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Wang R, Li X, Long L, Li M, Chen H, Zhang H, Ruan W, Zhang H, Zheng P, Xu S. Novel ALK inhibitors containing DAAP fragments: Rational drug design and anti-tumor activity research. Bioorg Chem 2025; 160:108416. [PMID: 40209355 DOI: 10.1016/j.bioorg.2025.108416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/24/2025] [Accepted: 03/25/2025] [Indexed: 04/12/2025]
Abstract
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor subfamily, involved in cellular signaling pathways associated with insulin. While ALK gene remains inactive in normal human tissues, it exhibits high expression specifically in the central nervous system. However, dysregulation of the ALK gene has been implicated in non-small cell lung cancer (NSCLC) development. Although commercially available ALK inhibitors demonstrate favorable clinical efficacy against most Ceritinib-resistant mutants, they exhibit resistance towards G1202R mutants. Therefore, developing novel ALK inhibitors is crucial for addressing drug resistance in patients. We designed and synthesized 48 novel 2,4-diarylpyrimidine-based ALK inhibitors and investigated their antitumor activities. Among them, Ld-10 showed significant inhibitory activity against ALK kinase with an IC50 value of 1135 nM and demonstrated excellent antiproliferative activity against lung cancer cells H2228 with an IC50 value of 1.35 ± 0.13 μM. To further validate the antitumor potential of Ld-10, we conducted a series of in vitro pharmacological experiments. These included a hemolysis assay to confirm its low toxicity profile, an AO assay, a JC-1 staining assay, and a Calcein-AM/PI cell double staining assay for assessing apoptosis induction. Additionally, we performed dose-dependent arrest at G0/G1 phase to evaluate inhibition of cell growth and carried out cell cycle analysis and cloning experiments to provide evidence for significant tumor growth inhibition by compound Ld-10. In vivo pharmacological experiments demonstrated effective tumor growth inhibition without any significant toxic effects on mouse organs caused by Ld-10 administration. Based on these comprehensive findings from our experimental investigations, it can be concluded that Ld-10 holds promising potential as a novel ALK inhibitor.
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Affiliation(s)
- Ran Wang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China
| | - Xiangjing Li
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China
| | - Li Long
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China
| | - Min Li
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China
| | - Huijing Chen
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China
| | - Han Zhang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China
| | - Wei Ruan
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China
| | - Hong Zhang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China.
| | - Pengwu Zheng
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China.
| | - Shan Xu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, Nanchang, Jiangxi, 330013, China.
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Waghmare PS, Chabukswar AR, Raut KG, Giri PT. A Review on Carbazole and Its Derivatives as Anticancer Agents From 2013 to 2024. Chirality 2025; 37:e70021. [PMID: 39887861 DOI: 10.1002/chir.70021] [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: 10/07/2024] [Revised: 12/21/2024] [Accepted: 01/15/2025] [Indexed: 02/01/2025]
Abstract
Carbazole, a natural alkaloid, has been recognized as an effective anticancer agent for over 40 years. However, only a limited number of carbazole-based compounds have received FDA approval for cancer treatment. Current cancer therapies are often associated with significant side effects, causing physical, emotional, and financial burdens for patients. Additionally, despite advancements, cancer prevention and treatment remain challenging due to suboptimal clinical outcomes. The development of new drugs is crucial for achieving safer and more effective cancer therapies. This review focuses on various carbazole derivatives and hybrid composites, highlighting their interactions with distinct receptors and their mechanisms of anticancer action, along with a general structure-activity relationship (SAR). It also emphasizes carbazole-based compounds employed in chemoprevention, which aim to delay or prevent malignant progression. By covering carbazole derivatives and their anticancer potential from 2013 to the present, along with their current clinical status, this study offers valuable insights and updates for researchers in the field.
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Affiliation(s)
- Priyanka Sanjay Waghmare
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, India
| | - Anuruddha Rajaram Chabukswar
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, India
| | - Kunal Ganesh Raut
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, India
| | - Pooja Tanaji Giri
- Department of Pharmaceutical Sciences, School of Health Sciences and Technology, Dr. Vishwanath Karad MIT World Peace University, Pune, India
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Chang ZH, Zhu TF, Ou W, Jiang H, Wang SY. A real-world retrospective study to assess efficacy and safety of alectinib as adjuvant therapy in IB-IIIB NSCLC patients harboring ALK rearrangement. Front Oncol 2024; 14:1422035. [PMID: 39497711 PMCID: PMC11532029 DOI: 10.3389/fonc.2024.1422035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 10/07/2024] [Indexed: 11/07/2024] Open
Abstract
Background Alectinib has demonstrated promising disease-free survival (DFS) benefit for early-stage non-small cell lung cancer (NSCLC) patients with ALK rearrangement positive in phase 3 ALINA trial. However, real-world evidence for the efficacy and safety of alectinib in early-stage ALK-positive NSCLC is limited. Materials and methods We retrospectively reviewed 68 patients with stage IB-IIIB ALK-positive NSCLC who underwent complete pulmonary resections from April 2010 to July 2023 at a single institution. 38 (55.9%) enrolled patients had N2 lymph node metastasis, and 17 (24.9%) patients had multi-station N2 metastasis. Patients were stratified into two groups according to the adjuvant treatment regimen, with 19 patients in the alectinib group and 49 patients in the chemotherapy group. There were no significant differences in clinicopathological characteristics between the two groups. After curative resection surgery, patients in alectinib group received oral alectinib at a dose of 600 mg twice daily and patients in chemotherapy group received platinum-based doublet chemotherapy regimen every 3 weeks for 4 cycles. The primary endpoint was 3-year DFS. The Kaplan-Meier method was used to estimate DFS and overall survival (OS). Safety analyses were conducted by comparing the incidence of adverse events between the two groups. Results At the last follow-up date (January 22th, 2024), A total of 1 (5.3%) and 28 (57.1%) DFS events were observed in alectinib group and chemotherapy group respectively. The 3-year DFS showed significant improvement in the alectinib group compared with chemotherapy group (91.7% vs 60.7%, P=0.051). In the IIIAN2 subgroup, the 3-year DFS rate in the alectinib group reached a satisfactory 87.5%. In both groups, the majority of AEs were graded as level 1 or 2, No grade 3-4 AEs were observed in alectinib group. Conclusion Alectinib, as adjuvant therapy, demonstrated favorable efficacy and manageable safety in patients with completely resected ALK-positive stage I B-IIIB non-small cell lung cancer. A limitation of this study is the small sample size, and a larger-scale real-world sample study is needed to further evaluate the efficacy and safety of alectinib as adjuvant therapy.
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Affiliation(s)
| | | | | | | | - Si-Yu Wang
- Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
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Okuno T, Isobe T, Tsubata Y. Current pharmacologic treatment of brain metastasis in non-small cell lung cancer. Clin Exp Metastasis 2024; 41:549-565. [PMID: 38466521 PMCID: PMC11499348 DOI: 10.1007/s10585-024-10276-4] [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: 11/17/2023] [Accepted: 01/28/2024] [Indexed: 03/13/2024]
Abstract
Lung cancer is a type of cancer that can metastasize to the lungs, brain, bones, liver, adrenal glands, and other organs; however, the occurrence of brain metastases is the most common event. Symptoms of brain metastasis include motor dysfunction, mental dysfunction, seizures, headaches, nausea, and vomiting, and significantly reduce the quality of life of cancer patients. Brain metastases are a poor prognostic factor, and controlling them is extremely important for prolonging prognosis and improving the quality of life. Currently, local surgery and radiotherapy are recommended for their treatment. However, recently, cancer treatments using molecular-targeted drugs and immune checkpoint inhibitors have been introduced, which may also be effective against brain metastases. Therefore, it is necessary to determine whether local or systemic therapy is optimal for each case. In this review, we focus on recent findings regarding drug therapy in treating brain metastases from advanced non-small cell lung cancer.
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Affiliation(s)
- Takae Okuno
- Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, 89-1, Enyacho, Izumo, Shimane, 693-8501, Japan
| | - Takeshi Isobe
- Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, 89-1, Enyacho, Izumo, Shimane, 693-8501, Japan
| | - Yukari Tsubata
- Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Shimane University Faculty of Medicine, 89-1, Enyacho, Izumo, Shimane, 693-8501, Japan.
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Pfeil AJ, Hale JD, Zhang TS, Wakayama K, Miyazaki I, Odintsov I, Somwar R. Preclinical evaluation of targeted therapies for central nervous system metastases. Dis Model Mech 2024; 17:dmm050836. [PMID: 39344915 PMCID: PMC11463968 DOI: 10.1242/dmm.050836] [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] [Indexed: 10/01/2024] Open
Abstract
The central nervous system (CNS) represents a site of sanctuary for many metastatic tumors when systemic therapies that control the primary tumor cannot effectively penetrate intracranial lesions. Non-small cell lung cancers (NSCLCs) are the most likely of all neoplasms to metastasize to the brain, with up to 60% of patients developing CNS metastases during the disease process. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have helped reduce lung cancer mortality but vary considerably in their capacity to control CNS metastases. The ability of these therapies to effectively target lesions in the CNS depends on several of their pharmacokinetic properties, including blood-brain barrier permeability, affinity for efflux transporters, and binding affinity for both plasma and brain tissue. Despite the existence of numerous preclinical models with which to characterize these properties, many targeted therapies have not been rigorously tested for CNS penetration during the discovery process, whereas some made it through preclinical testing despite poor brain penetration kinetics. Several TKIs have now been engineered with the characteristics of CNS-penetrant drugs, with clinical trials proving these efforts fruitful. This Review outlines the extent and variability of preclinical evidence for the efficacy of NSCLC-targeted therapies, which have been approved by the US Food and Drug Administration (FDA) or are in development, for treating CNS metastases, and how these data correlate with clinical outcomes.
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Affiliation(s)
- Alexander J. Pfeil
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA
| | - Joshua D. Hale
- University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA
| | - Tiger S. Zhang
- University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA
| | - Kentaro Wakayama
- Taiho Pharmaceutical Co. Ltd. 3, Okubo, Tsukuba, Ibaraki 300-2611, Japan
| | - Isao Miyazaki
- Taiho Pharmaceutical Co. Ltd. 3, Okubo, Tsukuba, Ibaraki 300-2611, Japan
| | - Igor Odintsov
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 021105, USA
| | - Romel Somwar
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
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Tang M, Wu Y, Bai X, Lu Y. KRAS G12C Inhibitors in Non-Small Cell Lung Cancer: A Review. Onco Targets Ther 2024; 17:683-695. [PMID: 39206059 PMCID: PMC11352592 DOI: 10.2147/ott.s473368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 08/06/2024] [Indexed: 09/04/2024] Open
Abstract
Rat sarcoma virus (RAS) GTPase is one of the most important drivers of non-small cell lung cancer (NSCLC). RAS has three different isoforms (Harvey rat sarcoma viral oncogene homolog [HRAS], Kirsten rat sarcoma viral oncogene homolog [KRAS] and Neuroblastoma ras viral oncogene homolog [NRAS]), of which KRAS is most commonly mutated in NSCLC. The mutated KRAS protein was historically thought to be "undruggable" until the development of KRASG12C inhibitors. In this review, from the aspect of brain metastasis, we aim to provide an overview of the advances in therapies that target KRASG12C, the limitations of the current treatments, and future prospects in patients with KRAS p.G12C mutant NSCLC.
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Affiliation(s)
- Min Tang
- Division of Thoracic Tumor Multimodality Treatment and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Yijun Wu
- Division of Thoracic Tumor Multimodality Treatment and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China
| | - Xiufeng Bai
- Laboratory of Human Disease and Immunotherapies, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
- Institute of Inflammation and Immunology (I), Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
| | - You Lu
- Division of Thoracic Tumor Multimodality Treatment and Department of Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China
- Laboratory of Clinical Cell Therapy, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China
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Boldig C, Boldig K, Mokhtari S, Etame AB. A Review of the Molecular Determinants of Therapeutic Response in Non-Small Cell Lung Cancer Brain Metastases. Int J Mol Sci 2024; 25:6961. [PMID: 39000069 PMCID: PMC11241836 DOI: 10.3390/ijms25136961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 06/20/2024] [Accepted: 06/21/2024] [Indexed: 07/16/2024] Open
Abstract
Lung cancer is a leading cause of cancer-related morbidity and mortality worldwide. Metastases in the brain are a common hallmark of advanced stages of the disease, contributing to a dismal prognosis. Lung cancer can be broadly classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). NSCLC represents the most predominant histology subtype of lung cancer, accounting for the majority of lung cancer cases. Recent advances in molecular genetics, coupled with innovations in small molecule drug discovery strategies, have facilitated both the molecular classification and precision targeting of NSCLC based on oncogenic driver mutations. Furthermore, these precision-based strategies have demonstrable efficacy across the blood-brain barrier, leading to positive outcomes in patients with brain metastases. This review provides an overview of the clinical features of lung cancer brain metastases, as well as the molecular mechanisms that drive NSCLC oncogenesis. We also explore how precision medicine-based strategies can be leveraged to improve NSCLC brain metastases.
