geriatrics and Department of General Practice, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xuewen Fu
- Jinhua Huanke Environmental Technology Co., Ltd., Jinhua 321000, China
| | - Xinyu Ouyang
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Peng
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Chengdu 610212, China.
| | - Wenchen Pu
- Laboratory of Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610064, China; West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, China.
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6
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Poklepovic AS, Gordon SW, Kothadia S, McGuire WP, Thacker LR, Deng X, Tombes MB, Shrader E, Hudson D, Bandyopadhyay D, Ryan AA, Kmieciak M, Smith S, Dent P. A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors. Anticancer Drugs 2024; 35:450-458. [PMID: 38452059 PMCID: PMC11168782 DOI: 10.1097/cad.0000000000001584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 01/25/2024] [Indexed: 03/09/2024]
Abstract
The purpose of this study is to establish the recommended phase 2 dose for regorafenib in combination with sildenafil for patients with advanced solid tumors. Secondary outcomes included identification of antitumor effects of regorafenib and sildenafil, toxicity of the combination, determination of PDE5 expression in tumor samples, and the impact of sildenafil on the pharmacokinetics of regorafenib. This study was a phase 1, open-label single-arm dose-escalation trial using a 3 + 3 design. Additional patients were enrolled at the maximum tolerated dose (MTD) until a total of 12 patients were treated at the MTD. A total of 29 patients were treated in this study. The median duration of treatment was 8 weeks. The recommended phase 2 doses determined in this study are regorafenib 160 mg daily with sildenafil 100 mg daily. The most common toxicities included palmar-plantar erythrodysesthesia syndrome (20 patients, 69%) and hypophosphatemia (18 patients, 62%). Two patients (7%) experienced grade 4 lipase increase. Objective responses were not observed; however, 14 patients (48%) had a period of stable disease during the study. Stable disease for up to 12 months was observed in patients with ovarian cancer as well as up to 20 months for a patient with cervical cancer. The combination of regorafenib and sildenafil at the recommended phase 2 dose is safe and generally well tolerated. Disease control in patients with gynecologic malignancies was especially encouraging. Further evaluation of the combination of regorafenib and sildenafil in gynecologic malignancies is warranted. Clinical Trial Registration Number: NCT02466802.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Paul Dent
- Massey Cancer Center
- Biochemistry, Virginia Commonwealth University, Richmond, Virginia, USA
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Zeng J, Li K, Cao F, Zheng Y. The development of a prediction model based on deep learning for prognosis prediction of gastrointestinal stromal tumor: a SEER-based study. Sci Rep 2024; 14:6609. [PMID: 38504089 PMCID: PMC10951333 DOI: 10.1038/s41598-024-56701-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 03/09/2024] [Indexed: 03/21/2024] Open
Abstract
Accurately predicting the prognosis of Gastrointestinal stromal tumor (GIST) patients is an important task. The goal of this study was to create and assess models for GIST patients' survival patients using the Surveillance, Epidemiology, and End Results Program (SEER) database based on the three different deep learning models. Four thousand five hundred thirty-eight patients were enrolled in this study and divided into training and test cohorts with a 7:3 ratio; the training cohort was used to develop three different models, including Cox regression, RSF, and DeepSurv model. Test cohort was used to evaluate model performance using c-index, Brier scores, calibration, and the area under the curve (AUC). The net benefits at risk score stratification of GIST patients based on the optimal model was compared with the traditional AJCC staging system using decision curve analysis (DCA). The clinical usefulness of risk score stratification compared to AJCC tumor staging was further assessed using the Net Reclassification Index (NRI) and Integrated Discrimination Improvement (IDI). The DeepSurv model predicted cancer-specific survival (CSS) in GIST patients showed a higher c-index (0.825), lower Brier scores (0.142), and greater AUC of receiver operating characteristic (ROC) analysis (1-year ROC:0.898; 3-year:0.853, and 5-year ROC: 0.856). The calibration plots demonstrated good agreement between the DeepSurv model's forecast and actual results. The NRI values ( training cohort: 0.425 for 1-year, 0.329 for 3-year and 0.264 for 5-year CSS prediction; test cohort:0.552 for 1-year,0.309 for 3-year and 0.255 for 5-year CSS prediction) and IDI (training cohort: 0.130 for 1-year,0.141 for 5-year and 0.155 for 10-year CSS prediction; test cohort: 0.154 for 1-year,0.159 for 3-year and 0.159 for 5-year CSS prediction) indicated that the risk score stratification performed significantly better than the AJCC staging alone (P < 0.001). DCA demonstrated the risk score stratification as more clinically beneficial and discriminatory than AJCC staging. Finally, an interactive native web-based prediction tool was constructed for the survival prediction of GIST patients. This study established a high-performance prediction model for projecting GIST patients based on deep learning, which has advantages in predicting each person's prognosis and risk stratification.
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Affiliation(s)
- Junjie Zeng
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Kai Li
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Fengyu Cao
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China
| | - Yongbin Zheng
- Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China.
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Cicala CM, Olivares-Rivas I, Aguirre-Carrillo JA, Serrano C. KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem. Expert Opin Investig Drugs 2024; 33:159-170. [PMID: 38344849 DOI: 10.1080/13543784.2024.2318317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 02/09/2024] [Indexed: 02/15/2024]
Abstract
INTRODUCTION Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations. AREAS COVERED In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable. EXPERT OPINION The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.
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Affiliation(s)
- Carlo María Cicala
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Iván Olivares-Rivas
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - César Serrano
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
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Golčić M, Jones RL, Huang P, Napolitano A. Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours. Cancers (Basel) 2023; 15:4081. [PMID: 37627109 PMCID: PMC10452236 DOI: 10.3390/cancers15164081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/28/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.
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Affiliation(s)
- Marin Golčić
- Department of Radiotherapy and Oncology, Clinical Hospital Center Rijeka, Krešimirova 42, 51000 Rijeka, Croatia
| | - Robin L. Jones
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK
| | - Paul Huang
- Division of Molecular Pathology, The Institute of Cancer Research, Sutton SM2 5NG, UK;
| | - Andrea Napolitano
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK
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10
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Kim HD, Yoo C, Ryu MH, Kang YK. A randomised phase 2 study of continuous or intermittent dosing schedule of imatinib re-challenge in patients with tyrosine kinase inhibitor-refractory gastrointestinal stromal tumours. Br J Cancer 2023; 129:275-282. [PMID: 37179439 PMCID: PMC10338488 DOI: 10.1038/s41416-023-02269-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 03/27/2023] [Accepted: 04/04/2023] [Indexed: 05/15/2023] Open
Abstract
BACKGROUND Imatinib re-challenge is one of the available therapeutic options for patients with treatment-refractory gastrointestinal stromal tumours (GIST). Intermittent dosing of imatinib was suggested to delay outgrow of the imatinib-resistant clones in a preclinical study, and it could potentially reduce the adverse events. METHODS A randomised phase 2 study was performed to evaluate the efficacy and safety of a continuous or intermittent imatinib schedule in GIST patients whose disease had progressed to at least imatinib and sunitinib. RESULTS Fifty patients were included in the full analysis set. The disease control rate at 12 weeks was 34.8% and 43.5%, and median progression-free survival was 1.68 and 1.57 months in the continuous and intermittent groups, respectively. The frequency of diarrhoea, anorexia, decreased neutrophil, or dysphagia was lower in the intermittent group. The scores for global health status/quality of life was not significantly deteriorated over the 8 weeks in both groups. CONCLUSIONS The intermittent dosage did not improve the efficacy outcomes as compared to the continuous dosage, but showed slightly better safety profiles. Given the limited efficacy of imatinib re-challenge, intermittent dosage may also be considered in clinical circumstances where standard fourth-line agent is unavailable or all other viable treatments failed.
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Affiliation(s)
- Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Changhoon Yoo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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Venkataraman V, George S, Cote GM. Molecular Advances in the Treatment of Advanced Gastrointestinal Stromal Tumor. Oncologist 2023:oyad167. [PMID: 37315115 PMCID: PMC10400151 DOI: 10.1093/oncolo/oyad167] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/19/2023] [Indexed: 06/16/2023] Open
Abstract
Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of effective therapies targeting these mutations has revolutionized the management of advanced GIST. However, following initiation of first-line imatinib, a tyrosine kinase inhibitor (TKI), nearly all patients will develop resistance within 2 years through the emergence of secondary resistance mutations in KIT, typically in the Adenosine Triphosphate (ATP)-binding site or activation loop of the kinase domain. Moreover, some patients have de novo resistance to imatinib, such as those with mutations in PDGFRA exon 18 or those without KIT or PDGFRA mutation. To target resistance, research efforts are primarily focused on developing next-generation inhibitors of KIT and/or PDGFRA, which can inhibit alternate receptor conformations or unique mutations, and compounds that impact complimentary pathogenic processes or epigenetic events. Here, we review the literature on the medical management of high-risk localized and advanced GIST and provide an update on clinical trial approaches to this disease.
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Affiliation(s)
- Vinayak Venkataraman
- Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA
- Mass General Hospital Cancer Center, Center for Sarcoma and Connective Tissue Oncology, Boston, MA, USA
| | - Suzanne George
- Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA
| | - Gregory M Cote
- Mass General Hospital Cancer Center, Center for Sarcoma and Connective Tissue Oncology, Boston, MA, USA
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12
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Vaamonde-Martín RJ, Ballesta-Ruiz M, Sánchez-Gil A, Fernández JÁ, Martínez-Barba E, Martínez-García J, Gatta G, Chirlaque-López MD. Incidence Trends and Main Features of Gastro-Intestinal Stromal Tumours in a Mediterranean Region: A Population-Based Study. Cancers (Basel) 2023; 15:cancers15112994. [PMID: 37296956 DOI: 10.3390/cancers15112994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/26/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Gastro-Intestinal Stromal Tumours (GISTs) are a kind of neoplasm whose diagnosis in common clinical practice just started in the current century, implying difficulties for proper registration. Staff from the Cancer Registry of Murcia, in southeastern Spain, were commissioned by the EU Joint Action on Rare Cancers into a pilot study addressing GIST registration that also yielded a population-based depiction of GISTs in the region, including survival figures. We examined reports from 2001 to 2015 from hospitals as well as cases already present in the registry. The variables collected were sex, date of diagnosis, age, vital status, primary location, presence of metastases, and risk level according to Joensuu's Classification. In total, 171 cases were found, 54.4% occurred in males, and the mean age value was 65.0 years. The most affected organ was the stomach, with 52.6% of cases. Risk level was determined as "High" for 45.0%, with an increment of lower levels in recent years. Incidence for the year 2015 doubled that of 2001. Overall, the 5-year net survival estimation was 77.0%. The rising incidence magnitude is consistent with trends in other European countries. Survival evolution lacked statistical significance. A more interventional approach in clinical management could explain the increase in the proportion of "Low Risk GISTs" and the first occurrence of "Very Low Risk" in recent years.
