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Xie J, Gao Y, Xu W, Zhu J. Mechanisms of Resistance to ALK Inhibitors and Corresponding Treatment Strategies in Lung Cancer. Int J Gen Med 2025; 18:2151-2171. [PMID: 40259931 PMCID: PMC12010037 DOI: 10.2147/ijgm.s512395] [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: 12/16/2024] [Accepted: 04/02/2025] [Indexed: 04/23/2025] Open
Abstract
Lung cancer continues to be a leading cause of cancer-related mortality and morbidity worldwide. The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene accounts for approximately 3%-5% of gene mutation types. Targeted therapies for ALK mutations have made significant advancements in recent decades, enabling a considerable number of patients to achieve the goal of five-year survival benefits. However, overcoming the drug resistance that arises with current ALK tyrosine kinase inhibitors (TKIs) remain a major challenge in ALK-targeted therapies. In this review, we briefly discuss the primary and secondary mechanisms of resistance to ALK-TKIs, and explore treatment strategies based on progressive resistance models. Meanwhile, novel drugs and combination therapies are being actively researched and developed to address these challenges. The aim is to offer new insights into the mechanisms of resistance and the corresponding treatment strategies to ALK inhibitors.
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Affiliation(s)
- Jiajun Xie
- Department of Respiratory and Critical Care Medicine, Mian yang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, People’s Republic of China
| | - Yinghao Gao
- Department of pulmonology, Mianyang hospital of T.C.M, Mianyang, People’s Republic of China
| | - Weiguo Xu
- Department of Respiratory and Critical Care Medicine, Mian yang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, People’s Republic of China
| | - Jing Zhu
- Department of Respiratory and Critical Care Medicine, Mian yang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, People’s Republic of China
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D'Amours MF, Ho C. Targeting a cure in anaplastic lymphoma kinase-positive non-small cell lung cancer. Transl Lung Cancer Res 2024; 13:3815-3818. [PMID: 39830747 PMCID: PMC11736586 DOI: 10.21037/tlcr-24-844] [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: 09/18/2024] [Accepted: 12/04/2024] [Indexed: 01/22/2025]
Affiliation(s)
| | - Cheryl Ho
- Department of Medical Oncology, BC Cancer Agency, Vancouver, Canada
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Itchins M, Liang S, Brown C, Barnes T, Marx G, Chin V, Kao S, Yip PY, Mersiades AJ, Nagrial A, Bray V, Peters G, Parakh S, Garg K, Li BT, McKay M, O'Byrne K, John T, Gill AJ, Molloy MP, Solomon BJ, Pavlakis N. ALKTERNATE: A Pilot Study Alternating Lorlatinib With Crizotinib in ALK-Positive NSCLC With Prior ALK Inhibitor Resistance. JTO Clin Res Rep 2024; 5:100703. [PMID: 39309618 PMCID: PMC11416292 DOI: 10.1016/j.jtocrr.2024.100703] [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: 03/04/2024] [Revised: 06/09/2024] [Accepted: 06/29/2024] [Indexed: 09/25/2024] Open
Abstract
Introduction ALK-positive lung cancers represent a molecularly diverse disease. With drug exposure, driving selection pressure, and resistance pathways, disease relapse will emerge. There is compelling rationale to investigate novel treatment strategies, informed by dynamic circulating tumor DNA (ctDNA) monitoring. Methods The single-arm, pilot study ALKTERNATE investigated fixed alternating cycles of lorlatinib intercalated with crizotinib in individuals resistant to second-generation ALK inhibitors. Dynamic ctDNA explored the correlation with disease response and disease recurrence and defined disease resistance. The primary outcome was time-to-treatment failure, a composite of tolerability, feasibility, and efficacy. Secondary outcomes included standard survival measures, toxicity, pharmacokinetic analysis, and patient-reported outcomes. Tertiary outcomes were proteogenomic analyses of tissue and plasma. Results A total of 15 individuals were enrolled; three encountered primary resistance to lorlatinib induction. There were 12 participants who received alternating therapy, and this approach revealed safety, feasibility, and effectiveness. Patient-reported outcomes were maintained or improved on therapy, and toxicity was consistent with previous reports. The pharmacokinetic measures were similar to the single-arm drug experience. Median time-to-treatment failure was 10 months; overall survival was 23 months. ctDNA profiles indicated inferior survival in those with preexistent TP53 mutations and those without clear or cleared ctDNA at trial induction. The study defined a vastly heterogeneous population with an abundance of ALK coexisting with non-ALK resistance variants. Conclusions ALKTERNATE revealed feasibility with a novel alternating ALK inhibitor strategy in ALK-positive NSCLC. Results support progressing inquiry into this approach and propose a flexible design with drug(s) selected and alternating time frames, informed by real-time plasma profiling. Moving this concept to treatment naive may also optimize impact.