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Affiliation(s)
- Catherine Boldig
- Department of Neurology, University of South Florida, 2 Tampa General Circle, Tampa, FL 33606, USA
| | - Kimberly Boldig
- Department of Internal Medicine, University of Florida Jacksonville, 655 W. 8th St., Jacksonville, FL 32209, USA
| | - Sepideh Mokhtari
- Moffitt Cancer Center, Department of Neuro-Oncology, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
| | - Arnold B Etame
- Moffitt Cancer Center, Department of Neuro-Oncology, 12902 USF Magnolia Drive, Tampa, FL 33612, USA
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Madlool DT, Al-Ani I, Ata T, Dayyih WA. Solubility, pH-Solubility Profile, pH-Rate Profile, and Kinetic Stability of the Tyrosine Kinase Inhibitor, Alectinib. Pharmaceuticals (Basel) 2024; 17:776. [PMID: 38931444 PMCID: PMC11206852 DOI: 10.3390/ph17060776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/01/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
Abstract
Alectinib HCl (ALBHCl) is a tyrosine kinase inhibitor used for non-small cell lung carcinoma (NSCLC). The aim of this study is to unlock some of the physicochemical properties of ALBHCL that serve as a database for any future studies. A solubility study of ALBHCL was performed in different solvents. Also, photostability was tested in the solution and solid states, and the order of reaction and rate constant were calculated. In addition to the pH solubility relation, the pH-rate relation at different temperatures was also studied, and the profiles were constructed. A solubility study was also performed in different media for the purpose of optimizing suitable sink conditions for the in vitro dissolution testing of solid dosage forms. Solubility tests in multiple solvents and pH conditions revealed that the highest solubility was in DMSO, methanol, and chloroform, with acidic media yielding the maximum solubility but degrading at rather low pH levels. ALBHCL proved unstable at high temperatures and under light exposure, with varying stability across different pH levels. The optimal dissolution media for in vitro oral dosage form evaluation were determined, achieving sink conditions at pH levels of 6.8 and 4.5 with specific additives. This study enhances the existing database on ALBHCL's physicochemical properties, emphasizing the importance of pH optimization in pharmaceutical processes and providing valuable insights into its pharmaceutical application.
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Affiliation(s)
- Dheyaa Tohma Madlool
- Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan; (D.T.M.); (T.A.)
| | - Israa Al-Ani
- Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan; (D.T.M.); (T.A.)
| | - Tha’er Ata
- Faculty of Pharmacy, Al-Ahliyya Amman University, Amman 19328, Jordan; (D.T.M.); (T.A.)
| | - Wael Abu Dayyih
- Faculty of Pharmacy, Mutah University, Al-Karak 61710, Jordan;
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Poei D, Ali S, Ye S, Hsu R. ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:20. [PMID: 38835344 PMCID: PMC11149099 DOI: 10.20517/cdr.2024.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/18/2024] [Accepted: 05/08/2024] [Indexed: 06/06/2024]
Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangements have been identified as potent oncogenic drivers in several malignancies, including non-small cell lung cancer (NSCLC). The discovery of ALK inhibition using a tyrosine kinase inhibitor (TKI) has dramatically improved the outcomes of patients with ALK-mutated NSCLC. However, the emergence of intrinsic and acquired resistance inevitably occurs with ALK TKI use. This review describes the molecular mechanisms of ALK TKI resistance and discusses management strategies to overcome therapeutic resistance.
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Affiliation(s)
- Darin Poei
- Department of Internal Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Sana Ali
- Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Shirley Ye
- Department of Internal Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Robert Hsu
- Division of Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
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Meng Y, Zhu M, Yang J, Wang X, Liang Y, Yu M, Li L, Kong F. Treatment Advances in Lung Cancer with Leptomeningeal Metastasis. Curr Cancer Drug Targets 2024; 24:910-919. [PMID: 38279718 DOI: 10.2174/0115680096276133231201061114] [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: 08/07/2023] [Revised: 10/11/2023] [Accepted: 11/16/2023] [Indexed: 01/28/2024]
Abstract
Leptomeningeal metastasis (LM) is a serious and often fatal complication in patients with advanced lung cancer, resulting in significant neurological deficits, decreased quality of life, and a poor prognosis. This article summarizes current research advances in treating lung cancer with meningeal metastases, discusses clinical challenges, and explores treatment strategies. Through an extensive review of relevant clinical trial reports and screening of recent conference abstracts, we collected clinical data on treating patients with lung cancer with meningeal metastases to provide an overview of the current research progress. Exciting progress has been made by focusing on specific mutations within lung cancer, including the use of EGFR tyrosine kinase inhibitors or inhibitors for anaplastic lymphoma kinase gene rearrangement, such as osimertinib, alectinib, and lorlatinib. These targeted therapies have shown impressive results in penetrating the central nervous system (CNS). Regarding whole-brain radiotherapy, there is currently some controversy among investigators regarding its effect on survival. Additionally, immune checkpoint inhibitors (ICIs) have demonstrated reliable clinical benefits due to their ability to retain anticancer activity in CNS metastases. Moreover, combination therapy shows promise in providing further treatment possibilities. Considerable progress has been made in the clinical research of lung cancer with LM. However, the sample size of prospective clinical trials investigating LM for lung cancer is still limited, with most reports being retrospective. Developing more effective management protocols for metastatic LM in lung cancer remains an ongoing challenge for the future.
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Affiliation(s)
- Yuan Meng
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Meiying Zhu
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Jie Yang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Xuerui Wang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Yangyueying Liang
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Minghui Yu
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Longhui Li
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Fanming Kong
- Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Anshanxi Road, Nankai District, 300193, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
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Zhao Z, Chen Y, Sun T, Jiang C. Nanomaterials for brain metastasis. J Control Release 2024; 365:833-847. [PMID: 38065414 DOI: 10.1016/j.jconrel.2023.12.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/21/2023] [Accepted: 12/01/2023] [Indexed: 12/19/2023]
Abstract
Tumor metastasis is a significant contributor to the mortality of cancer patients. Specifically, current conventional treatments are unable to achieve complete remission of brain metastasis. This is due to the unique pathological environment of brain metastasis, which differs significantly from peripheral metastasis. Brain metastasis is characterized by high tumor mutation rates and a complex microenvironment with immunosuppression. Additionally, the presence of blood-brain barrier (BBB)/blood tumor barrier (BTB) restricts drug leakage into the brain. Therefore, it is crucial to take account of the specific characteristics of brain metastasis when developing new therapeutic strategies. Nanomaterials offer promising opportunities for targeted therapies in treating brain metastasis. They can be tailored and customized based on specific pathological features and incorporate various treatment approaches, which makes them advantageous in advancing therapeutic strategies for brain metastasis. This review provides an overview of current clinical treatment options for patients with brain metastasis. It also explores the roles and changes that different cells within the complex microenvironment play during tumor spread. Furthermore, it highlights the use of nanomaterials in current brain treatment approaches.
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Affiliation(s)
- Zhenhao Zhao
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Yun Chen
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Tao Sun
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Chen Jiang
- Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
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Shen CI, Chiang CL, Huang HC, Tseng YH, Luo YH, Yang HC, Chen YM. Management strategies for intracranial progression in ALK-positive non-small cell lung cancer: a real-world cohort study. J Neurooncol 2023; 165:459-465. [PMID: 38051455 DOI: 10.1007/s11060-023-04497-y] [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: 09/29/2023] [Accepted: 11/01/2023] [Indexed: 12/07/2023]
Abstract
PURPOSE ALK-positive NSCLC patients exhibit a particularly high propensity for the development of brain metastases. Current guidelines suggest transit to next-line therapy (SysTx) or local radiotherapy (RadTx) including whole-brain radiotherapy and radiosurgery. However, the clinical impact of these two strategies remains unclear. METHODS We conducted a retrospective analysis focusing on patients with stage IV ALK-positive NSCLC who underwent first-line ALK TKI treatment. Patients with intracranial progression may receive two different treatment strategies: SysTx and RadTx. Our objective was to investigate the outcomes associated with these two distinct treatment pathways. RESULTS A total 20 patients of ALK-positive NSCLC who received first-line ALK TKI therapy and subsequently developed intracranial progression were enrolled. About 55% of patients had brain metastasis initially. Nine patients (45%) were treated with crizotinib at first. Patients treated with crizotinib demonstrated a significantly shorter intracranial PFS1 (crizotinib: 8.27 months vs. others: 27.0 months, p = 0.006). Following intracranial progression, approximately 60% of patients transitioned to the next line of systemic treatment (SysTx), while the remaining 40% opted for local cranial radiotherapy (RadTx). Intriguingly, our analysis revealed no statistically significant difference in intracranial progression-free survival (PFS2) between these two distinct treatment strategies. (SysTx: 20.87 months vs. RadTx: 28.23 months, p = 0.461). CONCLUSION The intracranial progression-free survival showed no difference between the two strategies suggesting that both local radiotherapy and systemic therapy may be valid options. Individualized strategy, molecular analysis, and multidisciplinary conferences may all play a pivotal role in decision-making.
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Affiliation(s)
- Chia-I Shen
- Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chi-Lu Chiang
- Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsu-Ching Huang
- Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yen-Han Tseng
- Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yung-Hung Luo
- Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Huai-Che Yang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yuh-Min Chen
- Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan.
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
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13
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Zhao Y, Yu L, Wang L, Wu Y, Chen H, Wang Q, Wu Y. The Riddle of the Sphinx: Progress in Leptomeningeal Metastasis of Non-Small Cell Lung Cancer. Clin Med Insights Oncol 2023; 17:11795549231205206. [PMID: 37915530 PMCID: PMC10617270 DOI: 10.1177/11795549231205206] [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: 06/02/2023] [Accepted: 09/15/2023] [Indexed: 11/03/2023] Open
Abstract
Leptomeningeal metastasis (LM) is a serious complication of advanced non-small cell lung cancer (NSCLC), and the incidence of LM has been increasing yearly in recent times. There is no consensus on the best treatment modality for LM, which underscores a difficult problem in the management of advanced NSCLC patients. The existing treatments include molecular targeted therapy, systemic chemotherapy, local radiotherapy, antivascular tumor therapy, intrathecal chemotherapy, and immunotherapy, but their efficacy is not satisfactory. In this article, we briefly describe the clinical manifestations, diagnosis, and treatment of NSCLC-LM and discuss progress regarding evaluation of the efficacy of LM treatment to better provide a necessary reference for clinical practice and clinical trial evaluation.
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Affiliation(s)
| | | | | | | | | | | | - Yufeng Wu
- Yufeng Wu, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
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14
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Kiełbowski K, Żychowska J, Becht R. Anaplastic lymphoma kinase inhibitors-a review of anticancer properties, clinical efficacy, and resistance mechanisms. Front Pharmacol 2023; 14:1285374. [PMID: 37954850 PMCID: PMC10634320 DOI: 10.3389/fphar.2023.1285374] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/16/2023] [Indexed: 11/14/2023] Open
Abstract
Fusions and mutations of anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, have been identified in several neoplastic diseases. Rearranged ALK is a driver of tumorigenesis, which activates various signaling pathway associated with proliferation and survival. To date, several agents that target and inhibit ALK have been developed. The most studied ALK-positive disease is non-small cell lung cancer, and three generations of ALK tyrosine kinase inhibitors (TKIs) have been approved for the treatment of metastatic disease. Nevertheless, the use of ALK-TKIs is associated with acquired resistance (resistance mutations, bypass signaling), which leads to disease progression and may require a substitution or introduction of other treatment agents. Understanding of the complex nature and network of resistance mutations may allow to introduce sequential and targeted therapies. In this review, we aim to summarize the efficacy and safety profile of ALK inhibitors, describe off-target anticancer effects, and discuss resistance mechanisms in the context of personalized oncology.