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Affiliation(s)
- Ricardo J Vaamonde-Martín
- Service of Epidemiology, Region of Murcia Health Council, Ronda de Levante 11, 30008 Murcia, Spain
- Institute for Biomedical Research of Murcia, IMIB-Arrixaca, 30120 Murcia, Spain
| | - Mónica Ballesta-Ruiz
- Service of Epidemiology, Region of Murcia Health Council, Ronda de Levante 11, 30008 Murcia, Spain
- Institute for Biomedical Research of Murcia, IMIB-Arrixaca, 30120 Murcia, Spain
- School of Medicine, University of Murcia, 30100 Murcia, Spain
| | - Antonia Sánchez-Gil
- Service of Epidemiology, Region of Murcia Health Council, Ronda de Levante 11, 30008 Murcia, Spain
- SMS (Region of Murcia Health Service) Calle Central, 7, 30100 Murcia, Spain
| | - Juan Ángel Fernández
- School of Medicine, University of Murcia, 30100 Murcia, Spain
- University Hospital "Virgen de la Arrixaca", 30120 Murcia, Spain
| | - Enrique Martínez-Barba
- School of Medicine, University of Murcia, 30100 Murcia, Spain
- University Hospital "Virgen de la Arrixaca", 30120 Murcia, Spain
| | | | - Gemma Gatta
- Evaluative Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20131 Milan, Italy
| | - María D Chirlaque-López
- Service of Epidemiology, Region of Murcia Health Council, Ronda de Levante 11, 30008 Murcia, Spain
- Institute for Biomedical Research of Murcia, IMIB-Arrixaca, 30120 Murcia, Spain
- School of Medicine, University of Murcia, 30100 Murcia, Spain
- CIBER Epidemiología y Salud Pública (CIBERESP), 28029 Madrid, Spain
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13
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Villa A, Kuten-Shorrer M. Pathogenesis of Oral Toxicities Associated with Targeted Therapy and Immunotherapy. Int J Mol Sci 2023; 24:ijms24098188. [PMID: 37175898 PMCID: PMC10179284 DOI: 10.3390/ijms24098188] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/04/2023] [Accepted: 04/28/2023] [Indexed: 05/15/2023] Open
Abstract
Targeted therapy and immunotherapy have redefined cancer treatment. While they have enhanced tumor response and improved survival rates in many cancer types, toxicities continue to occur, and these often involve the oral cavity. Broadly reported as "mucositis" or "stomatitis," oral toxicities induced by targeted therapies differ clinically and mechanistically from those associated with conventional chemotherapy. Manifesting primarily as mucosal lesions, salivary gland hypofunction, or orofacial neuropathies, these oral toxicities may nonetheless lead to significant morbidity and impact patients' quality of life, thereby compromising clinical outcomes. We conclude that familiarity with the spectrum of associated toxicities and understanding of their pathogenesis represent important areas of clinical research and may lead to better characterization, prevention, and management of these adverse events.
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Affiliation(s)
- Alessandro Villa
- Oral Medicine, Oral Oncology and Dentistry, Miami Cancer Institute, Baptist Health South Florida, Miami, FL 33176, USA
- The Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33176, USA
- Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA 94143, USA
| | - Michal Kuten-Shorrer
- Eastman Institute for Oral Health, University of Rochester Medical Center, Rochester, New York, NY 14642, USA
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14
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Ge Q, Liu Y, Yang F, Sun G, Guo J, Sun S. Chinese Pedigree with Hereditary Gastrointestinal Stromal Tumors: A Case Report and Literature Review. Int J Mol Sci 2023; 24:830. [PMID: 36614290 PMCID: PMC9820900 DOI: 10.3390/ijms24010830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 12/19/2022] [Accepted: 12/29/2022] [Indexed: 01/06/2023] Open
Abstract
Familial gastrointestinal stromal tumor (GIST) is a rare autosomal dominant genetic disorder with only a few affected families reported to date. Here, we report a case of familial GISTs harboring a novel germline mutation within exon 18 of KIT. A 58-year-old male patient presented with gastric subepithelial lesions accompanied by cutaneous hyperpigmentation, which were subsequently diagnosed as multinodular GISTs. Endoscopic surgery was initially conducted to remove the larger lesions, and pathological examinations were then conducted for the diagnosis of GISTs. Family history revealed that some other family members had similar cutaneous pigmentations. Whole-exome sequencing was used to search for potential driver mutations, and Sanger sequencing was used for mutation validation. A novel primary driver mutation of KIT (c.G2485C, p.A829P) was detected in these hereditary GISTs, which has been reported in some targeted chemotherapy-resistant GISTs. Cell models were subsequently established for the rapid screening of candidate drugs and exploring potential mechanisms. This mutation could lead to cell proliferation and imatinib resistance by ligand-independent activation of KIT; however, ripretinib administration was identified as an applicable targeted therapy for this mutation. The mutation activated the JAK/STAT3 and MAPK/ERK pathways, which could be inhibited by ripretinib administration. To the best of our knowledge, this is the first report of the KIT-A829P mutation in familial GISTs, complementing the pathogenesis of familial GISTs and providing valuable information for the precision treatment of this disease.
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Affiliation(s)
- Qichao Ge
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, China
- Innovative Research Center for Integrated Cancer Omics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Yang Liu
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, China
- Innovative Research Center for Integrated Cancer Omics, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Fan Yang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, China
| | - Guangwei Sun
- Innovative Engineering Technology Research Center for Cell Therapy, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Jintao Guo
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, China
| | - Siyu Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang 110004, China
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15
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Khosroyani HM, Klug LR, Heinrich MC. TKI Treatment Sequencing in Advanced Gastrointestinal Stromal Tumors. Drugs 2023; 83:55-73. [PMID: 36607590 PMCID: PMC10029090 DOI: 10.1007/s40265-022-01820-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2022] [Indexed: 01/07/2023]
Abstract
Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.
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Affiliation(s)
- Homma M Khosroyani
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA
| | - Lillian R Klug
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA
| | - Michael C Heinrich
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA.
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16
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Schöffski P, George S, Heinrich MC, Zalcberg JR, Bauer S, Gelderblom H, Serrano C, Jones RL, Attia S, D'Amato G, Chi P, Reichardt P, Becker C, Shi K, Meade J, Ruiz-Soto R, Blay JY, von Mehren M. Patient-reported outcomes in individuals with advanced gastrointestinal stromal tumor treated with ripretinib in the fourth-line setting: analysis from the phase 3 INVICTUS trial. BMC Cancer 2022; 22:1302. [PMID: 36514034 PMCID: PMC9746146 DOI: 10.1186/s12885-022-10379-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Ripretinib is a novel switch-control kinase inhibitor that inhibits KIT and PDGFRA signaling. In the INVICTUS phase 3 trial, ripretinib increased median progression-free survival and prolonged overall survival vs. placebo in ≥ fourth-line advanced GIST. Here, we report prespecified analysis of quality of life (QoL) as assessed by patient-reported outcome (PRO) measures and an exploratory analysis evaluating the impact of alopecia on QoL. METHODS In the INVICTUS trial (NCT03353753), QoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30; physical function, role function, overall health, and overall QoL) and the EuroQoL 5-Dimension 5-Level (EQ-5D-5 L; visual analogue scale). Analysis of covariance (ANCOVA) models compared changes in scores from baseline to treatment cycle 2, day 1 within and between ripretinib and placebo. Within the ripretinib arm, repeated measures models assessed the impact of alopecia on QoL. RESULTS Patients receiving ripretinib maintained QoL (as assessed by the EORTC QLQ-C30 and EQ-5D-5 L PRO measures) from baseline to cycle 2, day 1 whereas QoL declined with placebo, resulting in clinically significant differences between treatments (nominal P < 0.01). The most common treatment-emergent adverse event with ripretinib was alopecia; however, QoL was similarly maintained out to treatment cycle 10, day 1 in patients receiving ripretinib who developed alopecia and those who did not. CONCLUSION PRO assessments in the INVICTUS trial suggest that patients on ripretinib maintain their QoL out to C2D1, unlike patients receiving placebo. Longitudinal QoL was maintained for patients receiving ripretinib out to cycle 10, day 1 (approximately 8 months; past the point of median progression-free survival with ripretinib [6.3 months]), even if the patients developed alopecia. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03353753 ; first posted: November 27, 2017.
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Affiliation(s)
- Patrick Schöffski
- General Medical Oncology, University Hospitals Leuven, Herestraat 49, B-3000, Leuven, Belgium.
| | - Suzanne George
- Dana-Farber Cancer Institute, 450 Brookline Ave, 02215, Boston, MA, USA
| | - Michael C Heinrich
- VA Portland Veterans Health Care System, 3710 SW US Veterans Hospital Rd., 97239, Portland, OR, USA
- OHSU Knight Cancer Institute, 3161 SW Pavilion Loop, 97239, Portland, OR, USA
| | - John R Zalcberg
- Monash University and Alfred Health, 553 St Kilda Road, VIC, 3004, Melbourne, Australia
| | - Sebastian Bauer
- Department of Medical Oncology, University Hospital Essen, Sarcoma Center/West German Cancer Center, University Duisburg-Essen, Hufelandstraße 55, D - 45147, Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen, Essen, Germany
| | - Hans Gelderblom
- Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, Netherlands
| | - César Serrano
- Centro Cellex, Vall d'Hebron Institute of Oncology, Carrer de Natzaret, 115-117, 08035, Barcelona, Spain
| | - Robin L Jones
- Royal Marsden and Institute of Cancer Research, 15 Cotswold Rd, SM2 5NG, London, UK
| | - Steven Attia
- Mayo Clinic, 4500 San Pablo Road S, 32224, Jacksonville, FL, USA
| | - Gina D'Amato
- Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW 12th Ave, 33136, Miami, FL, USA
| | - Ping Chi
- Memorial Sloan Kettering Cancer Center, 1275 York Ave, 10065, New York, NY, USA
| | - Peter Reichardt
- Sarcoma Center, Helios Klinikum Berlin-Buch, Schwanebecker Ch 50, 13125, Berlin, Germany
| | - Claus Becker
- Deciphera Pharmaceuticals, LLC, 200 Smith St., 02451, Waltham, MA, USA
| | - Kelvin Shi
- Deciphera Pharmaceuticals, LLC, 200 Smith St., 02451, Waltham, MA, USA
| | - Julie Meade
- Deciphera Pharmaceuticals, LLC, 200 Smith St., 02451, Waltham, MA, USA
| | - Rodrigo Ruiz-Soto
- Deciphera Pharmaceuticals, LLC, 200 Smith St., 02451, Waltham, MA, USA
| | - Jean-Yves Blay
- Centre Leon Berard, 28 Prom. Léa et Napoléon Bullukian, 69008, Lyon, France
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17
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Ferguson RJ, Manculich J, Chang H, Sareen NJ, Snitz BE, Terhorst L, Bovbjerg DH, Duensing AU. Self-reported cognitive impairments and quality of life in patients with gastrointestinal stromal tumor: Results of a multinational survey. Cancer 2022; 128:4017-4026. [PMID: 36125989 PMCID: PMC9633548 DOI: 10.1002/cncr.34469] [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: 01/28/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 01/11/2023]
Abstract
BACKGROUND Cancer-related cognitive impairment (CRCI) has long-term effects on survivor quality of life, but CRCI research on patients with gastrointestinal stromal tumor (GIST) is lacking. The aims of this study were to investigate CRCI and concomitant quality of life among patients with GIST. METHODS An online survey was used to assess CRCI in adult patients with GIST using the validated Functional Assessment of Cancer Therapy-Cognitive-v.3. Age, education, demographically indexed IQ, general health, and quality of life factors (e.g., fatigue, emotional distress) were also assessed. The online survey was administered through five international GIST and sarcoma support organizations. RESULTS Over the 3-month recruitment period, the survey was completed by 485 participants: mean age, 57.80 (SD, 11.51), median 5 years after diagnosis. A majority (63.91%) reported experiencing cognitive symptoms with a significant negative quality of life impact. Controlling for age, patients with GIST ≥5 years after diagnosis reported worse cognitive function than those <5 years after diagnosis (p < .05) but did not differ in educational level or IQ. Whereas longer term survivors were more likely to have been treated with tyrosine kinase inhibitor (TKI) therapies, there was no observed association of TKI therapy with self-reported cognitive impairments. CONCLUSIONS A majority of GIST patients report cognitive symptoms that have a negative impact on quality of life, with longer term survivors (≥5 years) tending to report more cognitive impairments. Given the success of TKI therapy to substantially increase overall survival of patients with GIST, addressing CRCI in clinical practice may improve long-term GIST survivor function and quality of life.