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Affiliation(s)
- Malinda Itchins
- Royal North Shore Hospital, St Leonards, Australia
- Northern Clinical School, University of Sydney, St Leonards, Australia
- Chris O'Brien Lifehouse, Camperdown, Australia
| | | | - Chris Brown
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia
| | | | - Gavin Marx
- Sydney Adventist Hospital, Wahroonga, Australia
- Australian National University, Sydney, Australia
| | - Venessa Chin
- The Kinghorn Cancer Centre, St Vincent’s Hospital Sydney, Darlinghurst, Australia
- The Garvan Institute of Medical Research, Darlinghurst, Australia
- University of New South Wales, Darlinghurst, Australia
| | - Steven Kao
- Chris O'Brien Lifehouse, Camperdown, Australia
- Sydney Medical School, University of Sydney, Camperdown, Australia
| | - Po Yee Yip
- Macarthur Cancer Therapy Centre, Campbelltown Hospital, Campbelltown, Australia
- School of Medicine, Western Sydney University, Campbelltown, Australia
| | - Antony J. Mersiades
- NHMRC Clinical Trials Centre, University of Sydney, Camperdown, Australia
- Northern Beaches Hospital, Frenchs Forest, Australia
| | - Adnan Nagrial
- Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead, Australia
- Blacktown Hospital, Blacktown, Australia
- Westmead Clinical School, University of Sydney, Westmead, Australia
| | | | - Geoffrey Peters
- Canberra Hospital, Canberra, Australia
- Australian National University, Canberra, Australia
| | - Sagun Parakh
- Olivia Newton-John Cancer Research Institute, Austin Hospital, Heidelberg, Australia
- School of Cancer Medicine, La Trobe University, Bundoora, Australia
| | | | - Bob T. Li
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Matthew McKay
- Kolling Institute, University of Sydney, St Leonards, Australia
| | | | - Thomas John
- Peter MacCallum Cancer Centre, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - Anthony J. Gill
- Royal North Shore Hospital, St Leonards, Australia
- Northern Clinical School, University of Sydney, St Leonards, Australia
| | - Mark P. Molloy
- Northern Clinical School, University of Sydney, St Leonards, Australia
- Kolling Institute, University of Sydney, St Leonards, Australia
| | - Benjamin J. Solomon
- Peter MacCallum Cancer Centre, Melbourne, Australia
- University of Melbourne, Melbourne, Australia
| | - Nick Pavlakis
- Royal North Shore Hospital, St Leonards, Australia
- Northern Clinical School, University of Sydney, St Leonards, Australia
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Bauman JR, Liu G, Preeshagul I, Liu SV, Melosky B, Abrahami D, Li B, Thomaidou D, Duncan K, Krulewicz S, Rupp M, Lin JJ. Real-world treatment sequencing and effectiveness of second- and third-generation ALK tyrosine kinase inhibitors for ALK-positive advanced non-small cell lung cancer. Lung Cancer 2024; 195:107919. [PMID: 39197358 DOI: 10.1016/j.lungcan.2024.107919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/31/2024] [Accepted: 08/02/2024] [Indexed: 09/01/2024]
Abstract
INTRODUCTION With multiple targeted therapies approved for anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC), it is increasingly important to understand outcomes with various sequences of next-generation ALK tyrosine kinase inhibitors (TKIs). We describe contemporary sequencing patterns and treatment effectiveness of first-line (1L) and second-line (2L) treatments in patients who received second-generation ALK TKIs in the 1L treatment of ALK-positive NSCLC in the United States. METHODS A cohort of adults with ALK-positive advanced NSCLC who initiated treatment with 1L alectinib or brigatinib between June 2017 and April 2021 in the Flatiron Health electronic health record-derived de-identified database were followed through April 2023. Time to treatment discontinuation (TTD) in 1L and 2L, TTD on 1L plus 2L sequential therapy (TTD2), and total time on sequential ALK TKI therapy (including beyond 2L) were evaluated. RESULTS Patients (N=273) were followed up for a median duration of 28.9 months. Among patients who discontinued 1L therapy, 22% died after 1L discontinuation (median time from discontinuation to death, 4.0 months) without receiving 2L therapy. Median (95% confidence interval [CI]) TTD was 21.9 (15.2-25.8) and 7.3 (5.3-10.2) months in 1L and 2L, respectively. Median (95% CI) TTD2 was 29.4 (25.1-36.1) months and total time on sequential ALK TKI treatment was 28.0 (23.6-32.9) months. CONCLUSIONS In this large real-world study, TTD2 and the total time on sequential ALK TKIs was approximately 2.5 years. The high attrition rate from 1L to 2L and the longest clinical benefit observed with 1L therapy support using the drug with the longest 1L effectiveness up front in patients with ALK-positive advanced NSCLC.
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Affiliation(s)
- Jessica R Bauman
- Department of Hematology and Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, United States.
| | - Geoffrey Liu
- Medical Oncology and Hematology, Princess Margaret Cancer, 200 Elizabeth Street, Toronto, ON M5G 0A3, Canada.
| | - Isabel Preeshagul
- Thoracic Oncology, Memorial Sloan Kettering Cancer Center, 225 Summit Avenue, Montvale, NJ 07645, United States.
| | - Stephen V Liu
- Thoracic Oncology, Georgetown University, 37th and O Streets NW, Washington, DC 20057, United States.
| | - Barbara Melosky
- Department of Medicine, BC Cancer - Vancouver, 2775 Laurel Street, Vancouver, BC V5Z 1M9, Canada.
| | - Devin Abrahami
- HTA Value and Evidence, Oncology, Pfizer, 66 Hudson Boulevard, New York, NY 10001, United States.
| | - Benjamin Li
- Biostatistics, Pfizer, 66 Hudson Boulevard, New York, NY 10001, United States.
| | - Despina Thomaidou
- Global Medical Affairs, Pfizer, 243 Mesogeion Avenue, Neo Psychiko, Athens 154 51, Greece.
| | - Kirsten Duncan
- US Medical Affairs, Pfizer, 66 Hudson Boulevard, New York, NY 10001, United States.
| | - Stan Krulewicz
- US Medical Affairs, Pfizer, 66 Hudson Boulevard, New York, NY 10001, United States.
| | - Martin Rupp
- Medical Affairs Oncology, Pfizer Canada, 17300 Trans-Canada Highway Kirkland, Québec, H9J 2M5, Canada.
| | - Jessica J Lin
- Center for Thoracic Cancers, Department of Medicine, Cancer Center, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, United States.