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Affiliation(s)
| | | | - Rafał Becht
- Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University, Szczecin, Poland
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15
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Attwa MW, AlRabiah H, Mostafa GAE, Kadi AA. Evaluation of Alectinib Metabolic Stability in HLMs Using Fast LC-MS/MS Method: In Silico ADME Profile, P450 Metabolic Lability, and Toxic Alerts Screening. Pharmaceutics 2023; 15:2449. [PMID: 37896209 PMCID: PMC10610548 DOI: 10.3390/pharmaceutics15102449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 09/29/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
Alectinib, also known as Alecensa®, is prescribed for the therapeutic treatment of individuals diagnosed with metastatic non-small cell lung cancer (NSCLC) who have a specific genetic mutation referred to as anaplastic lymphoma kinase (ALK) positivity. The Food and Drug Administration granted regular approval to alectinib, a drug developed by Hoffmann-La Roche, Inc. (Basel, Switzerland)/Genentech, Inc. (South San Francisco, CA, USA), on 6 November 2017. The screening of the metabolic stability and identification of hazardous alarms within the chemical structure of ALC was conducted using the StarDrop software package (version 6.6), which incorporates the P450 metabolic module and DEREK software (KB 2018 1.1). The primary aim of this investigation was to develop a high-throughput and accurate LC-MS/MS technique for the quantification of ALC in the metabolic matrix (human liver microsomes; HLMs). The aforementioned methodology was subsequently employed to assess the metabolic stability of ALC in HLMs through in vitro tests, with the obtained results further validated using in silico software. The calibration curve of the ALC showed a linear correlation that exists within the concentration range from 1 to 3000 ng/mL. The LC-MS/MS approach that was recommended exhibited accuracy and precision levels for both inter-day and intra-day measurements. Specifically, the accuracy values ranged from -2.56% to 3.45%, while the precision values ranged from -3.78% to 4.33%. The sensitivity of the established approach was proved by its ability to adhere to an LLOQ of 0.82 ng/mL. The half-life (t1/2) and intrinsic clearance (Clint) of ALC were estimated to be 22.28 min and 36.37 mL/min/kg, correspondingly, using in vitro experiments. The ALC exhibited a moderate extraction ratio. The metabolic stability and safety properties of newly created derivatives can be enhanced by making modest adjustments to the morpholine and piperidine rings or by substituting the substituent, as per computational software. In in silico ADME prediction, ALC was shown to have poor water solubility and high gastrointestinal absorption along with inhibition of some cytochrome P450s (CYP2C19 and CYP2C9) without inhibition of others (CYP1A2, CYP3A4, and CYP2D6) and P-glycoprotein substrate. The study design that involves using both laboratory experiments and different in silico software demonstrates a novel and groundbreaking approach in the establishment and uniformization of LC-MS/MS techniques for the estimation of ALC concentrations, identifying structural alerts and the assessment of its metabolic stability. The utilization of this study strategy has the potential to be employed in the screening and optimization of prospective compounds during the drug creation process. This strategy may also facilitate the development of novel derivatives of the medicine that maintain the same biological action by targeted structural modifications, based on an understanding of the structural alerts included within the chemical structure of ALC.
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Affiliation(s)
- Mohamed W. Attwa
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; (H.A.); (G.A.E.M.); (A.A.K.)
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16
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Pan K, Concannon K, Li J, Zhang J, Heymach JV, Le X. Emerging therapeutics and evolving assessment criteria for intracranial metastases in patients with oncogene-driven non-small-cell lung cancer. Nat Rev Clin Oncol 2023; 20:716-732. [PMID: 37592034 PMCID: PMC10851171 DOI: 10.1038/s41571-023-00808-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/21/2023] [Indexed: 08/19/2023]
Abstract
The improved survival outcomes of patients with non-small-cell lung cancer (NSCLC), largely owing to the improved control of systemic disease provided by immune-checkpoint inhibitors and novel targeted therapies, have highlighted the challenges posed by central nervous system (CNS) metastases as a devastating yet common complication, with up to 50% of patients developing such lesions during the course of the disease. Early-generation tyrosine-kinase inhibitors (TKIs) often provide robust systemic disease control in patients with oncogene-driven NSCLCs, although these agents are usually unable to accumulate to therapeutically relevant concentrations in the CNS owing to an inability to cross the blood-brain barrier. However, the past few years have seen a paradigm shift with the emergence of several novel or later-generation TKIs with improved CNS penetrance. Such agents have promising levels of activity against brain metastases, as demonstrated by data from preclinical and clinical studies. In this Review, we describe current preclinical and clinical evidence of the intracranial activity of TKIs targeting various oncogenic drivers in patients with NSCLC, with a focus on newer agents with enhanced CNS penetration, leptomeningeal disease and the need for intrathecal treatment options. We also discuss evolving assessment criteria and regulatory considerations for future clinical investigations.
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Affiliation(s)
- Kelsey Pan
- Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kyle Concannon
- Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jing Li
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jianjun Zhang
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - John V Heymach
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiuning Le
- Department of Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
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17
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Weiss JB, Raber J. Inhibition of Anaplastic Lymphoma Kinase (Alk) as Therapeutic Target to Improve Brain Function in Neurofibromatosis Type 1 (Nf1). Cancers (Basel) 2023; 15:4579. [PMID: 37760547 PMCID: PMC10526845 DOI: 10.3390/cancers15184579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 05/17/2023] [Accepted: 09/09/2023] [Indexed: 09/29/2023] Open
Abstract
Neurofibromatosis type 1 (Nf1) is a neurodevelopmental disorder and tumor syndrome caused by loss of function mutations in the neurofibromin gene (Nf1) and is estimated to affect 100,000 people in the US. Behavioral alterations and cognitive deficits have been found in 50-70% of children with Nf1 and include specific problems with attention, visual perception, language, learning, attention, and executive function. These behavioral alterations and cognitive deficits are observed in the absence of tumors or macroscopic structural abnormalities in the central nervous system. No effective treatments for the behavioral and cognitive disabilities of Nf1 exist. Inhibition of the anaplastic lymphoma kinase (Alk), a kinase which is negatively regulated by neurofibromin, allows for testing the hypothesis that this inhibition may be therapeutically beneficial in Nf1. In this review, we discuss this area of research and directions for the development of alternative therapeutic strategies to inhibit Alk. Even if the incidence of adverse reactions of currently available Alk inhibitors was reduced to half the dose, we anticipate that a long-term treatment would pose challenges for efficacy, safety, and tolerability. Therefore, future efforts are warranted to investigate alternative, potentially less toxic and more specific strategies to inhibit Alk function.
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Affiliation(s)
- Joseph B. Weiss
- Cardiovascular Institute and Warren Alpert School of Medicine at Brown University, Providence, RI 02840, USA
| | - Jacob Raber
- Departments of Behavioral Neuroscience, Neurology, and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health & Science University, Portland, OR 97239, USA
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18
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Blandin AF, Giglio R, Graham MS, Garcia G, Malinowski S, Woods JK, Ramkissoon S, Ramkissoon L, Dubois F, Schoolcraft K, Tsai J, Wang D, Jones R, Vogelzang J, Pelton K, Becker S, Watkinson F, Sinai C, Cohen EF, Booker MA, Tolstorukov MY, Haemels V, Goumnerova L, Wright K, Kieran M, Fehnel K, Reardon D, Tauziede-Espariat A, Lulla R, Carcamo B, Chaleff S, Charest A, DeSmet F, Ligon AH, Dubuc A, Pages M, Varlet P, Wen PY, Alexander BM, Chi S, Alexandrescu S, Kittler R, Bachoo R, Bandopadhayay P, Beroukhim R, Ligon KL. ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma. Clin Cancer Res 2023; 29:2651-2667. [PMID: 36780194 PMCID: PMC10363218 DOI: 10.1158/1078-0432.ccr-21-3521] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/31/2022] [Accepted: 02/07/2023] [Indexed: 02/14/2023]
Abstract
PURPOSE Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established. EXPERIMENTAL DESIGN We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations. RESULTS ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0-80 years). Recurrent as well as novel ALK fusions (LRRFIP1-ALK, DCTN1-ALK, PRKD3-ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib. CONCLUSIONS These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. See related commentary by Mack and Bertrand, p. 2567.
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Affiliation(s)
- Anne-Florence Blandin
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
| | - Ross Giglio
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | | | - Jared K. Woods
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | | | | | - Frank Dubois
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
| | | | - Jessica Tsai
- Dana-Farber Cancer Institute, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Dayle Wang
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | | | | | | | | | | | - Elizabeth F Cohen
- Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Matthew A Booker
- Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Veerle Haemels
- Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | | | - Karen Wright
- Dana-Farber Cancer Institute, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Mark Kieran
- Day One Biopharmaceuticals, Brisbane, CA 94005
| | - Katie Fehnel
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | | | | | - Rishi Lulla
- Hasbro Children's Hospital, Providence, RI, USA
| | - Benjamin Carcamo
- Texas Tech University, Health Science Center, Paul L. Foster School of Medicine, El Paso, TX, USA
- El Paso Children's Hospital, El Paso, TX, USA
| | | | - Alain Charest
- Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Frederik DeSmet
- Laboratory for Precision Cancer Medicine, Translational Cell and Tissue Research Unit, Department of Imaging and Pathology, KU Leuven, Leuven, Belgium
| | - Azra H. Ligon
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Adrian Dubuc
- Dana-Farber Cancer Institute, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Melanie Pages
- Department of Genetics, Institute Curie, Paris, France. INSERM U830, Laboratory of Translational Research in Pediatric Oncology, SIREDO Pediatric Oncology Center, Institute Curie, Paris, France
| | | | - Patrick Y. Wen
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Brian M. Alexander
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Susan Chi
- Dana-Farber Cancer Institute, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Sanda Alexandrescu
- Dana-Farber Cancer Institute, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Ralf Kittler
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Robert Bachoo
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Pratiti Bandopadhayay
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
| | - Rameen Beroukhim
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
| | - Keith L. Ligon
- Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
- Broad institute of Harvard and MIT, Cambridge, MA, USA
- Brigham and Women's Hospital, Boston, MA, USA
- Boston Children's Cancer and Blood Disorder Center, Boston, MA, USA
- Dana-Farber Cancer Institute, Center for Patient Derived Models (CPDM), Boston, MA, USA
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Zhou Y, Yin Y, Xu J, Xu Z, Yang B, He Q, Luo P, Yan H, Yang X. An update on Alectinib: a first line treatment for ALK-positive advanced lung cancer. Expert Opin Pharmacother 2023; 24:1361-1373. [PMID: 37278051 DOI: 10.1080/14656566.2023.2221786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/01/2023] [Indexed: 06/07/2023]
Abstract
INTRODUCTION Alectinib is a second-generation, anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) for the treatment of ALK+ non-small cell lung cancer (NSCLC) and is able to induce significant and durable CNS responses. However, long-term use of alectinib has been clinically reported to cause some serious and even life-threatening adverse events. There are currently no effective interventions for its adverse events, and this undoubtedly leads to delays in patient treatment and limits its long-term clinical use. AREAS COVERED Based on the clinical trials conducted so far, we summarize the efficacy and adverse events that occurred, especially those related to cardiovascular disorders, gastrointestinal disorders, hepatobiliary disorders, musculoskeletal and connective tissue disorders, skin and subcutaneous tissue disorders, and respiratory disorders. The factors that may influence alectinib selection are also described. Findings are based on a PubMed literature search of clinical and basic science research papers spanning 1998-2023. EXPERT OPINION The significant prolongation of patient survival compared with first-generation ALK inhibitor suggests its potential as a first-line treatment for the NSCLC, but the severe adverse events of alectinib limit its long-term clinical use. Future research should focus on the exact mechanisms of these toxicities, how to alleviate the adverse events caused by alectinib clinically, and the development of next-generation drugs with reduced toxicities.