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Affiliation(s)
- Robert J. Ferguson
- Biobehavioral Cancer Control ProgramUPMC Hillman Cancer CenterPittsburghPennsylvaniaUSA,Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
| | - Jessica Manculich
- Biobehavioral Cancer Control ProgramUPMC Hillman Cancer CenterPittsburghPennsylvaniaUSA
| | - Hsuan Chang
- Biobehavioral Cancer Control ProgramUPMC Hillman Cancer CenterPittsburghPennsylvaniaUSA,Present address:
Hsuan Chang does not currently have an academic or corporate affiliation
| | - Nikita J. Sareen
- Biobehavioral Cancer Control ProgramUPMC Hillman Cancer CenterPittsburghPennsylvaniaUSA,Cancer Therapeutics ProgramUPMC Hillman Cancer CenterPittsburghPennsylvaniaUSA,Present address:
University of Florida, College of MedicineGainesvilleFloridaUSA
| | - Beth E. Snitz
- Department of NeurologyUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
| | - Lauren Terhorst
- School of Health and Rehabilitation Sciences Data CenterUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Dana H. Bovbjerg
- Biobehavioral Cancer Control ProgramUPMC Hillman Cancer CenterPittsburghPennsylvaniaUSA,Department of PsychiatryUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
| | - Anette U. Duensing
- Cancer Therapeutics ProgramUPMC Hillman Cancer CenterPittsburghPennsylvaniaUSA,Department of PathologyUniversity of Pittsburgh School of MedicinePittsburghPennsylvaniaUSA
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18
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Blay JY, Duffaud F, George S, Maki RG, Penel N. Regorafenib for the Treatment of Sarcoma. Curr Treat Options Oncol 2022; 23:1477-1502. [PMID: 36178573 DOI: 10.1007/s11864-022-00990-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2022] [Indexed: 01/30/2023]
Abstract
OPINION STATEMENT Sarcomas are a rare group of tumors with many subtypes, conventionally classified into soft-tissue sarcomas and bone sarcomas. Chemotherapeutic regimens form the mainstay of systemic therapy but are not well defined beyond the first-line setting and clinical outcomes are variable. Tyrosine kinase inhibitors (TKIs), with a broad inhibition profile which have been shown to target tumor angiogenesis, have an established role in the treatment of sarcomas without characteristic driver alterations. One such TKI, regorafenib, has been evaluated in sarcomas and clinical data are discussed in this review. An overview of regorafenib data from five phase 2 and one phase 1b clinical trials in over 10 sarcoma subtypes (both soft-tissue and bone) in adult and pediatric patients is reviewed. Regorafenib demonstrated clinical benefit in patients with non-adipocytic soft-tissue sarcomas, osteosarcoma and Ewing sarcoma who had progressed on prior therapy. Patients with otherwise limited treatment options may therefore benefit from regorafenib therapy.
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Affiliation(s)
- Jean-Yves Blay
- Department of Medicine, Léon Bérard Center, Lyon, France.
| | - Florence Duffaud
- Medical Oncology Unit, La Timone University Hospital, Marseille, France.,Aix Marseille University (AMU), Marseille, France
| | - Suzanne George
- Dana-Farber Cancer Institute, Harvard Medical School, Cambridge, MA, USA
| | - Robert G Maki
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicolas Penel
- Medical Oncology Department, Oscar Lambret Cancer Center and Lille University, Lille, France
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19
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Treiber H, von der Brelie C, Malinova V, Mielke D, Rohde V, Chapuy CI. Regorafenib for recurrent high-grade glioma: a unicentric retrospective analysis of feasibility, efficacy, and toxicity. Neurosurg Rev 2022; 45:3201-3208. [PMID: 35725846 PMCID: PMC9492606 DOI: 10.1007/s10143-022-01826-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 05/13/2022] [Accepted: 06/07/2022] [Indexed: 02/03/2023]
Abstract
We describe here 11 consecutive patients with recurrence of high-grade glioma treated with regorafenib at our university medical center. The majority of patients had MGMT promoter methylation (9/11 cases). Regorafenib was given as 2nd line systemic treatment in 6/11 patients and 3rd or higher line treatment in 5/11 patients. The median number of applied cycles was 2 with dosage reductions in 5/11. Response to treatment was observed in 4/11 (PR in 1/11, and SD in 3/11). Median overall survival for the cohort was 16.1 months, median progression-free survival 9.0 months, and median time to treatment failure 3.3 months. Side effects of any CTCAE grade were noted in all patients, hereby 6/11 with CTCAE °III-IV reactions. High-grade side effects were of dermatologic, cardiovascular, and hematologic nature. A mean treatment delay of 57.5 days (range 23-119) was noted between tumor board recommendation and treatment initiation due to the application process for off-label use in this indication. In conclusion, treatment with regorafenib in relapsed high-grade glioma is a feasible treatment option but has to be considered carefully due to the significant side effect profile.
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Affiliation(s)
- Hannes Treiber
- Department of Hematology and Medical Oncology, University Medicine Göttingen, Robert-Koch-Straße 40, 37075, Göttingen, Germany.
| | | | - Vesna Malinova
- Department of Neurosurgery, University Medicine Göttingen, Göttingen, Germany
| | - Dorothee Mielke
- Department of Neurosurgery, University Medicine Göttingen, Göttingen, Germany
| | - Veit Rohde
- Department of Neurosurgery, University Medicine Göttingen, Göttingen, Germany
| | - Claudia Ilse Chapuy
- Department of Hematology and Medical Oncology, University Medicine Göttingen, Robert-Koch-Straße 40, 37075, Göttingen, Germany
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20
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Khachatryan V, Muazzam A, Hamal C, Velugoti LSDR, Tabowei G, Gaddipati GN, Mukhtar M, Alzubaidee MJ, Dwarampudi RS, Mathew S, Bichenapally S, Mohammed L. The Role of Regorafenib in the Management of Advanced Gastrointestinal Stromal Tumors: A Systematic Review. Cureus 2022; 14:e28665. [PMID: 36199644 PMCID: PMC9526434 DOI: 10.7759/cureus.28665] [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: 07/26/2022] [Accepted: 09/01/2022] [Indexed: 11/20/2022] Open
Abstract
Regorafenib, a multi-kinase inhibitor, has been widely used to treat patients with gastrointestinal stromal tumors (GIST) who failed the initial treatment with imatinib and sunitinib. This systematic review aims to demonstrate the efficacy and safety of regorafenib for patients with metastatic and/or unresectable GIST. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to perform this systematic review. We searched PubMed, Science Direct, and Cochrane databases to identify relevant articles based on predefined selection criteria. The implication of the search strategy results in 776 records from all databases. We excluded conference abstracts, discussion articles, case reports, case series, systematic reviews, and other observational non-intervention studies from the study, along with the articles published in languages other than English. After the screening and quality assessment, 10 studies were selected for final review - two randomized controlled trials and eight non-randomized prospective and retrospective review articles of intervention. Regorafenib improved the survival rates of patients after the failure of imatinib and sunitinib treatment, with an acceptable safety profile. Close monitoring of the patients may be needed to detect and manage the grade 4 or higher adverse events.
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Affiliation(s)
- Vahe Khachatryan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Asmaa Muazzam
- Pathology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Chandani Hamal
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Godfrey Tabowei
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Greeshma N Gaddipati
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Maria Mukhtar
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Mohammed J Alzubaidee
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | | | - Sheena Mathew
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Sumahitha Bichenapally
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Lubna Mohammed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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21
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Sun Y, Yue L, Xu P, Hu W. An overview of agents and treatments for PDGFRA-mutated gastrointestinal stromal tumors. Front Oncol 2022; 12:927587. [PMID: 36119525 PMCID: PMC9471148 DOI: 10.3389/fonc.2022.927587] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 08/15/2022] [Indexed: 11/25/2022] Open
Abstract
Platelet-derived growth factor receptor A (PDGFRA) mutations occur in approximately 10-15% of gastrointestinal stromal tumors (GISTs). These tumors with PDGFRA mutations have a different pathogenesis, clinical characteristics, and treatment response compared to tumors with receptor tyrosine kinase protein (KIT) mutations (60-70%). Many clinical studies have investigated the use of tyrosine kinase inhibitors mainly in patients with KIT mutations; however, there is a lack of attention to the PDGFRA-mutated molecular subtype. The main effective inhibitors of PDGFRA are ripretinib, avapritinib, and crenolanib, and their mechanisms and efficacy in GIST (as confirmed in clinical trials) are described in this review. Some multi-targeted tyrosine kinase inhibitors with inhibitory effects on this molecular subtype are also introduced and summarized in this paper. This review focuses on PDGFRA-mutated GISTs, introduces their clinical characteristics, downstream molecular signaling pathways, and existing resistance mechanisms. We focus on the most recent literature that describes the development of PDGFRA inhibitors and their use in clinical trials, as well as the potential benefits from different combination therapy strategies.
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Affiliation(s)
- Yingchao Sun
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Lei Yue
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
| | - Pengfu Xu
- Department of Gastrointestinal Surgery, Taizhou Hospital, Zhejiang University, Taizhou, China
| | - Weiling Hu
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Medical School, Zhejiang University, Hangzhou, China
- Institute of Gastroenterology, Zhejiang University (IGZJU), Hangzhou, China
- Zhejiang University Cancer Center, Hangzhou, China
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22
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Regua AT, Najjar M, Lo HW. RET signaling pathway and RET inhibitors in human cancer. Front Oncol 2022; 12:932353. [PMID: 35957881 PMCID: PMC9359433 DOI: 10.3389/fonc.2022.932353] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Rearranged during transfection (RET) receptor tyrosine kinase was first identified over thirty years ago as a novel transforming gene. Since its discovery and subsequent pathway characterization, RET alterations have been identified in numerous cancer types and are most prevalent in thyroid carcinomas and non-small cell lung cancer (NSCLC). In other tumor types such as breast cancer and salivary gland carcinomas, RET alterations can be found at lower frequencies. Aberrant RET activity is associated with poor prognosis of thyroid and lung carcinoma patients, and is strongly correlated with increased risk of distant metastases. RET aberrations encompass a variety of genomic or proteomic alterations, most of which confer constitutive activation of RET. Activating RET alterations, such as point mutations or gene fusions, enhance activity of signaling pathways downstream of RET, namely PI3K/AKT, RAS/RAF, MAPK, and PLCγ pathways, to promote cell proliferation, growth, and survival. Given the important role that mutant RET plays in metastatic cancers, significant efforts have been made in developing inhibitors against RET kinase activity. These efforts have led to FDA approval of Selpercatinib and Pralsetinib for NSCLC, as well as, additional selective RET inhibitors in preclinical and clinical testing. This review covers the current biological understanding of RET signaling, the impact of RET hyperactivity on tumor progression in multiple tumor types, and RET inhibitors with promising preclinical and clinical efficacy.