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Gemelli M, Albini A, Catalano G, Incarbone M, Cannone M, Balladore E, Ricotta R, Pelosi G. Navigating resistance to ALK inhibitors in the lorlatinib era: a comprehensive perspective on NSCLC. Expert Rev Anticancer Ther 2024; 24:347-361. [PMID: 38630549 DOI: 10.1080/14737140.2024.2344648] [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: 10/19/2023] [Accepted: 04/15/2024] [Indexed: 04/19/2024]
Abstract
INTRODUCTION The emergence of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) has revolutionized targeted therapy. This dynamic landscape, featuring novel ALK inhibitors and combination therapies, necessitates a profound understanding of resistance mechanisms for effective treatment strategies. Recognizing two primary categories - on-target and off-target resistance - underscores the need for comprehensive assessment. AREAS COVERED This review delves into the intricacies of resistance to ALK inhibitors, exploring complexities in identification and management. Molecular testing, pivotal for early detection and accurate diagnosis, forms the foundation for patient stratification and resistance management. The literature search methodology involved comprehensive exploration of Pubmed and Embase. The multifaceted perspective encompasses new therapeutic horizons, ongoing clinical trials, and their clinical implications post the recent approval of lorlatinib. EXPERT OPINION Our expert opinion encapsulates the critical importance of understanding resistance mechanisms in the context of ALK inhibitors for shaping successful treatment approaches. With a focus on molecular testing and comprehensive assessment, this review contributes valuable insights to the evolving landscape of NSCLC therapy.
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Affiliation(s)
- Maria Gemelli
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Adriana Albini
- Departement of Scientific Directorate, European Institute of Oncology (IEO) Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy
| | - Gianpiero Catalano
- Radiation Oncology Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Matteo Incarbone
- Department of Surgery, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Maria Cannone
- Inter-Hospital Division of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Emanuela Balladore
- Inter-Hospital Division of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Riccardo Ricotta
- Medical Oncology Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
| | - Giuseppe Pelosi
- Inter-Hospital Division of Pathology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
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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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Zheng J, Wang T, Yang Y, Huang J, Feng J, Zhuang W, Chen J, Zhao J, Zhong W, Zhao Y, Zhang Y, Song Y, Hu Y, Yu Z, Gong Y, Chen Y, Ye F, Zhang S, Cao L, Fan Y, Wu G, Guo Y, Zhou C, Ma K, Fang J, Feng W, Liu Y, Zheng Z, Li G, Wang H, Cang S, Wu N, Song W, Liu X, Zhao S, Ding L, Selvaggi G, Wang Y, Xiao S, Wang Q, Shen Z, Zhou J, Zhou J, Zhang L. Updated overall survival and circulating tumor DNA analysis of ensartinib for crizotinib-refractory ALK-positive NSCLC from a phase II study. Cancer Commun (Lond) 2024; 44:455-468. [PMID: 38421881 PMCID: PMC11024683 DOI: 10.1002/cac2.12524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 12/13/2023] [Accepted: 02/03/2024] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. METHODS In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. RESULTS At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. CONCLUSION Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.