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Affiliation(s)
- Yourong Zhou
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Yiming Yin
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Jiangxin Xu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Department of Pharmacy, Hangzhou Red Cross Hospital (Hangzhou Chest Hospital Affiliated to Zhejiang University Medical College), Hangzhou, China
| | - Zhifei Xu
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Bo Yang
- Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Qiaojun He
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Innovation Institute for Artificial Intelligence in Medicine, Zhejiang University, Hangzhou, China
| | - Peihua Luo
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
- Department of Pharmacology and Toxicology, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hao Yan
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Xiaochun Yang
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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Nagasaka M, Azmi AS. Penetrating the central nervous system sanctuary of KRAS, a target once thought "undruggable". Transl Lung Cancer Res 2023; 12:665-668. [PMID: 37197620 PMCID: PMC10183396 DOI: 10.21037/tlcr-23-71] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 03/23/2023] [Indexed: 05/19/2023]
Affiliation(s)
- Misako Nagasaka
- University of California Irvine School of Medicine, Chao Family Comprehensive Cancer Center, Orange, CA, USA
- Division of Neurology, Department of Internal Medicine, St. Marianna University, Kawasaki, Japan
| | - Asfar S. Azmi
- Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA
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Candido MF, Medeiros M, Veronez LC, Bastos D, Oliveira KL, Pezuk JA, Valera ET, Brassesco MS. Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario. Pharmaceutics 2023; 15:pharmaceutics15020664. [PMID: 36839989 PMCID: PMC9966033 DOI: 10.3390/pharmaceutics15020664] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Childhood cancer is considered rare, corresponding to ~3% of all malignant neoplasms in the human population. The World Health Organization (WHO) reports a universal occurrence of more than 15 cases per 100,000 inhabitants around the globe, and despite improvements in diagnosis, treatment and supportive care, one child dies of cancer every 3 min. Consequently, more efficient, selective and affordable therapeutics are still needed in order to improve outcomes and avoid long-term sequelae. Alterations in kinases' functionality is a trademark of cancer and the concept of exploiting them as drug targets has burgeoned in academia and in the pharmaceutical industry of the 21st century. Consequently, an increasing plethora of inhibitors has emerged. In the present study, the expression patterns of a selected group of kinases (including tyrosine receptors, members of the PI3K/AKT/mTOR and MAPK pathways, coordinators of cell cycle progression, and chromosome segregation) and their correlation with clinical outcomes in pediatric solid tumors were accessed through the R2: Genomics Analysis and Visualization Platform and by a thorough search of published literature. To further illustrate the importance of kinase dysregulation in the pathophysiology of pediatric cancer, we analyzed the vulnerability of different cancer cell lines against their inhibition through the Cancer Dependency Map portal, and performed a search for kinase-targeted compounds with approval and clinical applicability through the CanSAR knowledgebase. Finally, we provide a detailed literature review of a considerable set of small molecules that mitigate kinase activity under experimental testing and clinical trials for the treatment of pediatric tumors, while discuss critical challenges that must be overcome before translation into clinical options, including the absence of compounds designed specifically for childhood tumors which often show differential mutational burdens, intrinsic and acquired resistance, lack of selectivity and adverse effects on a growing organism.
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Affiliation(s)
- Marina Ferreira Candido
- Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Mariana Medeiros
- Regional Blood Center, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - Luciana Chain Veronez
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - David Bastos
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Karla Laissa Oliveira
- Department of Biology, Faculty of Philosophy, Sciences and Letters at Ribeirão Preto, University of São Paulo, Ribeirão Preto 14040-901, SP, Brazil
| | - Julia Alejandra Pezuk
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
| | - Elvis Terci Valera
- Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil
| | - María Sol Brassesco
- Departament of Biotechnology and Innovation, Anhanguera University of São Paulo, UNIAN/SP, São Paulo 04119-001, SP, Brazil
- Correspondence: ; Tel.: +55-16-3315-9144; Fax: +55-16-3315-4886
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22
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Chanthong S, Sathitsamitphong L, Natesirinilkul R, Charoenkwan P, Suwansirikul S, Choed-Amphai C. Treatment modalities of ALK-positive relapsed/refractory inflammatory myofibroblastic tumor of the brain and lungs in 7-year-old girl: case-based reviews. Childs Nerv Syst 2023; 39:331-342. [PMID: 36515740 DOI: 10.1007/s00381-022-05789-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 12/08/2022] [Indexed: 12/15/2022]
Abstract
PURPOSE Inflammatory myofibroblastic tumor (IMT) belongs to mesenchymal neoplasm of intermediate malignancy in WHO classification. Primary CNS disease or CNS metastases (CNS-IMT) occur in minority. We describe a case of relapsed/refractory IMT of lungs with multiple brain metastases in young child who achieved long-term complete response after alectinib. This systematic review also summarizes treatment modalities and outcome of children and adolescent with CNS-IMT. METHODS PRISMA 2020 guideline was applied to select an article from PubMed, Scopus, and Cochrane databases without time limits. This review focused on children and adolescent 0-24 years of age with CNS-IMT or inflammatory pseudotumor (CNS-IPT). The clinical characteristics and treatment outcome were explored. RESULTS A total of 51 patients in 49 publications were identified. Median age of patients with CNS-IMT/IPT was 15-year-old and 60.8% were male. The most common location of tumor was cerebral cortex (54.9%). Complete resection of CNS-IMT/IPT was performed in 27 cases with 100% complete response and 18.5% recurrence. Nearly half of patients who received partial resection without adjuvant therapy experienced progressive disease, while the contrast group totally achieved partial response. Overall responses in 7 patients treating with ALK inhibitors were 57.1% durable complete response and 42.9% transient partial response. CONCLUSION First-line treatment of CNS-IMT/IPT is complete resection. Patients who received partial tumor removal might have benefit from adjuvant therapy. ALK inhibitors reveal a promising result in unresectable CNS-IMT/IPT. Our case has shown a success in treating relapsed and refractory CNS-IMT as well as the primary site using 2nd-generation ALK inhibitor.
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23
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Billena C, Lobbous M, Cordova CA, Peereboom D, Torres-Trejo A, Chan T, Murphy E, Chao ST, Suh J, Yu JS. The role of targeted therapy and immune therapy in the management of non-small cell lung cancer brain metastases. Front Oncol 2023; 13:1110440. [PMID: 36910642 PMCID: PMC9997098 DOI: 10.3389/fonc.2023.1110440] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 01/30/2023] [Indexed: 02/25/2023] Open
Abstract
Brain metastases are a significant source of morbidity and mortality in patients with non-small cell lung cancer. Historically, surgery and radiation therapy have been essential to maintaining disease control within the central nervous system due to poorly penetrant conventional chemotherapy. With the advent of targeted therapy against actionable driver mutations, there is potential to control limited and asymptomatic intracranial disease and delay local therapy until progression. In this review paper, intracranial response rates and clinical outcomes to biological and immune therapies are summarized from the literature and appraised to assist clinical decision making and identify areas for further research. Future clinical trials ought to prioritize patient-centered quality of life and neurocognitive measures as major outcomes and specifically stratify patients based on mutational marker status, disease burden, and symptom acuity.
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Affiliation(s)
- Cole Billena
- Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Mina Lobbous
- Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Christine A Cordova
- Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - David Peereboom
- Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Alejandro Torres-Trejo
- Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Timothy Chan
- Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Erin Murphy
- Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Samuel T Chao
- Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - John Suh
- Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Jennifer S Yu
- Department of Radiation Oncology, Cleveland Clinic Foundation, Cleveland, OH, United States.,Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Foundation, Cleveland, OH, United States.,Center for Cancer Stem Cell Biology, Department of Cancer Biology, Cleveland Clinic Foundation, Cleveland, OH, United States
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24
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Rossi S, Marinello A, Pagliaro A, Franceschini D, Navarria P, Finocchiaro G, Toschi L, Scorsetti M, Santoro A. Current treatment approaches for brain metastases in ALK/ ROS1/ NTRK-positive non-small-cell lung cancer. Expert Rev Anticancer Ther 2023; 23:29-41. [PMID: 36548111 DOI: 10.1080/14737140.2023.2162044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Oncogene-addicted non-small cell lung cancer (NSCLC) patients present a high incidence of CNS metastases either at diagnosis or during the course of the disease. In this case, patients present with worse prognosis and are often excluded from clinical trials unless brain metastases are pre-treated or clinically stable. AREAS COVERED As a result of the discovery of several oncogenic drivers in ALK/ROS1/NTRK-positive NSCLC, targeted agents have been tested in several trials. We evaluate and compare the intracranial efficacy of available targeted agents in ALK/ROS1/NTRK-positive NSCLC based on subgroup analysis from pivotal trials. EXPERT OPINION Last-generation ALK inhibitors have shown slightly superior intracranial activity but pivotal trials do not consider the same endpoints for intracranial efficacy, therefore data are not comparable. Local treatments for BM including surgical resection, stereotactic radiosurgery (SRS) and WBRT, should be integrated with systemic therapies basing on specific criteria like presence of oligoprogression or symptomatic progression.
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Affiliation(s)
- Sabrina Rossi
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Arianna Marinello
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Arianna Pagliaro
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Davide Franceschini
- Department of Radiotherapy and Radiosurgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Pierina Navarria
- Department of Radiotherapy and Radiosurgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Giovanna Finocchiaro
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Luca Toschi
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Marta Scorsetti
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Department of Radiotherapy and Radiosurgery, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Armando Santoro
- Medical Oncology and Hematology Unit, IRCCS Humanitas Research Hospital, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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25
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Wang Z, Xing Y, Li B, Li X, Liu B, Wang Y. Molecular pathways, resistance mechanisms and targeted interventions in non-small-cell lung cancer. MOLECULAR BIOMEDICINE 2022; 3:42. [PMID: 36508072 PMCID: PMC9743956 DOI: 10.1186/s43556-022-00107-x] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 11/03/2022] [Indexed: 12/14/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related mortality worldwide. The discovery of tyrosine kinase inhibitors effectively targeting EGFR mutations in lung cancer patients in 2004 represented the beginning of the precision medicine era for this refractory disease. This great progress benefits from the identification of driver gene mutations, and after that, conventional and new technologies such as NGS further illustrated part of the complex molecular pathways of NSCLC. More targetable driver gene mutation identification in NSCLC patients greatly promoted the development of targeted therapy and provided great help for patient outcomes including significantly improved survival time and quality of life. Herein, we review the literature and ongoing clinical trials of NSCLC targeted therapy to address the molecular pathways and targeted intervention progress in NSCLC. In addition, the mutations in EGFR gene, ALK rearrangements, and KRAS mutations in the main sections, and the less common molecular alterations in MET, HER2, BRAF, ROS1, RET, and NTRK are discussed. The main resistance mechanisms of each targeted oncogene are highlighted to demonstrate the current dilemma of targeted therapy in NSCLC. Moreover, we discuss potential therapies to overcome the challenges of drug resistance. In this review, we manage to display the current landscape of targetable therapeutic patterns in NSCLC in this era of precision medicine.
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Affiliation(s)
- Zixi Wang
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Yurou Xing
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Bingjie Li
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Xiaoyu Li
- grid.412901.f0000 0004 1770 1022Clinical Trial Center, National Medical Products Administration Key Laboratory for Clinical Research and Evaluation of Innovative Drugs, West China Hospital, Sichuan University, Chengdu, Sichuan China ,grid.412901.f0000 0004 1770 1022State Key Laboratory Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
| | - Bin Liu
- grid.54549.390000 0004 0369 4060Department of Medical Oncology, School of Medicine, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China, Chengdu, Sichuan China
| | - Yongsheng Wang
- grid.412901.f0000 0004 1770 1022Thoracic Oncology Ward, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China ,grid.412901.f0000 0004 1770 1022State Key Laboratory Biotherapy, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan China
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26
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Dziadziuszko R, Peters S, Ruf T, Cardona A, Guerini E, Kurtsikidze N, Smoljanovic V, Planchard D. Clinical experience and management of adverse events in patients with advanced ALK-positive non-small-cell lung cancer receiving alectinib. ESMO Open 2022; 7:100612. [PMID: 36375271 PMCID: PMC9663323 DOI: 10.1016/j.esmoop.2022.100612] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Alectinib is a preferred first-line therapy for patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in several national clinical practice guidelines. The randomized, global, phase III ALEX study has demonstrated significant improvement in progression-free survival for alectinib over crizotinib in treatment-naive ALK-positive NSCLC. It was also the first study to show clinically meaningful improvement in overall survival for a next-generation ALK tyrosine kinase inhibitor relative to crizotinib. The J-ALEX and ALESIA phase III studies confirmed the clinical benefit of alectinib relative to crizotinib in the first-line ALK-positive NSCLC treatment setting in Japanese and Asian patients, respectively. Across these pivotal phase III trials, alectinib had a manageable, well-characterized safety profile. Here, we review the safety and tolerability of long-term alectinib treatment in patients with advanced ALK-positive NSCLC and provide guidance for physicians, based on clinical experience, on the management of the most frequently reported adverse events (AEs). Most AEs associated with alectinib can be managed by dose reduction. Some alectinib-related AEs are not yet fully characterized, including myalgia and peripheral oedema and deciphering their underlying mechanism of action could enhance their management. With longer-term follow-up, the safety profile of alectinib continues to remain consistent in the ALEX study, with no new safety signals observed. Safety and tolerability data from the first-line phase III alectinib trials are also consistent with those observed in clinical trials of alectinib in later-line settings. These results add to the weight of evidence recommending alectinib as a preferred therapy for treatment-naive advanced ALK-positive NSCLC.