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Affiliation(s)
- Angelina T. Regua
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Mariana Najjar
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States
| | - Hui-Wen Lo
- Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, United States
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC, United States
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23
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Dudzisz-Śledź M, Klimczak A, Bylina E, Rutkowski P. Treatment of Gastrointestinal Stromal Tumors (GISTs): A Focus on Younger Patients. Cancers (Basel) 2022; 14:2831. [PMID: 35740497 PMCID: PMC9221273 DOI: 10.3390/cancers14122831] [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: 05/21/2022] [Revised: 06/05/2022] [Accepted: 06/06/2022] [Indexed: 01/27/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) originate from Cajal's cells and are the most common mesenchymal neoplasms of the gastrointestinal tract. GISTs in young adults, i.e., patients before the age of 40, are rare and differ from those in older patients and GISTs in children in terms of the molecular and clinical features, including the location and type of mutations. They often harbor other molecular abnormalities than KIT and PDGFRA mutations (wild-type GISTs). The general principles of therapeutic management in young patients are the same as in the elderly. Considering some differences in molecular abnormalities, molecular testing should be the standard procedure to allow appropriate systemic therapy if needed. The optimal treatment strategy should be established by a multidisciplinary team experienced in sarcoma treatment. The impact of treatment on the quality of life and daily activities, including the impact on work, pregnancy, and fertility, in this patient population should be especially taken into consideration.
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Affiliation(s)
- Monika Dudzisz-Śledź
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781 Warsaw, Poland; (A.K.); (E.B.); (P.R.)
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Targeting the translational machinery in gastrointestinal stromal tumors (GIST): a new therapeutic vulnerability. Sci Rep 2022; 12:8275. [PMID: 35585158 PMCID: PMC9117308 DOI: 10.1038/s41598-022-12000-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 04/27/2022] [Indexed: 01/13/2023] Open
Abstract
Although KIT-mutant GISTs can be effectively treated with tyrosine kinase inhibitors (TKIs), many patients develop resistance to imatinib mesylate (IM) as well as the FDA-approved later-line agents sunitinib, regorafenib and ripretinib. Resistance mechanisms mainly involve secondary mutations in the KIT receptor tyrosine kinase gene indicating continued dependency on the KIT signaling pathway. The fact that the type of secondary mutation confers either sensitivity or resistance towards TKIs and the notion that secondary mutations exhibit intra- and intertumoral heterogeneity complicates the optimal choice of treatment in the imatinib-resistant setting. Therefore, new strategies that target KIT independently of its underlying mutations are urgently needed. Homoharringtonine (HHT) is a first-in-class inhibitor of protein biosynthesis and is FDA-approved for the treatment of chronic myeloid leukemia (CML) that is resistant to at least two TKIs. HHT has also shown activity in KIT-mutant mastocytosis models, which are intrinsically resistant to imatinib and most other TKIs. We hypothesized that HHT could be effective in GIST through downregulation of KIT expression and subsequent decrease of KIT activation and downstream signaling. Testing several GIST cell line models, HHT led to a significant reduction in nascent protein synthesis and was highly effective in the nanomolar range in IM-sensitive and IM-resistant GIST cell lines. HHT treatment resulted in a rapid and complete abolishment of KIT expression and activation, while KIT mRNA levels were minimally affected. The response to HHT involved induction of apoptosis as well as cell cycle arrest. The antitumor activity of HHT was confirmed in a GIST xenograft model. Taken together, inhibition of protein biosynthesis is a promising strategy to overcome TKI resistance in GIST.
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25
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Teranishi R, Takahashi T, Nishida T, Hirota S, Kurokawa Y, Saito T, Yamamoto K, Yamashita K, Tanaka K, Makino T, Motoori M, Omori T, Nakajima K, Eguchi H, Doki Y. Efficacy and safety of regorafenib in Japanese patients with advanced gastrointestinal stromal tumors. Int J Clin Oncol 2022; 27:1164-1172. [PMID: 35435530 DOI: 10.1007/s10147-022-02159-z] [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] [Received: 11/23/2021] [Accepted: 03/29/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND Regorafenib is an oral multi-kinase inhibitor that has been established as third-line treatment for patients after the failure of imatinib and sunitinib. However, since clinical data of regorafenib in the Japanese population are still lacking, the management of regorafenib is mainly based on the clinical experience of each oncologist. The aim of this study was to evaluate the efficacy and safety of regorafenib in a Japanese population. METHODS Thirty-three patients treated with regorafenib for metastatic and recurrent gastrointestinal stromal tumors were retrospectively enrolled. This study investigated the anti-tumor effect, including overall survival, progression-free survival, and safety, which was evaluated based on the incidence of adverse events. RESULTS The median overall survival of patients treated with regorafenib was 23.8 months and the 1-year overall survival rate was 80.0%, the median progression-free survival was 7.1 months and the 1-year progression-free survival rate was 40.2%. The responses to regorafenib were partial response in 3 cases (9.1%), stable disease in 17 (51.5%), progressive disease in 10 (30.3%), and non-evaluable in 3 (9.1%). The disease control rate was 54.0%. Treatment-related adverse events were reported in all patients, with the most common being hand-foot syndrome (72.7%), followed by liver damage (36.4%) and diarrhea (27.3%), and six patients (20.0%) were discontinued due to adverse events. CONCLUSION This is the first report of Japanese patients with gastrointestinal stromal tumors treated with regorafenib. Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced gastrointestinal stromal tumors, which was comparable with previous studies.
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Affiliation(s)
- Ryugo Teranishi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan.
| | - Toshirou Nishida
- Department of Surgery, Japan Community Health Care Organization Osaka Hospital, 4-2-78, Fukushima-ku, Osaka City, Osaka, 553-0003, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Hyogo, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
| | - Takuro Saito
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
| | - Kazuyoshi Yamamoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
| | - Kotaro Yamashita
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
| | - Koji Tanaka
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
| | - Masaaki Motoori
- Department of Surgery, Osaka General Medical Center, 3-1-56, Bandai-Higashi, Sumiyoshi-ku, Osaka City, Osaka, 558-8558, Japan
| | - Takeshi Omori
- Department of Surgery, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka City, Osaka, 541-8567, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita-City, Osaka, 565-0871, Japan
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26
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Khan TM, Verbus EA, Rossi AJ, Hernandez JM, Davis JL, Coakley BA, Blakely AM. Patient demographics, clinicopathologic features, and outcomes in wild-type gastrointestinal stromal tumor: a national cohort analysis. Sci Rep 2022; 12:5774. [PMID: 35388076 PMCID: PMC8987058 DOI: 10.1038/s41598-022-09745-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 03/08/2022] [Indexed: 11/09/2022] Open
Abstract
Wild-type KIT and PDGFRA gastrointestinal stromal tumors (GIST) are rare tumors with limited treatment options. We sought to determine the clinicopathologic features of wild-type GIST and identify factors that influence overall survival (OS) using a large national database. Retrospective evaluation of patients with wild-type GIST in the National Cancer Database (NCDB) was performed. Demographic, clinicopathologic, and treatment data were analyzed. Features associated with OS were investigated using Kaplan-Meier analysis and Cox proportional hazards model. 244 patients with median diagnosis age of 59 years (95% CI 57-63) were identified. The stomach was the most common primary site (57%) followed by the small intestine (35%). Surgical resection was performed on 85% of patients and 53% of patients received systemic therapy. Factors associated with decreased OS on multivariable analysis included small intestine primary (HR 2.72, 95% CI 1.13-6.69, P = 0.026) and > 5 mitoses per 50 HPF (HR 4.77, 95% CI 1.86-13.2, P = 0.001). Wild-type GISTs may be identified in older patients, with most arising in the stomach and small bowel. Surgery remains the principal treatment modality. Small intestine primary site and high mitotic count were associated with abbreviated OS.
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Affiliation(s)
- Tahsin M Khan
- Surgical Oncology Program, National Cancer Institute, Bethesda, MD, USA.,Department of Surgery, The Mount Sinai Hospital, New York, NY, USA
| | - Emily A Verbus
- Surgical Oncology Program, National Cancer Institute, Bethesda, MD, USA
| | - Alexander J Rossi
- Surgical Oncology Program, National Cancer Institute, Bethesda, MD, USA
| | | | - Jeremy L Davis
- Surgical Oncology Program, National Cancer Institute, Bethesda, MD, USA
| | - Brian A Coakley
- Department of Surgery, The Mount Sinai Hospital, New York, NY, USA
| | - Andrew M Blakely
- Surgical Oncology Program, National Cancer Institute, 9000 Rockville Pike Building 10, Room 4-3760, Bethesda, MD, 20892, USA.
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van de Wal D, Elie M, Le Cesne A, Fumagalli E, den Hollander D, Jones RL, Marquina G, Steeghs N, van der Graaf WTA, Husson O. Health-Related Quality of Life and Side Effects in Gastrointestinal Stromal Tumor (GIST) Patients Treated with Tyrosine Kinase Inhibitors: A Systematic Review of the Literature. Cancers (Basel) 2022; 14:cancers14071832. [PMID: 35406604 PMCID: PMC8997462 DOI: 10.3390/cancers14071832] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/30/2022] [Accepted: 04/01/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of gastrointestinal stromal tumors (GISTs), resulting in a substantial gain in median overall survival. Subsequently, health-related quality of life (HRQoL) has become more relevant. Here, we systematically review the available literature on HRQoL issues and side effects of different TKIs registered for the treatment of GIST. METHODS A search through five databases was performed. Full reports in English describing HRQoL outcomes and/or side effects in GIST patients on TKI therapy were included. RESULTS A total of 104 papers were included; 13 studies addressed HRQoL, and 96 studies investigated adverse events. HRQoL in patients treated with imatinib, regorafenib, and ripretinib remained stable, whereas most sunitinib-treated patients reported a decrease in HRQoL. Severe fatigue and fear of recurrence or progression were specifically assessed as HRQoL issues and had a negative impact on overall HRQoL as well as psychological and physical well-being. The majority of studies focused on physician-reported side effects. Nearly all GIST patients treated with a TKI experienced at least one adverse event, mostly mild to moderate. CONCLUSIONS Despite the fact that almost all patients treated with a TKI experienced side effects, this did not seem to affect overall HRQoL during TKI therapy. In daily practice, it are the side effects that hamper a patient's HRQoL resulting in treatment adjustments, suggesting that the reported side effects were underestimated by physicians, or the measures used to assess HRQoL do not capture all relevant issues that determine a GIST patient's HRQoL.