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Affiliation(s)
- Jing Zheng
- Department of Respiratory DiseaseThoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Provincial Clinical Research Center for Respiratory DiseaseHangzhouZhejiangP. R. China
| | - Tao Wang
- Hangzhou Repugene Technology Co., LtdHangzhouZhejiangP. R. China
| | - Yunpeng Yang
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Jie Huang
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Jifeng Feng
- Department of Medical OncologyJiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical UniversityNanjingJiangsuP. R. China
| | - Wu Zhuang
- Department of Thoracic OncologyFujian Provincial Cancer HospitalFujian Medical University Cancer HospitalFuzhouFujianP. R. China
| | - Jianhua Chen
- Department of Medical Oncology‐ChestHunan Cancer HospitalChangshaHunanP. R. China
| | - Jun Zhao
- Department of Thoracic OncologyBeijing Cancer HospitalBeijingP. R. China
| | - Wei Zhong
- Department of Pulmonary MedicinePeking Union Medical College HospitalChinese Academy of Medical Sciences, Peking Union Medical CollegeBeijingP. R. China
| | - Yanqiu Zhao
- Respiratory Department of Internal MedicineHenan Provincial Cancer HospitalAffiliated Cancer Hospital of Zhengzhou UniversityZhengzhouHenanP. R. China
| | - Yiping Zhang
- Thoracic Medical OncologyZhejiang Cancer HospitalHangzhouZhejiangP. R. China
| | - Yong Song
- Division of Respiratory MedicineJinling HospitalNanjing University School of MedicineNanjingJiangsuP. R. China
| | - Yi Hu
- Department of OncologyChinese People's Liberation Army (PLA) General HospitalBeijingP. R. China
| | - Zhuang Yu
- Department of OncologyThe Affiliated Hospital of Qingdao UniversityQingdaoShandongP. R. China
| | - Youling Gong
- Department of Thoracic OncologyCancer Center, West China HospitalSichuan UniversityChengduSichuanP. R. China
| | - Yuan Chen
- Department of OncologyTongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Feng Ye
- Department of Medical OncologyCancer HospitalThe First Affiliated Hospital of Xiamen UniversitySchool of Medicine, Xiamen University, Teaching Hospital of Fujian Medical UniversityXiamenFujianP. R. China
| | - Shucai Zhang
- Department of Medical OncologyBeijing Chest HospitalCapital Medical University, Beijing Tuberculosis and Thoracic Tumor Research InstituteBeijingP. R. China
| | - Lejie Cao
- Respiratory MedicineThe First Affiliated Hospital of the University of Science and Technology of ChinaAnhui Provincial HospitalHefeiAnhuiP. R. China
| | - Yun Fan
- Thoracic Medical OncologyZhejiang Cancer HospitalHangzhouZhejiangP. R. China
| | - Gang Wu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Yubiao Guo
- Pulmonary & Critical Care Medicine, The First Affiliated Hospital, Sun Yat‐sen UniversityGuangzhouGuangdongP. R. China
| | - Chengzhi Zhou
- Respiratory Medicine DepartmentState Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhouGuangdongP. R. China
| | - Kewei Ma
- Cancer Center, The First Hospital of Jilin UniversityChangchunJilinP. R. China
| | - Jian Fang
- Department of Thoracic OncologyBeijing Cancer HospitalBeijingP. R. China
| | - Weineng Feng
- Department of Head and Neck and Thoracic Medical OncologyThe First People's Hospital of FoshanFoshanGuangdongP. R. China
| | - Yunpeng Liu
- Oncology MedicineThe First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Zhendong Zheng
- Oncology DepartmentGeneral Hospital of Northern Theater CommandShenyangLiaoningP. R. China
| | - Gaofeng Li
- 2nd Department of Thoracic SurgeryYunnan Cancer HospitalKunmingYunnanP. R. China
| | - Huijie Wang
- Medical OncologyFudan University Shanghai Cancer CenterShanghaiShanghaiP. R. China
| | - Shundong Cang
- Medical OncologyHenan Province Peoples HospitalZhengzhouHenanP. R. China
| | - Ning Wu
- PET‐CT Center & Department of Diagnostic RadiologyNational Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical CollegeBeijingP. R. China
| | - Wei Song
- Department of RadiologyPeking Union Medical College HospitalChinese Academy of Medical Sciences, Peking Union Medical CollegeBeijingP. R. China
| | - Xiaoqing Liu
- Department of Pulmonary OncologyThe Fifth Medical Centre Chinese PLA General HospitalBeijingP. R. China
| | - Shijun Zhao
- Department of Diagnostic RadiologyNational Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical SciencesPeking Union Medical CollegeBeijingP. R. China
| | - Lieming Ding
- Betta Pharmaceuticals Co., LtdHangzhouZhejiangP. R. China
| | | | - Yang Wang
- Betta Pharmaceuticals Co., LtdHangzhouZhejiangP. R. China
| | - Shanshan Xiao
- Hangzhou Repugene Technology Co., LtdHangzhouZhejiangP. R. China
| | - Qian Wang
- Hangzhou Repugene Technology Co., LtdHangzhouZhejiangP. R. China
| | - Zhilin Shen
- Betta Pharmaceuticals Co., LtdHangzhouZhejiangP. R. China
| | - Jianya Zhou
- Department of Respiratory DiseaseThoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Provincial Clinical Research Center for Respiratory DiseaseHangzhouZhejiangP. R. China
| | - Jianying Zhou
- Department of Respiratory DiseaseThoracic Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Zhejiang Provincial Clinical Research Center for Respiratory DiseaseHangzhouZhejiangP. R. China
| | - Li Zhang
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
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Gálffy G, Morócz É, Korompay R, Hécz R, Bujdosó R, Puskás R, Lovas T, Gáspár E, Yahya K, Király P, Lohinai Z. Targeted therapeutic options in early and metastatic NSCLC-overview. Pathol Oncol Res 2024; 30:1611715. [PMID: 38605928 PMCID: PMC11006988 DOI: 10.3389/pore.2024.1611715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 02/21/2024] [Indexed: 04/13/2024]
Abstract
The complex therapeutic strategy of non-small cell lung cancer (NSCLC) has changed significantly in recent years. Disease-free survival increased significantly with immunotherapy and chemotherapy registered in perioperative treatments, as well as adjuvant registered immunotherapy and targeted therapy (osimertinib) in case of EGFR mutation. In oncogenic-addictive metastatic NSCLC, primarily in adenocarcinoma, the range of targeted therapies is expanding, with which the expected overall survival increases significantly, measured in years. By 2021, the FDA and EMA have approved targeted agents to inhibit EGFR activating mutations, T790 M resistance mutation, BRAF V600E mutation, ALK, ROS1, NTRK and RET fusion. In 2022, the range of authorized target therapies was expanded. With therapies that inhibit KRASG12C, EGFR exon 20, HER2 and MET. Until now, there was no registered targeted therapy for the KRAS mutations, which affect 30% of adenocarcinomas. Thus, the greatest expectation surrounded the inhibition of the KRAS G12C mutation, which occurs in ∼15% of NSCLC, mainly in smokers and is characterized by a poor prognosis. Sotorasib and adagrasib are approved as second-line agents after at least one prior course of chemotherapy and/or immunotherapy. Adagrasib in first-line combination with pembrolizumab immunotherapy proved more beneficial, especially in patients with high expression of PD-L1. In EGFR exon 20 insertion mutation of lung adenocarcinoma, amivantanab was registered for progression after platinum-based chemotherapy. Lung adenocarcinoma carries an EGFR exon 20, HER2 insertion mutation in 2%, for which the first targeted therapy is trastuzumab deruxtecan, in patients already treated with platinum-based chemotherapy. Two orally administered selective c-MET inhibitors, capmatinib and tepotinib, were also approved after chemotherapy in adenocarcinoma carrying MET exon 14 skipping mutations of about 3%. Incorporating reflex testing with next-generation sequencing (NGS) expands personalized therapies by identifying guideline-recommended molecular alterations.