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Affiliation(s)
- R Dziadziuszko
- Department of Oncology and Radiotherapy, Medical University of Gdansk, Gdansk, Poland
| | - S Peters
- Lausanne University Hospital, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
| | - T Ruf
- F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - A Cardona
- F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - E Guerini
- F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | | | | | - D Planchard
- Department of Medical Oncology, Thoracic Oncology Unit, Gustave Roussy Cancer Campus, Villejuif, France.
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27
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Cognigni V, Pecci F, Lupi A, Pinterpe G, De Filippis C, Felicetti C, Cantini L, Berardi R. The Landscape of ALK-Rearranged Non-Small Cell Lung Cancer: A Comprehensive Review of Clinicopathologic, Genomic Characteristics, and Therapeutic Perspectives. Cancers (Basel) 2022; 14:4765. [PMID: 36230686 PMCID: PMC9563286 DOI: 10.3390/cancers14194765] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Revised: 09/22/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022] Open
Abstract
During the last decade, the identification of oncogenic driver mutations and the introduction of tyrosine kinase inhibitors (TKIs) in daily clinical practice have substantially revamped the therapeutic approach of oncogene-addicted, non-small cell lung cancer (NSCLC). Rearrangements in the anaplastic lymphoma kinase (ALK) gene are detected in around 3-5% of all NSCLC patients. Following the promising results of Crizotinib, a first-generation ALK inhibitor (ALK-i), other second-generation and more recently third-generation TKIs have been developed and are currently a landmark in NSCLC treatment, leading to a significant improvement in patients prognosis. As clinical trials have already demonstrated high efficacy of each ALK-i, both in terms of systemic and intracranial disease control, comparative studies between second and third generation ALK-i are still lacking, and primary or secondary ALK-i resistance inevitably limit their efficacy. Resistance to ALK-i can be due to ALK-dependent or ALK-independent mechanisms, including the activation of bypass signaling pathways and histological transformation: these findings may play an important role in the future to select patients' subsequent therapy. This review aims to provide an overview of underlying molecular alterations of ALK-i resistance and point out promising role of liquid biopsy in predicting tumor response and monitoring resistance mutations. The purpose of this review is also to summarize current approval for ALK-rearranged NSCLC patients, to help clinicians in making decisions on therapeutic sequence, and to deepen the role of clinicopathological and genomic characteristics influencing patients' prognosis during treatment with ALK-i.
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Affiliation(s)
| | | | | | | | | | | | | | - Rossana Berardi
- Clinica Oncologica, Università Politecnica delle Marche, AOU Ospedali Riuniti, 60126 Ancona, Italy
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28
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Sabari JK, Velcheti V, Shimizu K, Strickland MR, Heist RS, Singh M, Nayyar N, Giobbie-Hurder A, Digumarthy SR, Gainor JF, Rajan AP, Nieblas-Bedolla E, Burns AC, Hallin J, Olson P, Christensen JG, Kurz SC, Brastianos PK, Wakimoto H. Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer. Clin Cancer Res 2022; 28:3318-3328. [PMID: 35404402 PMCID: PMC9662862 DOI: 10.1158/1078-0432.ccr-22-0383] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 03/07/2022] [Accepted: 04/04/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized. EXPERIMENTAL DESIGN A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated. RESULTS Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. CONCLUSIONS These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179.
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Affiliation(s)
- Joshua K. Sabari
- Laura and Isaac Perlmutter Cancer Center, NYU Langone, New York, New York.,Corresponding Author: Joshua K. Sabari, Laura and Isaac Perlmutter Cancer Center, NYU Langone, New York, NY 10016. Phone: 212-731-5662; E-mail:
| | - Vamsidhar Velcheti
- Laura and Isaac Perlmutter Cancer Center, NYU Langone, New York, New York
| | - Kazuhide Shimizu
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.,Tokyo Medical and Dental University, Tokyo, Japan
| | - Matthew R. Strickland
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.,Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Rebecca S. Heist
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Mohini Singh
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Naema Nayyar
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | | | - Subba R. Digumarthy
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Justin F. Gainor
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Anant P. Rajan
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | | | | | - Jill Hallin
- Mirati Therapeutics, Inc., San Diego, California
| | - Peter Olson
- Mirati Therapeutics, Inc., San Diego, California
| | | | - Sylvia C. Kurz
- Laura and Isaac Perlmutter Cancer Center, NYU Langone, New York, New York
| | | | - Hiroaki Wakimoto
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
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29
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Tong X, Wang D, Ding X, Tan X, Ren Q, Chen G, Rong Y, Xu T, Huang J, Jiang H, Zheng M, Li X. Blood-brain barrier penetration prediction enhanced by uncertainty estimation. J Cheminform 2022; 14:44. [PMID: 35799215 PMCID: PMC9264551 DOI: 10.1186/s13321-022-00619-2] [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: 09/17/2021] [Accepted: 05/28/2022] [Indexed: 01/01/2023] Open
Abstract
Blood–brain barrier is a pivotal factor to be considered in the process of central nervous system (CNS) drug development, and it is of great significance to rapidly explore the blood–brain barrier permeability (BBBp) of compounds in silico in early drug discovery process. Here, we focus on whether and how uncertainty estimation methods improve in silico BBBp models. We briefly surveyed the current state of in silico BBBp prediction and uncertainty estimation methods of deep learning models, and curated an independent dataset to determine the reliability of the state-of-the-art algorithms. The results exhibit that, despite the comparable performance on BBBp prediction between graph neural networks-based deep learning models and conventional physicochemical-based machine learning models, the GROVER-BBBp model shows greatly improvement when using uncertainty estimations. In particular, the strategy combined Entropy and MC-dropout can increase the accuracy of distinguishing BBB + from BBB − to above 99% by extracting predictions with high confidence level (uncertainty score < 0.1). Case studies on preclinical/clinical drugs for Alzheimer’ s disease and marketed antitumor drugs that verified by literature proved the application value of uncertainty estimation enhanced BBBp prediction model, that may facilitate the drug discovery in the field of CNS diseases and metastatic brain tumors.
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Affiliation(s)
- Xiaochu Tong
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Dingyan Wang
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Xiaoyu Ding
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Xiaoqin Tan
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Qun Ren
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.,Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, 210023, China
| | - Geng Chen
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.,School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, UCAS, Hangzhou, 310024, China
| | - Yu Rong
- Tencent AI Lab, Shenzhen, 518057, China
| | | | | | - Hualiang Jiang
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China
| | - Mingyue Zheng
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. .,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
| | - Xutong Li
- Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China. .,University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
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30
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Hizal M, Bilgin B, Paksoy N, Kılıçkap S, Atcı MM, Kahraman S, Keskinkılıç M, Bilgetekin İ, Ayhan M, Tural D, Eren Ö, Akkoç Mustafayev FN, Yaman Ş, Tatlı AM, Bayram E, Kutlu Y, Ertürk İ, Özcan E, Gülmez A, Korkmaz M, Akagündüz B, Erdem D, Telli TA, Aksoy A, Üskent N, İriağaç Y, Baytemür NK, Aydın D, Şakalar T, Arak H, Selçukbiricik F, Ergün Y, Korkmaz T, Ak N, Ünal Ç, Akdeniz N, Özgün MA, Öksüzoğlu B, Yalçın B, Öztop İ, Algın E, Sakin A, Aydıner A, Yumuk PF, Nahit Şendur MA. Real-world data on efficacy and safety of first-line alectinib treatment in advanced-stage, ALK-positive non-small-cell lung cancer patients: a Turkish Oncology Group study. Future Oncol 2022; 18:2573-2582. [PMID: 35734870 DOI: 10.2217/fon-2022-0083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aims: In this multicenter study, the authors aimed to determine the real-life efficacy and safety of first-line alectinib. Materials & methods: This retrospective trial included advanced-stage, ALK-positive non-small-cell lung cancer patients who were treated with first-line alectinib in terms of ALK-tyrosine kinase inhibitors, regardless of previous chemotherapy. The co-primary end points were progression-free survival both for all patients and for the treatment-naive population. The secondary end points were overall response rate, overall survival, rate of CNS progression and safety. Results & conclusion: A total of 274 patients (n = 177 for treatment-naive patients) were enrolled in the study. The median progression-free survival was 26 and 28.8 months for all patients and the treatment-naive group, respectively. The overall response rate, CNS progression rate and 1-year overall survival ratio were 77.9, 12.4 and 77%. Alectinib is a highly effective therapy with a favorable safety profile.
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Affiliation(s)
- Mutlu Hizal
- Department of Medical Oncology, Ankara City Hospital, Ankara, Turkey
| | - Burak Bilgin
- Atatürk Chest Disease & Chest Surgery Education & Research Hospital, Department of Medical Oncology, Ankara, Turkey
| | - Nail Paksoy
- Department of Medical Oncology, İstanbul Faculty of Medicine, İstanbul University, Istanbul, Turkey
| | - Saadettin Kılıçkap
- Department of Medical Oncology, İstinye University Faculty of Medicine, Ankara Liv Hospital, Ankara, Turkey
| | - Muhammed Mustafa Atcı
- Department of Medical Oncology, İstanbul Prof. Cemil Taşçıoglu City Hospital, Istanbul, Turkey
| | - Seda Kahraman
- Department of Medical Oncology, Yıldırım Beyazıt University Faculty of Medicine, Ankara, Turkey
| | - Merve Keskinkılıç
- Department of Medical Oncology, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey
| | - İrem Bilgetekin
- Department of Medical Oncology, Abdurrahman Yurtaslan Ankara Onkoloji Education & Research Hospital, Ankara, Turkey
| | - Murat Ayhan
- Department of Medical Oncology, Kartal Dr. Lütfi Kırdar City Hospital, Istanbul, Turkey
| | - Deniz Tural
- Department of Medical Oncology, Bakırköy Dr. Sadi Konuk Education & Research Hospital, Istanbul, Turkey
| | - Önder Eren
- Department of Medical Oncology, Selçuk University Faculty of Medicine, Konya, Turkey
| | - Fatma Nihan Akkoç Mustafayev
- Department of Medical Oncology, University of Health Sciences, Sultan 2. Abdülhamid Han Education & Research Hospital, Istanbul, Turkey
| | - Şebnem Yaman
- Atatürk Chest Disease & Chest Surgery Education & Research Hospital, Department of Medical Oncology, Ankara, Turkey
| | - Ali Murat Tatlı
- Department of Medical Oncology, Akdeniz University Faculty of Medicine, Antalya, Turkey
| | - Ertuğrul Bayram
- Department of Medical Oncology, Çukurova University Faculty of Medicine, Adana, Turkey
| | - Yasin Kutlu
- Department of Medical Oncology, İstanbul Medipol University Faculty of Medicine, Istanbul, Turkey
| | - İsmail Ertürk
- Department of Medical Oncology, Ankara Gülhane Education & Research Hospital, Ankara, Turkey
| | - Erkan Özcan
- Department of Medical Oncology, Trakya University Faculty of Medicine, Edirne, Turkey
| | - Ahmet Gülmez
- Department of Medical Oncology, İnönü University Faculty of Medicine, Malatya, Turkey
| | - Mustafa Korkmaz
- Department of Medical Oncology, Necmettin Erbakan University, Meram Faculty of Medicine, Konya, Turkey
| | - Baran Akagündüz
- Department of Medical Oncology, Erzincan Mengücek Gazi Education & Research Hospital, Erzincan, Turkey
| | - Dilek Erdem
- Department of Medical Oncology, Samsun Medical Park Hospital, Samsun, Turkey
| | - Tuğba Akın Telli
- Department of Medical Oncology, Marmara University Faculty of Medicine, Istanbul, Turkey
| | - Asude Aksoy
- Department of Medical Oncology, Fırat University Faculty of Medicine, Elazıg, Turkey
| | - Necdet Üskent
- Department of Medical Oncology, Anadolu Medical Center, Kocaeli, Turkey
| | - Yakup İriağaç
- Department of Medical Oncology, Tekirdağ Namık Kemal University Faculty of Medicine, Tekirdag, Turkey
| | | | - Dinçer Aydın
- Department of Medical Oncology, Kocaeli Derince Education & Research Hospital, Kocaeli, Turkey
| | - Teoman Şakalar
- Department of Medical Oncology, Necip Fazıl City Hospital, Kahramanmaras, Turkey
| | - Hacı Arak
- Gaziantep University Faculty of Medicine, Department of Medical Oncology, Gaziantep, Turkey
| | - Fatih Selçukbiricik
- Department of Medical Oncology, Koç University Faculty of Medicine, Istanbul, Turkey