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Affiliation(s)
- Deborah van de Wal
- Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands; (D.v.d.W.); (N.S.); (W.T.A.v.d.G.)
| | - Mai Elie
- Department of Medical Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (M.E.); (D.d.H.)
| | - Axel Le Cesne
- Department of Medical Oncology, Gustave Roussy, 94805 Villejuif, France;
| | - Elena Fumagalli
- Department of Medical Oncology, IRCCS Foundation National Cancer Institute, 20133 Milan, Italy;
| | - Dide den Hollander
- Department of Medical Oncology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands; (M.E.); (D.d.H.)
| | - Robin L. Jones
- Department of Clinical Oncology, The Royal Marsden Hospital and Institute of Cancer Research, London SM2 5 NG, UK;
| | - Gloria Marquina
- Department of Medical Oncology, Hospital Clinico San Carlos, 28040 Madrid, Spain;
| | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands; (D.v.d.W.); (N.S.); (W.T.A.v.d.G.)
- Department of Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands
| | - Winette T. A. van der Graaf
- Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands; (D.v.d.W.); (N.S.); (W.T.A.v.d.G.)
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
| | - Olga Husson
- Department of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands; (D.v.d.W.); (N.S.); (W.T.A.v.d.G.)
- Department of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, The Netherlands
- Division of Clinical Studies, Institute of Cancer Research, London SM2 5NG, UK
- Correspondence: ; Tel.: +31-614-549-755
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Liu R, Wu Y, Gong J, Zhao R, Li L, Wan Q, Lian N, Shen X, Xia L, Shen Y, Xiao H, Wu X, Chen Y, Cen Y, Xu X. Development and external validation of a nomogram for individualized adjuvant imatinib duration for high-risk gastrointestinal stromal tumors: A multicenter retrospective cohort study. Cancer Med 2022; 11:3093-3105. [PMID: 35297216 PMCID: PMC9385591 DOI: 10.1002/cam4.4673] [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: 08/13/2021] [Revised: 01/13/2022] [Accepted: 02/28/2022] [Indexed: 02/05/2023] Open
Abstract
Introduction The main emphasis of the research about adjuvant imatinib for high‐risk gastrointestinal stromal tumors (GISTs) is prolonging the treatment duration and ignores the heterogeneous that 10‐year recurrence rates ranged from about 20%–100%. Thus, this study evaluated the effect of different durations of adjuvant imatinib on outcomes in high‐risk GISTs to explore the feasibility of individual treatment. Methods We analyzed 855 high‐risk GIST patients from three centers who underwent macroscopically complete resection between December 2007 and September 2020. The patients were divided into training (n =564) and two validation cohorts (n = 238 and53) based on their source. Recurrence‐free survival (RFS) was the primary point. Cox multivariate analysis was used to develop the nomogram. C‐index, time‐dependent area under the curves, and calibration plots were used to assess the performance of the nomogram. Results Univariate analysis showed that longer adjuvant imatinib was significantly associated with better 5‐year RFS (p < 0.0001). Further investigation identified that the same high‐risk patients with lower tumor‐associated recurrence risk benefitted little from prolonged treatment and that the recommended adjuvant imatinib duration was insufficient for those with higher recurrence risk. A nomogram for predicting 2‐, 3‐, and 5‐year RFS based on different treatment durations and four major risk factors, namely, tumor site, size, mitotic count, and rupture status, was built and validated, with a C‐index of 0.82, 0.74, and 0.70 in training and two external validation cohorts, respectively. An online dynamic nomogram was further developed for clinical applications (https://ruolinliu666.shinyapps.io/GIST/), offering predictive recurrence rates based on different treatment durations and tumor features. Conclusions We developed a nomogram to predict the recurrence risk for high‐risk patients according to tumor features and treatment durations of imatinib to help physicians on decision‐making for individualized treatment duration.
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Affiliation(s)
- Ruolin Liu
- Department of Burn and Plastic Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Yingxin Wu
- Department of General Surgery, Center of Gastrointestinal and Minimally Invasive Surgery, The Third People's Hospital of Chengdu, Affiliated Hospital of Southwest Jiaotong University & The Second Affiliated Hospital of Chengdu, Chongqing Medical University, Chengdu, China
| | - Jin Gong
- Research and Education Department, Sichuan Friendship Hospital, Chengdu, China
| | - Rui Zhao
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China.,Laboratory of Mitochondrial and Metabolism, West China Hospital of Sichuan University, Chengdu, China
| | - Li Li
- Research and Education Department, Sichuan Friendship Hospital, Chengdu, China
| | - Qianyi Wan
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Nan Lian
- Laboratory of Mitochondrial and Metabolism, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoding Shen
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Lin Xia
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Yuhou Shen
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Haitao Xiao
- Department of Burn and Plastic Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Xiaoting Wu
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Yi Chen
- Department of Gastrointestinal Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Ying Cen
- Department of Burn and Plastic Surgery, West China Hospital of Sichuan University, Chengdu, China
| | - Xuewen Xu
- Department of Burn and Plastic Surgery, West China Hospital of Sichuan University, Chengdu, China
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29
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Brinch CM, Aggerholm-Pedersen N, Hogdall E, Krarup-Hansen A. Medical Oncological Treatment for Patients with Gastrointestinal Stromal Tumour (GIST) - a Systematic Review. Crit Rev Oncol Hematol 2022; 172:103650. [PMID: 35283299 DOI: 10.1016/j.critrevonc.2022.103650] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 02/11/2022] [Accepted: 03/07/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Chemotherapy is ineffective in treating patients with Gastrointestinal Stromal Tumour (GIST). However, several types of tyrosine kinase inhibitors have been investigated since the approval of imatinib in 2001. The purpose of this report was to systematically review studies on the efficacy of neoadjuvant, adjuvant, and lifelong medical oncological treatment of GIST. METHODS The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed throughout the review process. The protocol was submitted to the International prospective register of systematic reviews database (ID 251724). A systematic literature search was performed, including phase II- and III studies of biological treatment, reporting on treatment effect in patients with GIST. RESULTS Of 308 identified publications, 42 studies were included in this review. CONCLUSION This review gives an overview of the existing evidence for approved lines of oncological treatments and potential alternatives for patients with GIST in the neoadjuvant-, adjuvant- and life-long setting.
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Affiliation(s)
- Charlotte Margareta Brinch
- Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 1, DK-2730, Herlev.
| | - Ninna Aggerholm-Pedersen
- Department of Oncology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200, Aarhus, Denmark.
| | - Estrid Hogdall
- Department of Pathology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 73, DK-2730, Herlev, Denmark.
| | - Anders Krarup-Hansen
- Department of Oncology, Copenhagen University Hospital, Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 1, DK-2730, Herlev.
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30
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Foo T, Goldstein D, Segelov E, Shapiro J, Pavlakis N, Desai J, Yip D, Zalcberg J, Price TJ, Nagrial A, Chantrill L, Burge M, Karapetis CS, Tebbutt N, Roy AC. The Management of Unresectable, Advanced Gastrointestinal Stromal Tumours. Target Oncol 2022; 17:95-110. [PMID: 35290591 PMCID: PMC8995292 DOI: 10.1007/s11523-022-00869-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2022] [Indexed: 12/11/2022]
Abstract
Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.
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Affiliation(s)
- Tiffany Foo
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia
| | - David Goldstein
- Department of Medical Oncology, Prince of Wales Hospital, University of NSW, Sydney, NSW, Australia
| | - Eva Segelov
- Department of Medical Oncology, School of Clinical Sciences, Monash University and Monash Health, Melbourne, VIC, Australia
| | - Jeremy Shapiro
- Cabrini Health, Monash University, Melbourne, VIC, Australia
| | - Nick Pavlakis
- Department of Medical Oncology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia
| | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Desmond Yip
- Department of Medical Oncology, Canberra Region Cancer Centre, The Canberra Hospital, Canberra, ACT, Australia
| | - John Zalcberg
- Alfred Health, Monash University, Melbourne, VIC, Australia
| | - Timothy J Price
- The Queen Elizabeth Hospital/University of Adelaide, Adelaide, SA, Australia
| | - Adnan Nagrial
- Department of Medical Oncology, Westmead and Blacktown Hospitals, University of Sydney, Sydney, NSW, Australia
| | - Lorraine Chantrill
- Department of Medical Oncology, Wollongong Hospital, Illawarra Shoalhaven Local Health District, Illawarra, NSW, Australia
| | - Matt Burge
- Department of Cancer Care Services, Royal Brisbane Hospital, University of Queensland, Herston, QLD, Australia
| | - Christos S Karapetis
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia
| | - Niall Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - Amitesh C Roy
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia.
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Ishida T, Takahashi T, Nishida T, Ohnishi H, Tsuboyama T, Sato S, Nakahara Y, Miyazaki Y, Takeno A, Kurokawa Y, Saito T, Yamashita K, Tanaka K, Yamamoto K, Makino T, Yamasaki M, Motoori M, Kimura Y, Nakajima K, Eguchi H, Doki Y. New response evaluation criteria using early morphological change in imatinib treatment for patients with gastrointestinal stromal tumor. Gastric Cancer 2022; 25:218-225. [PMID: 34417657 DOI: 10.1007/s10120-021-01234-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 08/11/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND The introduction of molecularly targeted drugs, including imatinib, has greatly improved the prognosis of gastrointestinal stromal tumor (GIST), and based on the different response image, the methods of response evaluation have been established for GISTs. Furthrmore, the best response evaluation using them has been reported to be associated with progression-free survival (PFS) in imatinib treatment. However, since it is more important to predict the clinical outcomes of imatinib treatment in "early treatment phase", new predicting factor in earlier stage is desired to work out the whole strategy of each patient. Early morphological change (EMC) was previously reported as a predictive marker for molecularly targeted drugs in metastatic colorectal cancer. The purpose of the present study was to verify the efficacy of EMC in predicting the outcome in patients with GIST receiving imatinib at early evaluation. METHODS We retrospectively reviewed 66 patients. EMC in computed tomography (CT) image was evaluated, and the patients were categorized into two groups: active MR (morphological response) (+) group and active MR (-) group. We investigated the association between the presence of active MR and clinical outcomes. RESULTS Forty-five patients had active MR ( +). The median progression-free survival (PFS) in patients with/without active MR was 49/23 months (P = 0.0039). CONCLUSION The evaluation criteria based on EMC could be a sensitive method to predict the clinical outcome of imatinib treatment for patients with unresectable GIST.