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Rathbone M, O’Hagan C, Wong H, Khan A, Cook T, Rose S, Heseltine J, Escriu C. Intracranial Efficacy of Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel in Real-World Patients with Non-Small-Cell Lung Cancer and EGFR or ALK Alterations. Cancers (Basel) 2024; 16:1249. [PMID: 38610927 PMCID: PMC11011096 DOI: 10.3390/cancers16071249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 03/14/2024] [Accepted: 03/18/2024] [Indexed: 04/14/2024] Open
Abstract
Contrary to Pemetrexed-containing chemo-immunotherapy studies, Atezolizumab, Bevacizumab, Carboplatin, and Paclitaxel (ABCP) treatment has consistently shown clinical benefit in prospective studies in patients with lung cancer and actionable mutations, where intracranial metastases are common. Here, we aimed to describe the real-life population of patients fit to receive ABCP after targeted therapy and quantify its clinical effect in patients with brain metastases. Patients treated in Cheshire and Merseyside between 2019 and 2022 were identified. Data were collected retrospectively. A total of 34 patients with actionable EGFR or ALK alterations had treatment with a median age of 59 years (range 32-77). The disease control rate was 100% in patients with PDL1 ≥ 1% (n = 10). In total, 19 patients (56%) had brain metastases before starting ABCP, 17 (50%) had untreated CNS disease, and 4 (22%) had PDL1 ≥ 1%. The median time to symptom improvement was 12.5 days (range 4-21 days), with 74% intracranial disease control rates and 89.5% synchronous intracranial (IC) and extracranial (EC) responses. IC median Progression Free Survival (mPFS) was 6.48 months, EC mPFS was 10.75 months, and median Overall Survival 11.47 months. ABCP in real-life patients with brain metastases (treated or untreated) was feasible and showed similar efficacy to that described in patients without actionable mutations treated with upfront chemo-immunotherapy.
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Affiliation(s)
- Marcus Rathbone
- School of Medicine, University of Liverpool, Liverpool L69 3BX, UK; (M.R.); (C.O.)
| | - Conor O’Hagan
- School of Medicine, University of Liverpool, Liverpool L69 3BX, UK; (M.R.); (C.O.)
| | - Helen Wong
- The Clatterbridge Cancer Centre, Liverpool L7 8YA, UK; (H.W.); (A.K.); (T.C.); (S.R.)
| | - Adeel Khan
- The Clatterbridge Cancer Centre, Liverpool L7 8YA, UK; (H.W.); (A.K.); (T.C.); (S.R.)
| | - Timothy Cook
- The Clatterbridge Cancer Centre, Liverpool L7 8YA, UK; (H.W.); (A.K.); (T.C.); (S.R.)
| | - Sarah Rose
- The Clatterbridge Cancer Centre, Liverpool L7 8YA, UK; (H.W.); (A.K.); (T.C.); (S.R.)
| | - Jonathan Heseltine
- The Clatterbridge Cancer Centre, Liverpool L7 8YA, UK; (H.W.); (A.K.); (T.C.); (S.R.)
| | - Carles Escriu
- School of Medicine, University of Liverpool, Liverpool L69 3BX, UK; (M.R.); (C.O.)
- The Clatterbridge Cancer Centre, Liverpool L7 8YA, UK; (H.W.); (A.K.); (T.C.); (S.R.)