| | - Yakup Ergün
- Department of Medical Oncology, Batman Education & Research Hospital, Batman, Turkey
| | - Taner Korkmaz
- Department of Medical Oncology, Acıbadem Maslak Hospital, Istanbul, Turkey
| | - Naziye Ak
- Department of Medical Oncology, Yozgat City Hospital, Yozgat, Turkey
| | - Çağlar Ünal
- Department of Medical Oncology, Gayrettepe Florence Nightingale Hospital, Istanbul, Turkey
| | - Nadiye Akdeniz
- Department of Medical Oncology, Adıyaman University, Education & Research Hospital, Adıyaman, Turkey
| | - Mehmet Alpaslan Özgün
- Department of Medical Oncology, University of Health Sciences, Sultan 2. Abdülhamid Han Education & Research Hospital, Istanbul, Turkey
| | - Berna Öksüzoğlu
- Department of Medical Oncology, Abdurrahman Yurtaslan Ankara Onkoloji Education & Research Hospital, Ankara, Turkey
| | - Bülent Yalçın
- Department of Medical Oncology, Yıldırım Beyazıt University Faculty of Medicine, Ankara, Turkey
| | - İlhan Öztop
- Department of Medical Oncology, Dokuz Eylül University Faculty of Medicine, İzmir, Turkey
| | - Efnan Algın
- Department of Medical Oncology, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Abdullah Sakin
- Department of Medical Oncology, İstanbul Prof. Cemil Taşçıoglu City Hospital, Istanbul, Turkey
| | - Adnan Aydıner
- Department of Medical Oncology, İstanbul Faculty of Medicine, İstanbul University, Istanbul, Turkey
| | - Perran Fulden Yumuk
- Department of Medical Oncology, Koç University Faculty of Medicine, Istanbul, Turkey.,Department of Medical Oncology, American Hospital, Istanbul, Turkey
| | - Mehmet Ali Nahit Şendur
- Department of Medical Oncology, Yıldırım Beyazıt University Faculty of Medicine, Ankara, Turkey
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31
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Tan AC, Tan DSW. Targeted Therapies for Lung Cancer Patients With Oncogenic Driver Molecular Alterations. J Clin Oncol 2022; 40:611-625. [PMID: 34985916 DOI: 10.1200/jco.21.01626] [Citation(s) in RCA: 390] [Impact Index Per Article: 130.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Lung cancer has traditionally been classified by histology. However, a greater understanding of disease biology and the identification of oncogenic driver alterations has dramatically altered the therapeutic landscape. Consequently, the new classification paradigm of non-small-cell lung cancer is further characterized by molecularly defined subsets actionable with targeted therapies and the treatment landscape is becoming increasingly complex. This review encompasses the current standards of care for targeted therapies in lung cancer with driver molecular alterations. Targeted therapies for EGFR exon 19 deletion and L858R mutations, and ALK and ROS1 rearrangements are well established. However, there is an expanding list of approved targeted therapies including for BRAF V600E, EGFR exon 20 insertion, and KRAS G12C mutations, MET exon 14 alterations, and NTRK and RET rearrangements. In addition, there are numerous other oncogenic drivers, such as HER2 exon 20 insertion mutations, for which there are emerging efficacy data for targeted therapies. The importance of diagnostic molecular testing, intracranial efficacy of novel therapies, the optimal sequencing of therapies, role for targeted therapies in early-stage disease, and future directions for precision oncology approaches to understand tumor evolution and therapeutic resistance are also discussed.
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Affiliation(s)
- Aaron C Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore.,Duke-NUS Medical School, National University of Singapore, Singapore
| | - Daniel S W Tan
- Division of Medical Oncology, National Cancer Centre Singapore, Singapore.,Duke-NUS Medical School, National University of Singapore, Singapore.,Genome Institute of Singapore, Singapore
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Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer. ESMO Open 2022; 7:100333. [PMID: 35042152 PMCID: PMC8777286 DOI: 10.1016/j.esmoop.2021.100333] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 08/31/2021] [Accepted: 11/15/2021] [Indexed: 01/12/2023] Open
Abstract
Background At the primary data cut-off, the ALUR study demonstrated significantly improved progression-free survival (PFS) and central nervous system (CNS) objective response rate (ORR) with alectinib versus chemotherapy in pretreated, advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer. We report final efficacy and safety data, and exploratory molecular profiling. Patients and methods Patients who received prior platinum-doublet chemotherapy and crizotinib were randomized 2 : 1 to receive alectinib 600 mg twice daily (n = 79) or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, every 3 weeks; n = 40) until progressive disease, death or withdrawal. The primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, CNS ORR and safety. Plasma samples were collected at baseline, then every 6 weeks until progressive disease; molecular factors detected by next-generation sequencing were correlated with outcomes. Results Investigator-assessed PFS was significantly longer with alectinib than chemotherapy (median 10.9 versus 1.4 months; hazard ratio 0.20, 95% confidence interval 0.12-0.33; P < 0.001). ORR was 50.6% with alectinib versus 2.5% with chemotherapy (P < 0.001). In patients with measurable CNS metastases at baseline, CNS ORR was 66.7% with alectinib versus 0% with chemotherapy (P < 0.001). No new safety signals were seen. ALK rearrangement was identified in 69.5% (n = 41/59) of baseline plasma samples. Confirmed partial responses were observed with alectinib in 6/11 patients with a secondary ALK mutation and 4/6 patients with a non-EML4-ALK (where EML4 is echinoderm microtubule-associated protein-like 4) fusion. Detection of mutant TP53 in baseline plasma resulted in numerically shorter PFS with alectinib (hazard ratio 1.88, 95% confidence interval 0.9-3.93). Conclusions Final efficacy data from ALUR confirmed the superior PFS, ORR and CNS ORR of alectinib versus chemotherapy in pretreated, advanced ALK-positive non-small-cell lung cancer. Alectinib prolonged PFS versus chemotherapy in patients with wild-type or mutant TP53; however, alectinib activity was considerably decreased in patients with mutant TP53.
Median PFS was significantly longer with alectinib versus chemotherapy. ORR and CNS ORR (in patients with measurable baseline CNS lesions) were higher with alectinib than chemotherapy (P < 0.001). The safety profile of alectinib was consistent with the primary analysis and post-marketing experience. Alectinib demonstrated activity against several secondary ALK mutations detected in baseline plasma. Alectinib prolonged PFS versus chemotherapy in patients with wild-type or mutant TP53, and a prognostic difference was seen.
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33
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Yin Q, Li P, Wang P, Zhang Z, Liu Q, Sun Z, Li W, Ma L, Wang X. Alectinib Together with Intracranial Therapies Improved Survival Outcomes in Untreated ALK-Positive Patients with Non-Small-Cell Lung Cancer and Symptomatic and Synchronic Brain Metastases: A Retrospective Study. Onco Targets Ther 2022; 14:5533-5542. [PMID: 35002258 PMCID: PMC8722687 DOI: 10.2147/ott.s345439] [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: 10/20/2021] [Accepted: 12/17/2021] [Indexed: 12/23/2022] Open
Abstract
Purpose The performance of alectinib and crizotinib in untreated anaplastic lymphoma kinase (ALK)-positive patients with non-small-cell lung cancer (NSCLC) and symptomatic and synchronic brain metastases is largely unknown. This retrospective study assessed the effectiveness of alectinib and crizotinib, together with intracranial therapies in a cohort of these patients. Patients and Methods This study included 34 previously untreated ALK-positive NSCLC patients with three or fewer intracranial metastases. Of these patients, 13 received oral alectinib 600 mg twice daily, and 21 received oral crizotinib 250 mg twice daily, until progressive disease, unacceptable toxicity, or death. All intracranial metastases were treated with craniotomy, CyberKnife, or both. Results Median overall progression-free survival (PFS) was 32.8 months (95% CI 24.4–41.2 months) in patients treated with alectinib and 8.0 months (95% CI 7.3–8.7 months) in patients treated with crizotinib. Median PFS of brain lesions was not yet reached with alectinib (95% CI 30.1 months–not estimated) and was 8.5 months (95% CI 7.2–12.3 months) with crizotinib. Median PFS of lung lesions was 38.5 months (95% CI 27.5–49.5 months) with alectinib and 9.2 months (95% CI 7.4–11.0 months) with crizotinib. Median overall survival was not yet reached with alectinib (95% CI 31.0 months–not estimated) and 30.3 months (95% CI 27.3–37.1 months) with crizotinib. Conclusion Compared with crizotinib, alectinib showed superior efficacy and lower toxicity in the treatment of ALK-positive patients with NSCLC and symptomatic and synchronic brain metastases. The inclusion of intracranial therapies such as craniotomy or CyberKnife further improved the brain PFS and overall survival of these patients.
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Affiliation(s)
- Qiang Yin
- Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Peng Li
- Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Peng Wang
- Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Zhen Zhang
- Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Qun Liu
- Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Zengfeng Sun
- Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Wenliang Li
- Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Li Ma
- Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
| | - Xiaoguang Wang
- Department of Neurosurgery, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China
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34
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Long-term effects of pharmacological inhibition of Anaplastic lymphoma kinase in Neurofibromatosis 1 mutant mice. Behav Brain Res 2022; 423:113767. [DOI: 10.1016/j.bbr.2022.113767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/13/2021] [Accepted: 01/18/2022] [Indexed: 11/21/2022]
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35
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Shen D, Song H, Zhang J, Liao C, Wang Y, Fang M, Tang Y. Treatment of Relapsed and Refractory ALK-Positive Anaplastic Large Cell Lymphoma With ALK-Specific Tyrosine Kinase Inhibitor in Children: A Case Series. J Pediatr Hematol Oncol 2022; 44:e1-e4. [PMID: 33661174 DOI: 10.1097/mph.0000000000002137] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 01/28/2021] [Indexed: 11/26/2022]
Abstract
Relapsed and refractory ALK-positive anaplastic large cell lymphoma (ALCL) has a poor prognosis. In this report, we present 3 relapsed/refractory pediatric ALCL patients, 1 of these with central nervous system involvement. All 3 patients were treated with ALK inhibitor and achieved complete response. Both crizotinib and alectinib have shown significant activity in pediatric patients with refractory ALK-positive ALCL.
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Affiliation(s)
- Diying Shen
- Department of Hematology and Oncology, Pediatric Hematology-Oncology Center, Pediatric Leukemia Diagnosis and Therapeutic Technology Research Center of Zhejiang Province, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
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36
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Zeng Q, Zhang X, He S, Zhou Z, Xia L, Zhang W, Zeng L. Crizotinib versus Alectinib for the Treatment of ALK-Positive Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis. Chemotherapy 2021; 67:67-80. [PMID: 34915469 DOI: 10.1159/000521452] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 12/10/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Crizotinib and alectinib are the two most commonly used anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive non-small cell lung cancer (NSCLC). We compared their antitumor efficacies and adverse effects based on a pooled analysis of the ALEX, ALESIA and J-ALEX clinical trials. METHODS Seven databases were searched for eligible articles. The primary endpoints included overall survival (OS), progression-free survival (PFS), central nervous system (CNS)-PFS, drug responses and adverse effects (AEs). RESULTS Seven articles on three randomized controlled clinical trials (ALEX, ALESIA and J-ALEX) that included 697 patients were included. Compared with crizotinib, alectinib exhibited superior efficacy in PFS (HR [hazard ratio]: 0.35, [0.25-0.49], p < 0.00001), OS (HR: 0.66, [0.47-0.92], p = 0.02), CNS-PFS (HR: 0.17, [0.11-0.24], p < 0.00001), duration of response (HR: 0.31, [0.23-0.42], p < 0.00001), objective response rate (ORR) (risk ratio [RR]: 0.87, [0.80-0.94], p = 0.0003), partial response (PR) (RR: 0.88, [0.81-0.96], p = 0.004), and grade 3-5 AEs (RR: 1.43, [1.09-1.87], p = 0.009). Additionally, compared with crizotinib, alectinib exhibited a survival advantage that increased with its prolongation of survival time. The disease control rate, complete response and total AEs were comparable between the two groups. The crizotinib group reported higher rates of constipation, nausea, diarrhea, vomiting, peripheral edema, dysgeusia, visual impairment and levels of alanine aminotransferase and aspartate aminotransferase as well as greater decreases in appetite and neutrophil count. CONCLUSIONS In both antitumor efficacy and safety, alectinib appears to be superior to crizotinib for the treatment of ALK-positive NSCLC.