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Affiliation(s)
- Tomo Ishida
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Toshirou Nishida
- Department of Surgery, Japan Community Health Care Organization Osaka Hospital, 4-2-78, Fukushima, Fukushima-ku, Osaka, Japan
| | - Hiromitsu Ohnishi
- Department of Radiology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takahiro Tsuboyama
- Department of Radiology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shinsuke Sato
- Department of Gastroenterological Surgery, Shizuoka General Hospital, 4-27-1, Kita Ando Aoi-ku, Shizuoka, Japan
| | - Yujiro Nakahara
- Department of Gastroenterological Surgery, Osaka Police Hospital, 10-31Kitayama-choTennouji-ku, Osaka, Japan
| | - Yasuhiro Miyazaki
- Department of Surgery, Osaka General Medical Center, 3-1-56, Bandai-Higashi, Sumiyoshi-ku, Osaka, Japan
| | - Atsushi Takeno
- Departmrent of Surgery, Kansai Rosai Hospital, 3-1-69, Inabaso, Amagasaki, Hyogo, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takuro Saito
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kotaro Yamashita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Koji Tanaka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazuyoshi Yamamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Makoto Yamasaki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Masaaki Motoori
- Department of Surgery, Osaka General Medical Center, 3-1-56, Bandai-Higashi, Sumiyoshi-ku, Osaka, Japan
| | - Yutaka Kimura
- Department of Surgery, Kinki University Faculty of Medicine, 377-2, Ohno-Higashi, Sayama, Osaka, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamadaoka, Suita, Osaka, 565-0871, Japan
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Van den Abbeele AD, Sakellis CG, George S. PET imaging of Gastrointestinal Stromal Tumors (GIST). Nucl Med Mol Imaging 2022. [DOI: 10.1016/b978-0-12-822960-6.00110-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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33
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Moati E, Taly V, Garinet S, Didelot A, Taieb J, Laurent-Puig P, Zaanan A. Role of Circulating Tumor DNA in Gastrointestinal Cancers: Current Knowledge and Perspectives. Cancers (Basel) 2021; 13:4743. [PMID: 34638228 PMCID: PMC8507552 DOI: 10.3390/cancers13194743] [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: 07/23/2021] [Revised: 09/06/2021] [Accepted: 09/18/2021] [Indexed: 12/21/2022] Open
Abstract
Gastrointestinal (GI) cancers are major health burdens worldwide and biomarkers are needed to improve the management of these diseases along their evolution. Circulating tumor DNA (ctDNA) is a promising non-invasive blood and other bodily-fluid-based biomarker in cancer management that can help clinicians in various cases for the detection, diagnosis, prognosis, monitoring and personalization of treatment in digestive oncology. In addition to the well-studied prognostic role of ctDNA, the main real-world applications appear to be the assessment of minimal residual disease to further guide adjuvant therapy and predict relapse, but also the monitoring of clonal evolution to tailor treatments in metastatic setting. Other challenges such as predicting response to treatment including immune checkpoint inhibitors could also be among the potential applications of ctDNA. Although the level of advancement of ctDNA development in the different tumor localizations is still inhomogeneous, it might be now reliable enough to be soon used in clinical routine for colorectal cancers and shows promising results in other GI cancers.
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Affiliation(s)
- Emilie Moati
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
| | - Valerie Taly
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Simon Garinet
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
- Department of Biochemistry, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France
| | - Audrey Didelot
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
| | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
- Department of Biochemistry, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, Institut du Cancer Paris Carpem, Assistance Publique des Hôpitaux de Paris, European Georges Pompidou Hospital, 75015 Paris, France; (E.M.); (J.T.)
- Centre de Recherche des Cordeliers, INSERM UMRS1138, Centre National de la Recherche Scientifique, Sorbonne Université, USPC, Université de Paris, Equipe Labellisée Ligue Nationale Contre le Cancer, CNRS SNC 5096, 75006 Paris, France; (V.T.); (S.G.); (A.D.); (P.L.-P.)
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Luo T, Zhang FX, Zhao K, Gao HY, Zhang SG, Wang L, Dou GF, Liu T, Yu M, Zhan YQ, Chen H, Yang XM, Li CY. Preclinical Pharmacokinetics, Tissue Distribution, and Primary Safety Evaluation of Indo5, a Novel Selective Inhibitor of c-Met and Trks. Front Pharmacol 2021; 12:711126. [PMID: 34447310 PMCID: PMC8383318 DOI: 10.3389/fphar.2021.711126] [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: 05/18/2021] [Accepted: 07/30/2021] [Indexed: 11/17/2022] Open
Abstract
The compound [3-(1H-benzimidazol-2-methylene)-5-(2-methylphenylaminosulfo)-2-indolone], known as Indo5, is a novel selective inhibitor of c-Met and Trks, and it is a promising anticancer candidate against hepatocellular carcinoma (HCC). Assessing the pharmacokinetic properties, tissue distribution, and toxicity of Indo5 is critical for its medicinal evaluation. A series of sensitive and specific liquid chromatography-tandem mass spectrometry methods were developed and validated to determine the concentration of Indo5 in rat plasma and tissue homogenates. These methods were then applied to investigate the pharmacokinetics and tissue distribution of Indo5 in rats. After intravenous injection of Indo5, the maximum concentration (Cmax) and the time at which Cmax was reached (Tmax) were 1,565.3 ± 286.2 ng/ml and 1 min, respectively. After oral administration, Cmax and Tmax were 54.7 ± 10.4 ng/ml and 2.0 ± 0.48 h, respectively. We calculated the absolute oral bioavailability of Indo5 in rats to be 1.59%. Following intravenous injection, the concentrations of Indo5 in various tissues showed the following order: liver > kidney ≈ heart > lung ≈ large intestine ≈ small intestine ≈ stomach > spleen > brain ≈ testes; hence, Indo5 distributed highest in the liver and could not cross the blood–brain or blood–testes barriers. Continuous injection of Indo5 for 21 days did not lead to liver injury, considering unchanged ALT and AST levels, normal histological architecture of the liver, and normal number and frequencies of immune cells in the liver, indicating a very low toxicity of Indo5 in vivo. Collectively, our findings provide a comprehensive understanding of the biological actions of Indo5 in vivo and further support its development as an antitumor treatment for HCC patients.
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Affiliation(s)
- Teng Luo
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.,Beijing Institute of Radiation Medicine, Beijing, China.,Institute of NBC Defence, Beijing, China
| | - Fei-Xiang Zhang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Ke Zhao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Hui-Ying Gao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | | | - Lin Wang
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Gui-Fang Dou
- Beijing Institute of Radiation Medicine, Beijing, China
| | - Ting Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, China
| | - Miao Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Yi-Qun Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Hui Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
| | - Xiao-Ming Yang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.,Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, China
| | - Chang-Yan Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.,School of Basic Medical Sciences, Anhui Medical University, Hefei, China
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Wang S, Wang C, Wang X, Wang X, Huang L, Kuai J, Wei W, Lu X, Yan S. Antitumor efficacy of CHMFL-KIT-110 solid dispersion in mouse xenograft models of human gastrointestinal stromal tumors. Cancer Chemother Pharmacol 2021; 88:795-804. [PMID: 34309733 DOI: 10.1007/s00280-021-04332-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 06/14/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE CHMFL-KIT-110, a selective c-KIT kinase inhibitor for gastrointestinal stromal tumors (GISTs), possesses a poorly water-soluble, limiting the further development of the drug. This study was to investigate the antitumor efficacy of CHMFL-KIT-110 and CHMFL-KIT-110 solid dispersion (laboratory code: HYGT-110 SD) in GIST tumor xenograft models and to explore the PK/PD relationship of HYGT-110 SD. METHODS Plasma concentrations of HYGT-110 and HYGT-110 SD were determined by LC-MS/MS in KM mice. Antitumor activity was evaluated by measuring tumor volume and weight in c-KIT-dependent GIST xenograft models. PK/PD relationship was assessed by LC-MS/MS and Western Blot in the GIST-T1 xenografted mice. RESULTS HYGT-110 exhibited a low oral bioavailability (10.91%) in KM mice. Compared with HYGT-110 treatment, the Cmax and AUC0-t of HYGT-110 SD in mice plasma were substantially increased by 18.81 and 6.76-fold, respectively. HYGT-110 SD (10, 30, and 100 mg/kg/day) also could dose-dependently decrease the tumor volume and weight in the GIST-882 cell-inoculated xenograft mouse models and show 86.35% tumor growth inhibition (TGI) at 28 days at a 25 mg/kg bid dosage in the GIST-T1 cell-inoculated xenograft mouse model. The free concentration of HYGT-110 in plasma was closely correlated with the inhibition of c-KIT phosphorylation levels in tumor tissues. CONCLUSIONS In comparison with the HPMC formulation, both improved PK and PD characteristics of the solid dispersion formulation of CHMFL-KIT-110 were observed in in vivo animal experiments.
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Affiliation(s)
- Shengfu Wang
- Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education; Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, 81 Meishan Road, Hefei, 230032, China
| | - Chunyan Wang
- Hefei Blooming Drug Safety Evaluation Co., Ltd, 358 Ganquan Road, Hefei, 230031, China.,Anhui Province Key Laboratory of Druggability Evaluation for New Drugs, 358 Ganquan Road, Hefei, 230031, China
| | - Xiao Wang
- Hefei Blooming Drug Safety Evaluation Co., Ltd, 358 Ganquan Road, Hefei, 230031, China.,Anhui Province Key Laboratory of Druggability Evaluation for New Drugs, 358 Ganquan Road, Hefei, 230031, China
| | - Xiang Wang
- Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education; Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, 81 Meishan Road, Hefei, 230032, China
| | - Lina Huang
- Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education; Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, 81 Meishan Road, Hefei, 230032, China
| | - Jiajie Kuai
- Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education; Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, 81 Meishan Road, Hefei, 230032, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China.,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education; Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, 81 Meishan Road, Hefei, 230032, China
| | - Xiaorong Lu
- Hefei Blooming Drug Safety Evaluation Co., Ltd, 358 Ganquan Road, Hefei, 230031, China. .,Anhui Province Key Laboratory of Druggability Evaluation for New Drugs, 358 Ganquan Road, Hefei, 230031, China.
| | - Shangxue Yan
- Institute of Clinical Pharmacology, Anhui Medical University, 81 Meishan Road, Hefei, 230032, China. .,Key Laboratory of Anti-Inflammatory and Immune Medicine, Ministry of Education; Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, 81 Meishan Road, Hefei, 230032, China.
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Preseptal cellulitis, intraocular inflammatory reaction and corneal persistent epithelial defect as side effects of avapritinib. Anticancer Drugs 2021; 32:1127-1130. [PMID: 34282744 DOI: 10.1097/cad.0000000000001123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Avapritinib is a tyrosine kinase inhibitor currently being investigated on clinical trials for the treatment of unresectable or metastatic gastrointestinal stromal tumour (GIST). It has been recently approved by the Food and Drug Administration and the European Medicines Agency for the treatment of unresectable or metastatic GIST harbouring PDGFRa Exon 18 mutation and by the European Medicines Agency for the treatments of unresectable or metastatic GIST harbouring the PDGFRa D842V mutation. We report a clinical case of a 76-year-old female, diagnosed with a stage IV GIST, treated with avapritinib 300 mg once daily. through compassionate use who experienced an intraocular side effect not previously reported avapritinib. She developed preseptal cellulitis on her right eye following 2 months of treatment with avapritinib and, subsequently evolved to an intraocular inflammatory reaction and persistent corneal epithelial defect. The treatment with avapritinib was stopped and the patient received corticosteroid and corneal regenerating agents. The symptoms resolved within 1 month and the patient has remained on stable disease at two subsequent adjusted avapritinib doses (100 mg once daily) for over 1 year.