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10
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Cheung JM, Kang J, Yeap BY, Peterson JL, Do A, Gainor JF, Digumarthy SR, Lin JJ. Efficacy and Safety of Dose-Escalated Alectinib in Patients With Metastatic ALK-Positive NSCLC and Central Nervous System Relapse on Standard-Dose Alectinib. JTO Clin Res Rep 2024; 5:100645. [PMID: 38425547 PMCID: PMC10899067 DOI: 10.1016/j.jtocrr.2024.100645] [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: 10/16/2023] [Revised: 01/10/2024] [Accepted: 01/25/2024] [Indexed: 03/02/2024] Open
Abstract
Introduction Central nervous system (CNS) metastases remain a common challenge in patients with ALK-positive NSCLC. We previously reported reinduction of CNS responses using dose-intensified alectinib in two patients with CNS progression on standard-dose alectinib. Nevertheless, this strategy has not been assessed in larger cohorts. Methods Patients were eligible for this retrospective study if they had metastatic ALK-positive NSCLC with CNS relapse on alectinib 600 mg twice daily dosing and subsequently received escalated dosing (900 mg twice daily) of alectinib. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1. Results Among 27 patients, median duration of dose-escalated alectinib was 7.7 months (95% confidence interval [CI]: 4.8-10.9), with median overall time-to-progression (TTP) of 7.1 months (95% CI: 4.4-9.6). Among 25 CNS response-assessable patients, CNS objective response rate was 12.0% (95% CI: 2.5-31.2) and CNS disease control rate was 92.0% (95% CI: 74.0-99.0), with median CNS duration of disease control of 5.3 months (95% CI: 3.4-8.3) and median CNS TTP of 7.1 months (95% CI: 4.4-9.6). Among four patients with measurable CNS disease at baseline, three experienced a best intracranial response of stable disease and one experienced intracranial partial response with CNS TTP ranging from 4.1 to 7.7 months. No patient required drug discontinuation due to treatment-related adverse event or experienced grade 3 or higher treatment-related adverse events. Conclusions Dose-intensified alectinib was found to have tolerability and activity in patients with ALK-positive NSCLC who experienced CNS relapse on standard-dose alectinib and represents one clinically viable strategy for this population.
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Affiliation(s)
- Justin M. Cheung
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Jiyoon Kang
- Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts
| | - Beow Y. Yeap
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Jennifer L. Peterson
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Andrew Do
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Justin F. Gainor
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Subba R. Digumarthy
- Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts
| | - Jessica J. Lin
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts
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11
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Patil T, Staley A, Nie Y, Sakamoto M, Stalker M, Jurica JM, Koehler K, Cass A, Kuykendall H, Schmitt E, Filar E, Reventaite E, Davies KD, Nijmeh H, Haag M, Yoder BA, Bunn PA, Schenk EL, Aisner DL, Iams WT, Marmarelis ME, Camidge DR. The Efficacy and Safety of Treating Acquired MET Resistance Through Combinations of Parent and MET Tyrosine Kinase Inhibitors in Patients With Metastatic Oncogene-Driven NSCLC. JTO Clin Res Rep 2024; 5:100637. [PMID: 38361741 PMCID: PMC10867444 DOI: 10.1016/j.jtocrr.2024.100637] [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: 09/11/2023] [Revised: 01/11/2024] [Accepted: 01/14/2024] [Indexed: 02/17/2024] Open
Abstract
Introduction Acquired MET gene amplification, MET exon 14 skip mutations, or MET fusions can emerge as resistance mechanisms to tyrosine kinase inhibitors (TKIs) in patients with lung cancer. The efficacy and safety of combining MET TKIs (such as crizotinib, capmatinib, or tepotinib) with parent TKIs to target acquired MET resistance are not well characterized. Methods Multi-institutional retrospective chart review identified 83 patients with metastatic oncogene-driven NSCLC that were separated into the following two pairwise matched cohorts: (1) MET cohort (n = 41)-patients with acquired MET resistance continuing their parent TKI with a MET TKI added or (2) Chemotherapy cohort (n = 42)-patients without any actionable resistance continuing their parent TKI with a platinum-pemetrexed added. Clinicopathologic features, radiographic response (by means of Response Evaluation Criteria in Solid Tumors version 1.1), survival outcomes, adverse events (AEs) (by means of Common Terminology Criteria for Adverse Events version 5.0), and genomic data were collected. Survival outcomes were assessed using Kaplan-Meier methods. Multivariate modeling adjusted for lines of therapy, brain metastases, TP53 mutations, and oligometastatic disease. Results Within the MET cohort, median age was 56 years (range: 36-83 y). Most patients were never smokers (28 of 41, 68.3%). Baseline brain metastases were common (21 of 41, 51%). The most common oncogenes in the MET cohort were EGFR (30 of 41, 73.2%), ALK (seven of 41, 17.1%), and ROS1 (two of 41, 4.9%). Co-occurring TP53 mutations (32 of 41, 78%) were frequent. Acquired MET alterations included MET gene amplification (37 of 41, 90%), MET exon 14 mutations (two of 41, 5%), and MET gene fusions (two of 41, 5%). After multivariate adjustment, the objective response rate (ORR) was higher in the MET cohort versus the chemotherapy cohort (ORR: 69.2% versus 20%, p < 0.001). Within the MET cohort, MET gene copy number (≥10 versus 6-10) did not affect radiographic response (54.5% versus 68.4%, p = 0.698). There was no difference in ORR on the basis of MET TKI used (F [2, 36] = 0.021, p = 0.978). There was no difference in progression-free survival (5 versus 6 mo; hazard ratio = 0.64; 95% confidence interval: 0.34-1.23, p = 0.18) or overall survival (13 versus 11 mo; hazard ratio = 0.75; 95% confidence interval: 0.42-1.35, p = 0.34) between the MET and chemotherapy cohorts. In the MET cohort, dose reductions for MET TKI-related toxicities were common (17 of 41, 41.4%) but less frequent for parent TKIs (two of 41, 5%). Grade 3 AEs were not significant between crizotinib, capmatinib, and tepotinib (p = 0.3). The discontinuation rate of MET TKIs was 17% with no significant differences between MET TKIs (p = 0.315). Among pre- and post-treatment biopsies (n = 17) in the MET cohort, the most common next-generation sequencing findings were loss of MET gene amplification (15 of 17, 88.2%), MET on-target mutations (seven of 17, 41.2%), new Ras-Raf-MAPK alterations (three of 17, 17.6%), and EGFR gene amplification (two of 17, 11.7%). Conclusions The efficacy and safety of combining MET TKIs (crizotinib, capmatinib, or tepotinib) with parent TKIs for acquired MET resistance are efficacious. Radiographic response and AEs did not differ significantly on the basis of the underlying MET TKI used. Loss of MET gene amplification, development of MET on-target mutations, Ras-Raf-MAPK alterations, and EGFR gene amplification were molecular patterns found on progression with dual parent and MET TKI combinations.