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Affiliation(s)
- Qinghua Zeng
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiquan Zhang
- Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Shan He
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhiyong Zhou
- Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, China
| | - Luping Xia
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Wenxiong Zhang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lin Zeng
- Department of Oncology, Jiangxi Provincial People's Hospital, Nanchang, China
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37
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Steeg PS. The blood-tumour barrier in cancer biology and therapy. Nat Rev Clin Oncol 2021; 18:696-714. [PMID: 34253912 DOI: 10.1038/s41571-021-00529-6] [Citation(s) in RCA: 161] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/21/2021] [Indexed: 02/06/2023]
Abstract
The protective blood-brain barrier has a major role in ensuring normal brain function by severely limiting and tightly controlling the ingress of substances into the brain from the circulation. In primary brain tumours, such as glioblastomas, as well as in brain metastases from cancers in other organs, including lung and breast cancers and melanoma, the blood-brain barrier is modified and is referred to as the blood-tumour barrier (BTB). Alterations in the BTB affect its permeability, and this structure participates in reciprocal regulatory pathways with tumour cells. Importantly, the BTB typically retains a heterogeneous capacity to restrict the penetration of many therapeutic agents into intracranial tumours, and overcoming this challenge is a key to improving the effectiveness of treatment and patient quality of life. Herein, current knowledge of BTB structure and function is reviewed from a cell and cancer biology standpoint, with a focus on findings derived from in vivo models and human tumour specimens. Additionally, how this knowledge can be translated into clinical advances for patients with cancer is discussed.
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Affiliation(s)
- Patricia S Steeg
- Women's Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
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38
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Pan Y, Deng C, Qiu Z, Cao C, Wu F. The Resistance Mechanisms and Treatment Strategies for ALK-Rearranged Non-Small Cell Lung Cancer. Front Oncol 2021; 11:713530. [PMID: 34660278 PMCID: PMC8517331 DOI: 10.3389/fonc.2021.713530] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Accepted: 09/13/2021] [Indexed: 12/19/2022] Open
Abstract
Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance.
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Affiliation(s)
- Yue Pan
- Department of Oncology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Chao Deng
- Department of Oncology, Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhenhua Qiu
- Department of Oncology, Second Xiangya Hospital, Central South University, Changsha, China
| | | | - Fang Wu
- Department of Oncology, Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Cancer Mega-Data Intelligent Application and Engineering Research Centre, Changsha, China.,Hunan Key Laboratory of Tumor Models and Individualized Medicine, Second Xiangya Hospital, Central South University, Changsha, China.,Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, Second Xiangya Hospital, Central South University, Changsha, China
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39
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Zhao B, Han Y, Wang Y, Wang Y, Wang Y, Xing H, Dai C, Wang Y, Wang H, Ma W. A Bayesian network meta-analysis regarding the comparative efficacy of therapeutics for ALK-positive, brain metastatic non-small cell lung cancer. Pharmacol Res 2021; 174:105931. [PMID: 34626769 DOI: 10.1016/j.phrs.2021.105931] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 09/25/2021] [Accepted: 10/01/2021] [Indexed: 12/15/2022]
Abstract
More clinical evidence is needed regarding the ranking priority of interventions for ALK-positive, brain metastatic (BM) non-small cell lung cancer (NSCLC). Eligible randomized controlled trials (RCTs) were identified. Progression-free survival (PFS), objective response rate (ORR) and overall survival (OS) for the intended populations were analyzed with random effects, Bayesian network meta-analysis with the estimated hazard ratio (HR) and odds ratio (OR) with 95% credible interval (95% CrIs). We included 11 RCTs (2687 NSCLC and 991 BM patients) investigating 7 treatments and 5 medication classes. For PFS for BM patients, lorlatinib (hazard ratio (HR): 0.01, 95% CrI: 0.001-0.12), alectinib (HR: 0.05, 95% CrI: 0.01-0.21) and brigatinib (HR: 0.07, 95% CrI: 0.007-0.76) were top-ranking individual treatments; for ORR for BM patients, brigatinib, lorlatinib and alectinib were top-ranking treatments. For PFS for all NSCLC patients, the top-ranking individual treatments were lorlatinib (HR: 0.05, 95% CrI: 0.02-0.13), alectinib (HR: 0.09, 95% CrI: 0.05-0.18) and brigatinib (HR: 0.11, 95% CrI: 0.05-0.28). For OS for all NSCLC patients, we found that no individual treatments were superior to chemotherapy, whereas the following top-ranking interventions were alectinib (HR: 0.29, 95% CrI: 0.03-1.68), lorlatinib (HR: 0.41, 95% CrI: 0.04-4.13), and ceritinib (HR: 0.63, 95% CrI: 0.10-4.25). The results of individual treatments and medication classes were similar. Data were limited in regard to subgroup analyses and adverse events of BM patients. Lorlatinib has the most statistical superiority for BM patients, but ORR differences between third- and second-generation inhibitors are not obvious. All things considered, alectinib is recommended as first-line treatment, followed by lorlatinib, especially after developing drug resistance to alectinib.
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Affiliation(s)
- Binghao Zhao
- Departments of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yan Han
- Departments of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yadong Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China; Department of Thoracic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, PR China
| | - Yuekun Wang
- Departments of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Yaning Wang
- Departments of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Hao Xing
- Departments of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China
| | - Congxin Dai
- Department of Neurosurgery, Beijing Tongren Hospital, Capital Medical University, Beijing, PR China
| | - Yu Wang
- Departments of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China.
| | - Hanping Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China; Department of Respiratory Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
| | - Wenbin Ma
- Departments of Neurosurgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China; State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, PR China; China Pituitary Disease Registry Center, Chinese Pituitary Adenoma Cooperative Group, Beijing, PR China; China Alliance of Rare Diseases, Beijing, PR China.
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40
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Wang B, Guo H, Xu H, Yu H, Chen Y, Zhao G. Research Progress and Challenges in the Treatment of Central Nervous System Metastasis of Non-Small Cell Lung Cancer. Cells 2021; 10:2620. [PMID: 34685600 PMCID: PMC8533870 DOI: 10.3390/cells10102620] [Citation(s) in RCA: 9] [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: 07/25/2021] [Revised: 09/06/2021] [Accepted: 09/25/2021] [Indexed: 12/26/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors and has high morbidity and mortality rates. Central nervous system (CNS) metastasis is one of the most frequent complications in patients with NSCLC and seriously affects the quality of life (QOL) and overall survival (OS) of patients, with a median OS of untreated patients of only 1-3 months. There are various treatment methods for NSCLC CNS metastasis, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, which do not meet the requirements of patients in terms of improving OS and QOL. There are still many problems in the treatment of NSCLC CNS metastasis that need to be solved urgently. This review summarizes the research progress in the treatment of NSCLC CNS metastasis to provide a reference for clinical practice.
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Affiliation(s)
- Bin Wang
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
| | - Hanfei Guo
- Cancer Center, The First Hospital of Jilin University, Changchun 130021, China;
| | - Haiyang Xu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
| | - Hongquan Yu
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
| | - Yong Chen
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
| | - Gang Zhao
- Department of Neurosurgery, The First Hospital of Jilin University, Changchun 130021, China; (B.W.); (H.X.); (H.Y.)
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Hsu JC, Jaminion F, Guerini E, Balas B, Bordogna W, Morcos PN, Frey N. Pharmacometric analyses of alectinib to facilitate approval of the optimal dose for the first-line treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2021; 10:1357-1370. [PMID: 34547184 PMCID: PMC8592510 DOI: 10.1002/psp4.12702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/08/2021] [Accepted: 07/23/2021] [Indexed: 11/08/2022]
Abstract
Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK‐positive non‐small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib‐failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one‐compartment models with sequential zero/first‐order input and first‐order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment‐naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression‐free survival in treatment‐naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of treatment as a significant covariate, with an optimal response achieved for concentrations above 1040 nmol/L. With 600 mg twice daily (b.i.d.), 92% of global patients are above this threshold concentration, compared with only 43% of patients with 300 mg b.i.d. In Japan, where the body weight distribution is lower, the approved 300 mg b.i.d. dose brings about 70% of Japanese patients above this threshold. Logistic regression analyses found no significant relationship between the combined alectinib–M4 molar concentration and first occurrence of adverse events. These pharmacometric results were used to expedite and facilitate regulatory approvals of 600 mg b.i.d. for first‐line ALK‐positive NSCLC in the United States and European Union in 2017 and in China in 2018.
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Affiliation(s)
- Joy C Hsu
- Roche Innovation Center, F. Hoffmann-La Roche Ltd, New York, New York, USA
| | - Felix Jaminion
- Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Elena Guerini
- Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | | | | | - Peter N Morcos
- Roche Innovation Center, F. Hoffmann-La Roche Ltd, New York, New York, USA
| | - Nicolas Frey
- Roche Innovation Center, F. Hoffmann-La Roche Ltd, Basel, Switzerland
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Brenner AK, Gunnes MW. Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma-A Comprehensive Update. Pharmaceutics 2021; 13:pharmaceutics13091427. [PMID: 34575503 PMCID: PMC8470592 DOI: 10.3390/pharmaceutics13091427] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/27/2021] [Accepted: 08/29/2021] [Indexed: 01/27/2023] Open
Abstract
Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment regimens are probably less likely to induce drug resistance, a special focus will be on the combination of ALK inhibitors with drugs that either target downstream signalling pathways or that affect the survival and proliferation of cancer cells in general.
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Yamamoto S, Koga Y, Ono H, Goto H, Hata N, Yamamoto H, Suzuki SO, Sakai Y, Iwaki T, Ohga S. Alectinib-responsive infantile anaplastic ganglioglioma with a novel VCL-ALK gene fusion. Pediatr Blood Cancer 2021; 68:e29122. [PMID: 34019333 DOI: 10.1002/pbc.29122] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 11/07/2022]
Affiliation(s)
- Shunsuke Yamamoto
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Yuhki Koga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Hiroaki Ono
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Hironori Goto
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Nobuhiro Hata
- Department of Neurosurgery, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Hidetaka Yamamoto
- Department of Anatomic Pathology, Graduate of School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Satoshi O Suzuki
- Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Yasunari Sakai
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Toru Iwaki
- Department of Neuropathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
| | - Shouichi Ohga
- Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan
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Krenik D, Weiss JB, Raber J. Role of the parental NF1 carrier in effects of pharmacological inhibition of anaplastic lymphoma kinase in Neurofibromatosis 1 mutant mice. Brain Res 2021; 1769:147594. [PMID: 34339711 DOI: 10.1016/j.brainres.2021.147594] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 07/19/2021] [Accepted: 07/25/2021] [Indexed: 11/16/2022]
Abstract
Neurofibromatosis type 1 (NF1), a genetically determined neurodevelopmental disorder and tumor syndrome, is associated with cognitive impairments, including in executive function and sleep-related problems. Consistent with the human data, NF1 heterozygous (Het) mice show impaired spatial learning and memory in the water maze and extinction of contextual fear memory. It is not clear whether neurological phenotypes might depend on the parental carrier. In this study, we compared the behavioral and cognitive performance of NF1 Het and wild-type litter mates with either the father (PC) or the mother (MC) as the NF1 carrier on a F1 C57BL/66/129SvJ background. The behavioral and cognitive phenotypes and responsiveness to Alk inhibition in heterozygous NF1 offspring depended on whether the parental carrier was maternal or paternal. Alk inhibition (20 mg/kg) increased activity levels during the dark period in NF1 Het PC, but not MC, mice. In the water maze, NF1 Het PC, but not MC, mice showed reduced cognitive flexibility and impaired ability to locate the third hidden platform location, which was improved by Alk inhibition (3.6 mg/kg). Consistent with reduced cognitive flexibility, WT, but not NF1, mice showed better performance in the third than second water maze probe trial. Finally, Alk inhibition (10 mg/kg) increased baseline activity of NF1 MC, but not PC, mice during the fear conditioning test. Thus, the effective dose depends on the behavioral test and genotype but indicates that in NF1 patients cognitive flexibility might be particularly sensitive to Alk inhibition.