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Bauer S, George S, von Mehren M, Heinrich MC. Early and Next-Generation KIT/PDGFRA Kinase Inhibitors and the Future of Treatment for Advanced Gastrointestinal Stromal Tumor. Front Oncol 2021; 11:672500. [PMID: 34322383 PMCID: PMC8313277 DOI: 10.3389/fonc.2021.672500] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 06/22/2021] [Indexed: 12/21/2022] Open
Abstract
The majority of gastrointestinal stromal tumors (GIST) harbor an activating mutation in either the KIT or PDGFRA receptor tyrosine kinases. Approval of imatinib, a KIT/PDGFRA tyrosine kinase inhibitor (TKI), meaningfully improved the treatment of advanced GIST. Other TKIs subsequently gained approval: sunitinib as a second-line therapy and regorafenib as a third-line therapy. However, resistance to each agent occurs in almost all patients over time, typically due to secondary kinase mutations. A major limitation of these 3 approved therapies is that they target the inactive conformation of KIT/PDGFRA; thus, their efficacy is blunted against secondary mutations in the kinase activation loop. Neither sunitinib nor regorafenib inhibit the full spectrum of KIT resistance mutations, and resistance is further complicated by extensive clonal heterogeneity, even within single patients. To combat these limitations, next-generation TKIs were developed and clinically tested, leading to 2 new USA FDA drug approvals in 2020. Ripretinib, a broad-spectrum KIT/PDGFRA inhibitor, was recently approved for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Avapritinib, a type I kinase inhibitor that targets active conformation, was approved for the treatment of adults with unresectable or metastatic GIST harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. In this review, we will discuss how resistance mutations have driven the need for newer treatment options for GIST and compare the original GIST TKIs with the next-generation KIT/PDGFRA kinase inhibitors, ripretinib and avapritinib, with a focus on their mechanisms of action.
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Affiliation(s)
- Sebastian Bauer
- Department of Medical Oncology, West German Cancer Center, Essen University Hospital, University of Duisburg-Essen, Essen, Germany
| | - Suzanne George
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, United States
| | - Margaret von Mehren
- Department of Hematology and Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, United States
| | - Michael C. Heinrich
- Department of Medicine, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR, United States
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Abstract
PURPOSE OF REVIEW The current article revisits the most recent advances that occurred in the field of gastrointestinal stromal tumor (GIST) therapeutics. RECENT FINDINGS GIST is driven by the oncogenic activation of KIT or PDGFRA receptor tyrosine kinases, and agents targeting these receptors lead to substantial benefit throughout the entire course of the disease. Two new drugs were approved in 2020. On one hand, ripretinib obtained the regulatory approval for the treatment of GIST patients after progression to all standard treatments. On the other hand, avapritinib became the first agent ever displaying activity in GIST driven by the multiresistant PDGFRA D842V mutation. The addition of both drugs to GIST therapeutics constitutes a remarkable milestone, particularly considering that the last agent approved was back in 2012. Similarly, the recent identification of neurotrophic tyrosine receptor kinase (NTRK) fusions in a subset of KIT/PDGFRA wild-type GISTs led to an open window for tailored treatment using specific NTRK inhibitors. Finally, multiple efforts have been made toward the clinical implementation of circulating tumor DNA evaluation to guide clinical decisions in GIST. SUMMARY GIST has been consolidated over the years as a paradigmatic model in personalized medicine for the successful development of novel therapeutic strategies through targeted inhibition of oncogenic drivers.
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Affiliation(s)
- César Serrano
- Department of Medical Oncology, Vall d'Hebron University Hospital
- Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Nannini M, Rizzo A, Indio V, Schipani A, Astolfi A, Pantaleo MA. Targeted therapy in SDH-deficient GIST. Ther Adv Med Oncol 2021; 13:17588359211023278. [PMID: 34262616 PMCID: PMC8246492 DOI: 10.1177/17588359211023278] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/19/2021] [Indexed: 12/30/2022] Open
Abstract
The medical management of advanced gastrointestinal stromal tumors (GIST) has improved with the development of tyrosine kinase inhibitors (TKIs) targeting KIT and PDGFRA mutations. However, approximately 5-10% of GIST lack KIT and PDGFRA mutations, and about a half are deficient in succinate dehydrogenase (SDH) that promotes carcinogenesis by the cytoplasmic accumulation of succinate. This rare group of GIST primarily occurs in the younger patients than other subtypes, and is frequently associated with hereditary syndromes. The role of TKIs in patients with SDH-deficient GIST is controversial, with conflicting results; thus, there is an urgent need to uncover the disease mechanisms, treatment patterns, and responses to systemic therapy among these patients. Here, based on an extensive literature search, we have provided a rigorous overview of the current evidence on the medical treatment of SDH-deficient GIST.
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Affiliation(s)
- Margherita Nannini
- Division of Oncology, IRCSS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Alessandro Rizzo
- Department of Experimental, Diagnostic and Specialized Medicine, University of Bologna, Bologna, Italy
| | - Valentina Indio
- "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Angela Schipani
- Department of Experimental, Diagnostic and Specialized Medicine, University of Bologna, Bologna, Italy
| | - Annalisa Astolfi
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, Ferrara 44121, Italy
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40
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Recent Progress and Challenges in the Diagnosis and Treatment of Gastrointestinal Stromal Tumors. Cancers (Basel) 2021; 13:cancers13133158. [PMID: 34202544 PMCID: PMC8268322 DOI: 10.3390/cancers13133158] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/18/2021] [Accepted: 06/22/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary Gastrointestinal stromal tumors (GIST) are potentially malignant tumors and require evidence-based surgical and/or medical treatment. Laparoscopy has similar safety and prognostic outcomes to those of laparotomy and is currently a standard procedure for localized GISTs. However, surgery for gastric GISTs less than 2 cm may be re-evaluated due to the indolent nature of the GIST and other competing risks among GIST patients. A work-up with endoscopy and endoscopic ultrasonography as well as endoscopic or percutaneous biopsy is important for the preoperative diagnosis of GISTs. Medical treatment with tyrosine kinase inhibitors is the mainstay for recurrent/metastatic GISTs. The activity of an individual drug is well correlated with gene alterations, and, in the era of precision medicine, cancer genome profiling should be considered before medical treatment. Abstract Gastrointestinal stromal tumors (GISTs) are the most frequent malignant mesenchymal tumors in the gastrointestinal tract. The clinical incidence of GISTs is estimated 10/million/year; however, the true incidence is complicated by frequent findings of tiny GISTs, of which the natural history is unknown. The initial work-up with endoscopy and endoscopic ultrasonography plays important roles in the differential diagnosis of GISTs. Surgery is the only modality for the permanent cure of localized GISTs. In terms of safety and prognostic outcomes, laparoscopy is similar to laparotomy for GIST treatment, including tumors larger than 5 cm. GIST progression is driven by mutations in KIT or PDGFRA or by other rare gene alterations, all of which are mutually exclusive. Tyrosine kinase inhibitors (TKIs) are the standard therapy for metastatic/recurrent GISTs. Molecular alterations are the most reliable biomarkers for TKIs and for other drugs, such as NTRK inhibitors. The pathological and genetic diagnosis prior to treatment has been challenging; however, a newly developed endoscopic device may be useful for diagnosis. In the era of precision medicine, cancer genome profiling by targeted gene panel analysis may enable potential targeted therapy even for GISTs without KIT or PDGFRA mutations.
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Banks E, Grondine M, Bhavsar D, Barry E, Kettle JG, Reddy VP, Brown C, Wang H, Mettetal JT, Collins T, Adeyemi O, Overman R, Lawson D, Harmer AR, Reimer C, Drew L, Packer MJ, Cosulich S, Jones RDO, Shao W, Wilson D, Guichard S, Fawell S, Anjum R. Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors. Sci Transl Med 2021; 12:12/541/eaaz2481. [PMID: 32350132 DOI: 10.1126/scitranslmed.aaz2481] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 03/23/2020] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in KIT or platelet-derived growth factor α (PDGFRα). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary KIT/PDGFRα mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFRα in GIST, with median time to disease progression of 4 to 6 months and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) causing high-grade hypertension. Patients with GIST have an unmet need for a well-tolerated drug that robustly inhibits a range of KIT/PDGFRα mutations. Here, we report the discovery and pharmacological characterization of AZD3229, a potent and selective small-molecule inhibitor of KIT and PDGFRα designed to inhibit a broad range of primary and imatinib-resistant secondary mutations seen in GIST. In engineered and GIST-derived cell lines, AZD3229 is 15 to 60 times more potent than imatinib in inhibiting KIT primary mutations and has low nanomolar activity against a wide spectrum of secondary mutations. AZD3229 causes durable inhibition of KIT signaling in patient-derived xenograft (PDX) models of GIST, leading to tumor regressions at doses that showed no changes in arterial blood pressure (BP) in rat telemetry studies. AZD3229 has a superior potency and selectivity profile to standard of care (SoC) agents-imatinib, sunitinib, and regorafenib, as well as investigational agents, avapritinib (BLU-285) and ripretinib (DCC-2618). AZD3229 has the potential to be a best-in-class inhibitor for clinically relevant KIT/PDGFRα mutations in GIST.
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Affiliation(s)
- Erica Banks
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Michael Grondine
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Deepa Bhavsar
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Evan Barry
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Jason G Kettle
- Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | | | - Crystal Brown
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Haiyun Wang
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Jerome T Mettetal
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Teresa Collins
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Oladipupo Adeyemi
- Functional and Mechanistic Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Ross Overman
- Discovery Sciences, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Deborah Lawson
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Alexander R Harmer
- Functional and Mechanistic Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Corinne Reimer
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Lisa Drew
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | | | | | - Rhys DO Jones
- DMPK, Oncology R&D, AstraZeneca, Cambridge, CB10 1XL, UK
| | - Wenlin Shao
- Projects, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - David Wilson
- Chemistry, Oncology R&D, AstraZeneca, Cambridge CB4 0WG, UK
| | - Sylvie Guichard
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Stephen Fawell
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA
| | - Rana Anjum
- Bioscience, Oncology R&D, AstraZeneca, 35 Gatehouse Park, Boston, MA 02451, USA.
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Cheng K, Liu CF, Rao GW. Anti-angiogenic Agents: A Review on Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Inhibitors. Curr Med Chem 2021; 28:2540-2564. [PMID: 32407259 DOI: 10.2174/0929867327666200514082425] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/18/2020] [Accepted: 04/23/2020] [Indexed: 11/22/2022]
Abstract
Tumor growth inhibition can be achieved by inhibiting angiogenesis, which has been a field of great concern in recent years. Important targets to inhibit angiogenesis include vascular endothelial growth factor receptor (VEGFR) and its homologous tyrosine kinase receptor. Anti-angiogenic therapy based on inhibition of VEGFR-2 is an effective clinical treatment strategy. The research progress of VEGFR-2 inhibitors is reviewed in this paper from the aspects of drug development and chemical synthesis.
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Affiliation(s)
- Kang Cheng
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
| | - Chen-Fu Liu
- School of Pharmaceutical Sciences, Gannan Medical University, Ganzhou 341000, China
| | - Guo-Wu Rao
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
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43
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Patel SR, Reichardt P. An updated review of the treatment landscape for advanced gastrointestinal stromal tumors. Cancer 2021; 127:2187-2195. [PMID: 33974733 PMCID: PMC8252111 DOI: 10.1002/cncr.33630] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/14/2021] [Accepted: 04/19/2021] [Indexed: 12/21/2022]
Abstract
Before the introduction of tyrosine kinase inhibitors (TKIs), the overall survival of patients with advanced or metastatic gastrointestinal stromal tumors (GISTs) was 10 to 20 months because of the lack of approved therapies. In the last 20 years, a treatment algorithm for patients with advanced GISTs, which includes imatinib, sunitinib, and regorafenib as first‐, second‐, and third‐line therapies, respectively, has been established. Recently, 2 new TKIs have been approved: ripretinib for fourth‐line therapy and avapritinib as first‐line therapy in patients harboring platelet‐derived growth factor receptor α (PDGFRA) exon 18 D842V mutations. Additionally, there are several experimental therapies under investigation that could advance individualized patient care. All of these therapies have varying efficacies and safety profiles that warrant an updated treatment landscape review. This review article summarizes the efficacy and safety data currently available for conventional TKIs along with recently approved and experimental therapies. With evolving treatment options and effective toxicity management, patients with advanced gastrointestinal stromal tumors are living longer than ever before. Recently approved targeted therapies and the investigation of experimental treatment options have the potential to alter the current treatment algorithm and encourage personalized patient care.