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Affiliation(s)
- Tejas Patil
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Alyse Staley
- University of Colorado Cancer Center Biostatistics Core, University of Colorado School of Medicine, Aurora, Colorado
| | - Yunan Nie
- Department of Medical Oncology, Yale School of Medicine, Yale University, New Haven, Connecticut
| | - Mandy Sakamoto
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Margaret Stalker
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - James M. Jurica
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Kenna Koehler
- Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
| | - Amanda Cass
- Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
| | - Halle Kuykendall
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Emily Schmitt
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Emma Filar
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Evelina Reventaite
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Kurt D. Davies
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Hala Nijmeh
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Mary Haag
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Benjamin A. Yoder
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Paul A. Bunn
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Erin L. Schenk
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Dara L. Aisner
- Department of Pathology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
| | - Wade T. Iams
- Division of Medical Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee
| | - Melina E. Marmarelis
- Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - D. Ross Camidge
- Division of Medical Oncology, University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado
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12
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Li Y, Hao Z, Ma Y, Setiwalidi K, Zhang Y, Zhao Y, Fu X, Liang X, Ruan Z, Tian T, Yao Y. Alectinib continuation beyond progression in ALK-positive non-small cell lung cancer with alectinib-refractory. Transl Lung Cancer Res 2024; 13:152-162. [PMID: 38405000 PMCID: PMC10891411 DOI: 10.21037/tlcr-23-798] [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: 12/01/2023] [Accepted: 01/11/2024] [Indexed: 02/27/2024]
Abstract
Background Alectinib, a next-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK-TKI), has demonstrated noteworthy efficacy in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, 53.3% of untreated patients receiving first-line treatment with alectinib developed resistance to alectinib. However, despite the widespread use of alectinib, studies on the efficacy and safety of continuing alectinib with other necessary therapies after progression of alectinib and possible population of benefit are still limited. Methods This retrospective cohort study included fifteen patients with ALK-positive NSCLC from nine institutions in China who experienced disease progression after first- or second-line treatment and continued to receive alectinib treatment between 2019 and 2022. This study aimed to evaluate the median progression-free survival (mPFS), objective response rate (ORR), median overall survival (mOS), and adverse events (AEs) of continuing alectinib combined with other therapies after the emergence of drug resistance. Results Among fifteen patients eligible for this study, all patients started continuing treatment with alectinib after oligoprogression or central nervous system (CNS) progression. The mPFS for the whole cohort receiving continuing alectinib with other necessary therapies was 8 months [95% confidence interval (CI): 4 to not applicable (NA)], with an ORR of 46.7%. The mOS was not reached. During continuing alectinib treatment, only one patient experienced grade 2 elevation of aspartate aminotransferase (AST) and serum glutamic-oxaloacetic transaminase (SGOT). Conclusions The continuation of alectinib treatment combined with other necessary therapies demonstrates favorable response and safety in patients with ALK-positive NSCLC who experienced oligoprogression or CNS progression following alectinib in first- or second-line therapy. Instead of immediately switching to another ALK-TKI, continuing alectinib combined with other necessary therapies may offer greater survival benefits to the patients.