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Affiliation(s)
- Destine Krenik
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA
| | - Joseph B Weiss
- Cardiovascular Institute and Warren Alpert School of Medicine at Brown University Providence, RI 02840, USA
| | - Jacob Raber
- Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA; Departments of Neurology, Psychiatry, and Radiation Medicine, Division of Neuroscience ONPRC, Oregon Health & Science University, Portland, OR 97239, USA; College of Pharmacy, Oregon State University, Corvallis, Oregon, OR 97331, USA.
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45
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Schokrpur S, Hilburn V, Giustini N, Bazhenova L. An overview of alectinib hydrochloride as a treatment option for ALK positive non-small cell lung cancer. Expert Opin Pharmacother 2021; 22:1815-1824. [PMID: 34225542 DOI: 10.1080/14656566.2021.1948014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Introduction: Alectinib is a second-generation inhibitor of anaplastic lymphoma kinase (ALK) and RET. Phase III clinical trials have established its superiority to crizotinib in the first-line ALK inhibitor-naïve setting. Studies also support its use over chemotherapy in the post-crizotinib setting. It is currently one of several FDA- and EMA-approved ALK inhibitors, and it is listed as a preferred initial therapy for treatment-naïve ALK-positive non-small cell lung cancer (NSCLC).Areas covered: Herein, the authors provide the reader with details of the chemical structure, pharmacologic properties, resistance mutations, phase I, II, and III clinical trials, and safety profile of alectinib. Furthermore, the authors provide the reader with the expert opinion and future perspectives on the drug.Expert opinion: Alectinib compares favorably to other second-generation ALK inhibitors with regards to safety, tolerability, and efficacy. Based on currently available data, it is an appropriate first-line option. Ongoing studies will better resolve the ideal sequencing of ALK inhibitors in the treatment of ALK-positive NSCLC.
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Affiliation(s)
- Shiruyeh Schokrpur
- Division of Hematology, Oncology University of California San Diego Moores Cancer Center, San Diego, California, USA
| | - Van Hilburn
- Division of Pharmacy, University of California San Diego, San Diego, California, USA
| | - Nicholas Giustini
- Division of Hematology, Oncology University of California San Diego Moores Cancer Center, San Diego, California, USA
| | - Lyudmila Bazhenova
- Division of Hematology, Oncology University of California San Diego Moores Cancer Center, San Diego, California, USA
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46
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Li D, Song Z, Dong B, Song W, Cheng C, Zhang Y, Zhang W. Advances in targeted therapy in non-small cell lung cancer with actionable mutations and leptomeningeal metastasis. J Clin Pharm Ther 2021; 47:24-32. [PMID: 34309914 DOI: 10.1111/jcpt.13489] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/19/2021] [Accepted: 07/05/2021] [Indexed: 11/29/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE?: Leptomeningeal metastasis (LM) is a serious complication of advanced non-small cell lung cancer (NSCLC) that is diagnosed in approximately 3%-5% of patients. LM occurs more frequently in patients with NSCLC harbouring epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements and is usually accompanied by a poor prognosis, with a median overall survival (OS) of several months if patients receive conventional treatments. However, tyrosine kinase inhibitor (TKI) therapy after LM diagnosis is an independent predictive factor for extended survival. Here, we aim to summarize the latest advances in targeted therapy for LM and provide patients with better treatment options. METHODS: By reviewing the recent progress of targeted therapy in NSCLC with LM, especially the efficacy of newer generation TKIs, we aim to provide clinicians with a reference to further optimize patient treatment plans. RESULTS AND DISCUSSION: Osimertinib was confirmed to have a several-fold higher CNS permeability than other EGFR-TKIs and was recommended as the preferred choice for patients with EGFR-positive LM whether or not they harboured the T790M mutation. Second-generation ALK-TKIs have a higher rate of intracranial response and can be positioned as front-line drugs in NSCLC with LM. However, the sequence in which ALK-TKIs are administered for effective disease control requires further evaluation. In addition, targeted therapy revealed a potential choice in patients with LM and rare mutations, such as ROS1 and BRAF. WHAT IS NEW AND CONCLUSIONS?: The development of therapeutic agents with greater CNS penetration is vital for the management of CNS metastasis from NSCLC, particularly in the EGFR-mutant and ALK-rearranged subtypes. Systemic therapy with newer generation TKIs is preferred as the initial intervention. This is because newer generation TKIs are designed to penetrate the blood-brain barrier and possess significantly higher intracranial activities. However, their further effectiveness is limited by inadequate blood-brain barrier penetration and acquired drug resistance. Further studies are needed to further understand the mechanisms underlying resistance to treatment.
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Affiliation(s)
- Ding Li
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
| | - Zhenguo Song
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
| | - Bingqi Dong
- Department of Urology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Wenping Song
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
| | - Cheng Cheng
- Department of Hematology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yongna Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
| | - Wenzhou Zhang
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,Henan Engineering Research Center for Tumor Precision Medicine and Comprehensive Evaluation, Zhengzhou, China
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Ceddia S, Codacci-Pisanelli G. Treatment of brain metastases in ALK-positive non-small cell lung cancer. Crit Rev Oncol Hematol 2021; 165:103400. [PMID: 34147645 DOI: 10.1016/j.critrevonc.2021.103400] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Revised: 05/31/2021] [Accepted: 06/03/2021] [Indexed: 11/17/2022] Open
Abstract
Brain metastases are quite frequent in patients with ALK-translocated non-small cell lung cancer (NSCLC): they are often not amenable to surgical resection and are generally treated with radiotherapy (RT). This however causes severe late toxic side effects that may become invalidating considering the relatively long survival provided by recent medical treatment with target therapies. Several clinical trials have demonstrated that ALK-inhibitors (crizotinib, alectinib, brigatinib) show excellent activity also against brain metastases. It is therefore reasonable, in asymptomatic patients, to start treatment with specific inhibitors: RT will be used at the time of tumor progression or when symptoms appear. This sequence provides the best quality of life for patients.
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Affiliation(s)
- Serena Ceddia
- Department of Medical and Surgical Sciences and Biotechnology, University of Rome "la Sapienza", Corso della Repubblica, 79, 04100, Latina, Italy.
| | - Giovanni Codacci-Pisanelli
- Department of Medical and Surgical Sciences and Biotechnology, University of Rome "la Sapienza", Corso della Repubblica, 79, 04100, Latina, Italy.
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48
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Zhou H, Xu B, Xu J, Zhu G, Guo Y. Novel MRPS9-ALK Fusion Mutation in a Lung Adenocarcinoma Patient: A Case Report. Front Oncol 2021; 11:670907. [PMID: 34168990 PMCID: PMC8217641 DOI: 10.3389/fonc.2021.670907] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 05/10/2021] [Indexed: 12/25/2022] Open
Abstract
Anaplastic lymphoma kinase (ALK) rearrangements account for approximately 5-6% of non-small-cell lung cancer (NSCLC) patients. In this study, a case of lung adenocarcinoma harboring a novel MRPS9-ALK fusion is reported. The patient responded well to the first and second generation of ALK-tyrosine kinase inhibitors (ALK-TKIs) (crizotinib then alectinib), as her imaging findings and clinical symptoms significantly improved. At last follow-up, over 21 months of overall survival (OS) has been achieved since ALK-TKI treatment. The progression-free survival (PFS) is already ten months since alectinib. The adverse effects were manageable. The case presented here provides first clinical evidence of the efficacy of ALK-TKIs in NSCLC patients with MRPS9-ALK fusion.
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Affiliation(s)
- Huamiao Zhou
- Department of Oncology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Binyue Xu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Jili Xu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Guomeng Zhu
- Department of Oncology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Yong Guo
- Department of Oncology, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, China
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Pan Y, Xiao W, Ye F, Wang H, Shen Y, Yu X, Han X, Chu Q, Zhou C, Zhang Z, Ren S. Outcomes of switching from crizotinib to alectinib in patients with advanced non-small cell lung cancer with anaplastic lymphoma kinase fusion. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1014. [PMID: 34277814 PMCID: PMC8267309 DOI: 10.21037/atm-21-2769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 06/16/2021] [Indexed: 01/15/2023]
Abstract
BACKGROUND Alectinib and crizotinib have been approved as first-line therapies for advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene fusion. However, the therapeutic efficacy and side effects are still largely unknown of patients who switched to next-generation ALK tyrosine kinase inhibitors (ALK-TKIs), such as alectinib, after experiencing no disease progression with initial crizotinib treatment. METHODS This prospective real-world study enrolled patients who were treated with alectinib after experiencing no disease progression with initial crizotinib treatment. The patients' baseline characteristics, objective response rate (ORR) of crizotinib and alectinib, size change of target tumor lesions, treatment regimen and adverse events (AEs) were collected and analyzed. RESULTS The study included 53 patients, the majority of whom (96.2%) had non-squamous NSCLC. The median age was 51 (range, 31-80) years old. The ORR of first-line crizotinib was 54.7%. The ORR of sequential alectinib was 73.6%, and 90.5% of patients showed further tumor shrinkage after the alectinib treatment. The median progression-free survival was not reached, and 90.5% of patients were still enrolled in the study at the last follow-up. Among them, 34.0% of patients switched to alectinib treatment due to the toxicity. Crizotinib was associated with a higher frequency of AEs of grades 3 and 4 than alectinib (15.1% vs. 0%). Neither group had any AEs resulting in death. CONCLUSIONS Switching to alectinib might be an option for patients who do not experience disease progression with initial crizotinib therapy, and may promote better treatment compliance.
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Affiliation(s)
- Yingying Pan
- Department of Medical Oncology, Shanghai Pulmonary Hospital &Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Wenjing Xiao
- Department of Tumor Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Feng Ye
- Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Huijuan Wang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yihong Shen
- Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinmin Yu
- Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Xiao Han
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital &Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Zhihong Zhang
- Department of Respiratory Oncology, Anhui Provincial Cancer Hospital (The First Affiliated Hospital of USTC West District), Hefei, China
| | - Shengxiang Ren
- Department of Medical Oncology, Shanghai Pulmonary Hospital &Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
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50
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Alsmadi MM, Al-Daoud NM, Jaradat MM, Alzughoul SB, Abu Kwiak AD, Abu Laila SS, Abu Shameh AJ, Alhazabreh MK, Jaber SA, Abu Kassab HT. Physiologically-based pharmacokinetic model for alectinib, ruxolitinib, and panobinostat in the presence of cancer, renal impairment, and hepatic impairment. Biopharm Drug Dispos 2021; 42:263-284. [PMID: 33904202 DOI: 10.1002/bdd.2282] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 03/18/2021] [Accepted: 04/11/2021] [Indexed: 12/24/2022]
Abstract
Renal (RIP) and hepatic (HIP) impairments are prevalent conditions in cancer patients. They can cause changes in gastric emptying time, albumin levels, hematocrit, glomerular filtration rate, hepatic functional volume, blood flow rates, and metabolic activity that can modify drug pharmacokinetics. Performing clinical studies in such populations has ethical and practical issues. Using predictive physiologically-based pharmacokinetic (PBPK) models in the evaluation of the PK of alectinib, ruxolitinib, and panobinostat exposures in the presence of cancer, RIP, and HIP can help in using optimal doses with lower toxicity in these populations. Verified PBPK models were customized under scrutiny to account for the pathophysiological changes induced in these diseases. The PBPK model-predicted plasma exposures in patients with different health conditions within average 2-fold error. The PBPK model predicted an area under the curve ratio (AUCR) of 1, and 1.8, for ruxolitinib and panobinostat, respectively, in the presence of severe RIP. On the other hand, the severe HIP was associated with AUCR of 1.4, 2.9, and 1.8 for alectinib, ruxolitinib, and panobinostat, respectively, in agreement with the observed AUCR. Moreover, the PBPK model predicted that alectinib therapeutic cerebrospinal fluid levels are achieved in patients with non-small cell lung cancer, moderate HIP, and severe HIP at 1-, 1.5-, and 1.8-fold that of healthy subjects. The customized PBPK models showed promising ethical alternatives for simulating clinical studies in patients with cancer, RIP, and HIP. More work is needed to quantify other pathophysiological changes induced by simultaneous affliction by cancer and RIP or HIP.
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Affiliation(s)
- Mo'tasem M Alsmadi
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Nour M Al-Daoud
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Mays M Jaradat
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Saja B Alzughoul
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Amani D Abu Kwiak
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Salam S Abu Laila
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Ayat J Abu Shameh
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Mohammad K Alhazabreh
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Sana'a A Jaber
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Hala T Abu Kassab
- Department of Pharmaceutical Technology, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
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