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Affiliation(s)
- Shreyaskumar R Patel
- Department of Sarcoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Peter Reichardt
- Oncology and Palliative Care, Sarcoma Center, Helios Klinikum Berlin-Buch, Berlin, Germany
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44
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Dudzisz-Śledź M, Bylina E, Teterycz P, Rutkowski P. Treatment of Metastatic Gastrointestinal Stromal Tumors (GIST): A Focus on Older Patients. Drugs Aging 2021; 38:375-396. [PMID: 33651369 PMCID: PMC8096750 DOI: 10.1007/s40266-021-00841-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2021] [Indexed: 11/24/2022]
Abstract
Gastrointestinal stromal tumors (GIST) originating in the Cajal cells are the most common mesenchymal neoplasms of the gastrointestinal tract. The median age of patients with this diagnosis is 65 years, and over 20% of cases affect people over the age of 70 years. The effectiveness and tolerability of systemic treatment with tyrosine kinase inhibitors in older patients with GIST seem to be similar to that in younger patients, but some studies have shown that treatment of older patients is suboptimal. Disability, frailty, comorbidities, and concomitant medications may influence treatment decisions, and toxicities also more often lead to treatment discontinuation. The known safety profile and oral administration route of the tyrosine kinase inhibitors used in GIST may allow maximization of treatment and the best efficacy, especially in older patients. This review summarizes the efficacy data for the systemic treatment of GIST, including data for older patients and from real-world experiences, if available and significant. The reported safety data and general rules for toxicity management, including appropriate patient selection and the need for careful monitoring during treatment, are also discussed.
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Affiliation(s)
- Monika Dudzisz-Śledź
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland.
| | - Elżbieta Bylina
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland
| | - Paweł Teterycz
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland
| | - Piotr Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Roentgena 5, 02-781, Warsaw, Poland
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45
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Al-Share B, Alloghbi A, Al Hallak MN, Uddin H, Azmi A, Mohammad RM, Kim SH, Shields AF, Philip PA. Gastrointestinal stromal tumor: a review of current and emerging therapies. Cancer Metastasis Rev 2021; 40:625-641. [PMID: 33876372 DOI: 10.1007/s10555-021-09961-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumors (GIST) are rare neoplasms arising from the interstitial cell of Cajal in the gastrointestinal tract. Two thirds of GIST in adult patients have c-Kit mutation and smaller fractions have platelet derived growth factor receptor alpha (PDGFRA) mutation. Surgery is the only curative treatment for localized disease. Imatinib improves survival when used adjuvantly and in advanced disease. Several targeted therapies have also improved survival in GIST patients after progression on imatinib including sunitinib and regorafenib. Recently, United States Federal and Drug Administration (FDA) approved two new tyrosine kinase inhibitors for the treatment of heavily pretreated advanced/unresectable GIST including avapritinib (a selective inhibitor for PDGFRA exon 18 mutation including D842V mutations) and ripretinib (a broad-spectrum kinase inhibitor of c-Kit and PDGFRA). In this article, we will provide a comprehensive review of GIST including the current standard of care treatment and exploring future paradigm shifts in therapy.
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Affiliation(s)
- Bayan Al-Share
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Abdulrahman Alloghbi
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Mohammed Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Hafiz Uddin
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Asfar Azmi
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Ramzi M Mohammad
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Steve H Kim
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Anthony F Shields
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA.
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, USA.
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46
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Klug LR, Corless CL, Heinrich MC. Inhibition of KIT Tyrosine Kinase Activity: Two Decades After the First Approval. J Clin Oncol 2021; 39:1674-1686. [PMID: 33797935 DOI: 10.1200/jco.20.03245] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Lillian R Klug
- Oregon Health & Science University, Knight Cancer Institute, Portland, OR.,Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR.,VA Portland Health Care System, Portland, OR
| | - Christopher L Corless
- Oregon Health & Science University, Knight Cancer Institute, Portland, OR.,Department of Pathology, Oregon Health & Science University, Portland, OR
| | - Michael C Heinrich
- Oregon Health & Science University, Knight Cancer Institute, Portland, OR.,Division of Hematology and Medical Oncology, Oregon Health & Science University, Portland, OR.,VA Portland Health Care System, Portland, OR
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Abstract
Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 105 individuals per year in most countries. Around 80% of GIST have varying molecular changes, predominantly mutually exclusive activating KIT or PDGFRA mutations, but other, rare subtypes also exist. Localized GIST are curable, and surgery is their standard treatment. Risk factors for relapse are tumour size, mitotic index, non-gastric site and tumour rupture. Patients with GIST with KIT or PDGFRA mutations sensitive to the tyrosine kinase inhibitor (TKI) imatinib that are at high risk of relapse have improved survival with adjuvant imatinib treatment. In advanced disease, median overall survival has improved from 18 months to >70 months since the introduction of TKIs. The role of surgery in the advanced setting remains unclear. Resistance to TKIs arise mainly from subclonal selection of cells with resistance mutations in KIT or PDGFRA when they are the primary drivers. Advanced resistant GIST respond to second-line sunitinib and third-line regorafenib, as well as to the new broad-spectrum TKI ripretinib. Rare molecular forms of GIST with alterations involving NF1, SDH genes, BRAF or NTRK genes generally show primary resistance to standard TKIs, but some respond to specific inhibitors of the activated genes. Despite major advances, many questions in both advanced and localized disease remain unanswered.
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Affiliation(s)
- Jean-Yves Blay
- Department of Medicine, Centre Leon Berard, UNICANCER & University Lyon I, Lyon, France.
| | - Yoon-Koo Kang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Toshiroo Nishida
- Surgery Department, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
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48
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Liu S, Pan P, Han B, Wang J, Sun M, Sun Y. Extragastrointestinal Stromal Tumor Presenting as a Recurrent Vaginal Mass: Case Report. Onco Targets Ther 2021; 14:959-965. [PMID: 33603400 PMCID: PMC7882793 DOI: 10.2147/ott.s284101] [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: 10/17/2020] [Accepted: 12/24/2020] [Indexed: 12/20/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the dominant mesenchymal tumors of the digestive tract. Extragastrointestinal stromal tumors (EGISTs) usually originate outside the gastrointestinal tract without connection to the gastric or intestinal wall. However, EGISTs arising from the vaginal wall are very rare. Here, we report a case of EGIST that occurred in the vagina of a 60-year-old woman. The tumor was present in the posterior vaginal wall. It was surgically excised, and histological examination revealed spindle cell morphology with up to 14 mitoses per 50 high power field (HPF) and necrosis with the tumor-negative margins. Immunohistochemical analyses showed strongly positive CD34, CD117, and DOG-1 expression, but negative SMA, S-100, CD10, desmin, and actin expression. The patient underwent surgery and is currently being followed up. A literature review of EGSTs and treatments is also discussed in this report.
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Affiliation(s)
- Shuai Liu
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, People's Republic of China
| | - Pan Pan
- Department of Pathology, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, People's Republic of China
| | - Bing Han
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, 250012, Shandong, People's Republic of China
| | - Jingnan Wang
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, People's Republic of China
| | - Meili Sun
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, People's Republic of China
| | - Yuping Sun
- Department of Oncology, Jinan Central Hospital Affiliated to Shandong University; Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, 250013, Shandong, People's Republic of China
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Lostes-Bardaji MJ, García-Illescas D, Valverde C, Serrano C. Ripretinib in gastrointestinal stromal tumor: the long-awaited step forward. Ther Adv Med Oncol 2021; 13:1758835920986498. [PMID: 33473249 PMCID: PMC7797597 DOI: 10.1177/1758835920986498] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Accepted: 12/17/2020] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) represents a paradigm for clinically effective targeted inhibition of oncogenic driver mutations in cancer. Five drugs are currently positioned as the standard of care for the treatment of advanced or metastatic GIST patients. This is the result of continuous, deep understanding of KIT and PDGFRA GIST oncogenic drivers as well as the resistance mechanisms associated to tumor progression. However, the complexity of GIST molecular heterogeneity is an evolving field, and critical questions remain open. Specifically, the clinical benefit of approved and/or investigated targeted agents is strikingly modest at advanced stages of the disease when compared with the activity of first-line imatinib. Ripretinib is a novel switch-pocket inhibitor with broad activity against KIT and PDGFRA oncoproteins and has recently demonstrated antitumoral activity across phase I to phase III clinical trials. Therefore, ripretinib has emerged as a new standard of care for advanced, multi-resistant GIST patients. Based on this data, the Food and Drug Administration has granted in 2020 the approval of ripretinib for GIST patients after progression to imatinib, sunitinib and regorafenib. This, in turn, constitutes a major breakthrough in sarcoma drug development, as there have not been new treatment approvals in GIST for nearly a decade. Herein, we provide a critical review on the preclinical and clinical development of ripretinib in GIST. Furthermore, we seek to assess the biological and clinical impact of this new standard of care on the course of the disease, aiming to provide an insight on future treatments strategies for the next coming years.
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Affiliation(s)
| | | | - Claudia Valverde
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - César Serrano
- Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, P/Vall d'Hebron 119-129, Barcelona, 08035, Spain
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Kelly CM, Gutierrez Sainz L, Chi P. The management of metastatic GIST: current standard and investigational therapeutics. J Hematol Oncol 2021; 14:2. [PMID: 33402214 PMCID: PMC7786896 DOI: 10.1186/s13045-020-01026-6] [Citation(s) in RCA: 154] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/15/2020] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. The majority of GISTs harbor gain of function mutations in either KIT or PDGFRα. Determination of the GIST molecular subtype upon diagnosis is important because this information informs therapeutic decisions in both the adjuvant and metastatic setting. The management of GIST was revolutionized by the introduction of imatinib, a KIT inhibitor, which has become the standard first line treatment for metastatic GIST. However, despite a clinical benefit rate of 80%, the majority of patients with GIST experience disease progression after 2-3 years of imatinib therapy. Second and third line options include sunitinib and regorafenib, respectively, and yield low response rates and limited clinical benefit. There have been recent FDA approvals for GIST including ripretinib in the fourth-line setting and avapritinib for PDGFRA exon 18-mutant GIST. This article aims to review the optimal treatment approach for the management of patients with advanced GIST. It examines the standard treatment options available but also explores the novel treatment approaches in the setting of imatinib refractory GIST.
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Affiliation(s)
- Ciara M. Kelly
- grid.51462.340000 0001 2171 9952Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA ,grid.5386.8000000041936877XDepartment of Medicine, Weill Cornell Medical College, New York, USA
| | - Laura Gutierrez Sainz
- grid.81821.320000 0000 8970 9163Department of Medical Oncology, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
| | - Ping Chi
- grid.51462.340000 0001 2171 9952Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA ,grid.5386.8000000041936877XDepartment of Medicine, Weill Cornell Medical College, New York, USA ,grid.51462.340000 0001 2171 9952Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA
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