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Affiliation(s)
- Yimeng Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhanpeng Hao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yuyan Ma
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Kaidiriye Setiwalidi
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yingming Zhang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yujia Zhao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xiao Fu
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuan Liang
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhiping Ruan
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Tao Tian
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yu Yao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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13
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Ozawa Y, Koh Y, Hase T, Chibana K, Kaira K, Okishio K, Ichihara E, Murakami S, Shimokawa M, Yamamoto N. Prospective observational study to explore genes and proteins predicting efficacy and safety of brigatinib for ALK-gene rearranged non-small-cell lung cancer: study protocol for ABRAID study (WJOG11919L). Ther Adv Med Oncol 2024; 16:17588359231225046. [PMID: 38282663 PMCID: PMC10822087 DOI: 10.1177/17588359231225046] [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: 05/29/2023] [Accepted: 12/11/2023] [Indexed: 01/30/2024] Open
Abstract
Background ALK-tyrosine kinase inhibitors (ALK-TKIs) are effective for treating non-small-cell lung cancer with ALK gene rearrangement; however, resistance is inevitable. Brigatinib is a unique ALK-TKI that is effective against many resistance mutations. However, data on factors associated with its efficacy and resistance mechanisms are limited. Objectives This study will evaluate the efficacy and safety of brigatinib in the real world and explore factors related to its efficacy, safety, and resistance mechanisms. Design Prospective observational study. Ethics This study is approved by the Ethics Committee of Wakayama Medical University. Written informed consent will be obtained from all patients before study-related procedures. Methods and analysis This study comprises three cohorts. Cohorts A, B, and 0 will enroll patients receiving alectinib as the first ALK-TKI, receiving alectinib as the first ALK-TKI and subsequently cytotoxic agents and/or lorlatinib after alectinib, and without a history of ALK-TKI, respectively. Overall, 100, 30, and 50 patients will be enrolled in Cohorts A, B, and 0, respectively. Circulating tumor DNA before starting brigatinib and at disease progression will be analyzed in all cohorts using a hypersensitive next-generation sequencing (NGS) PGDx Elio plasma resolve panel. Serum protein levels will be analyzed using the Milliplex xMAP assay system with a Luminex 200 (Luminex, Austin, USA). The enrollment period is 31 months and the patients will be observed for 2 years after enrollment. Archived tissues will be collected for NGS analysis, gene expression analysis, and immunohistochemistry staining 1 year after completion of registration. Quality of life and safety evaluation using electronic patient-reported outcomes will be investigated. Discussion This study will elucidate predictors of ALK-TKI efficacy and resistance mechanisms and evaluate the efficacy and safety of brigatinib in a real-world setting. The results will provide crucial information for establishing treatment strategies, discovering novel biomarkers, and developing new therapeutic agents. Trial registration UMIN000042439.
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Affiliation(s)
- Yuichi Ozawa
- Department of Respiratory Medicine, Hamamatsu Medical Center, 328 Tomitsuka-cho, Naka-ku, Hamamatsu, Shizuoka 432-8580, Japan
- Internal Medicine III, Wakayama Medical University, Wakayama City, Wakayama 641-0012, Japan
| | - Yasuhiro Koh
- Internal Medicine III, Wakayama Medical University, Wakayama City, Wakayama, Japan
- Center for Biomedical Sciences, Wakayama Medical University, Wakayama City, Wakayama, Japan
| | - Tetsunari Hase
- Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Kenji Chibana
- Department of Respiratory Medicine, National Hospital Organization Okinawa National Hospital, Ginowan, Okinawa, Japan
| | - Kyoichi Kaira
- Department of Respiratory Medicine, Comprehensive Cancer Center, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan
| | - Kyoichi Okishio
- Department of Internal Medicine, National Hospital Organization Kinki-chuo Chest Medical Center, Sakai City, Osaka, Japan
| | - Eiki Ichihara
- Center for Clinical Oncology, Okayama University Hospital, Okayama, Okayama, Japan
| | - Shuji Murakami
- Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan
| | - Mototsugu Shimokawa
- Department of Biostatistics, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Nobuyuki Yamamoto
- Internal Medicine III, Wakayama Medical University, Wakayama City, Wakayama, Japan
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14
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Zheng X, Song X, Zhu G, Pan D, Li H, Hu J, Xiao K, Gong Q, Gu Z, Luo K, Li W. Nanomedicine Combats Drug Resistance in Lung Cancer. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2308977. [PMID: 37968865 DOI: 10.1002/adma.202308977] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 11/03/2023] [Indexed: 11/17/2023]
Abstract
Lung cancer is the second most prevalent cancer and the leading cause of cancer-related death worldwide. Surgery, chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy are currently available as treatment methods. However, drug resistance is a significant factor in the failure of lung cancer treatments. Novel therapeutics have been exploited to address complicated resistance mechanisms of lung cancer and the advancement of nanomedicine is extremely promising in terms of overcoming drug resistance. Nanomedicine equipped with multifunctional and tunable physiochemical properties in alignment with tumor genetic profiles can achieve precise, safe, and effective treatment while minimizing or eradicating drug resistance in cancer. Here, this work reviews the discovered resistance mechanisms for lung cancer chemotherapy, molecular targeted therapy, immunotherapy, and radiotherapy, and outlines novel strategies for the development of nanomedicine against drug resistance. This work focuses on engineering design, customized delivery, current challenges, and clinical translation of nanomedicine in the application of resistant lung cancer.
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Affiliation(s)
- Xiuli Zheng
- Department of Radiology, Department of Respiratory, Huaxi MR Research Center (HMRRC) and Critical Care Medicine, Institute of Respiratory Health, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
| | - Xiaohai Song
- Department of General Surgery, Gastric Cancer Center and Laboratory of Gastric Cancer, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
| | - Guonian Zhu
- Department of Radiology, Department of Respiratory, Huaxi MR Research Center (HMRRC) and Critical Care Medicine, Institute of Respiratory Health, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
| | - Dayi Pan
- Department of Radiology, Department of Respiratory, Huaxi MR Research Center (HMRRC) and Critical Care Medicine, Institute of Respiratory Health, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
| | - Haonan Li
- Department of Radiology, Department of Respiratory, Huaxi MR Research Center (HMRRC) and Critical Care Medicine, Institute of Respiratory Health, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
| | - Jiankun Hu
- Department of General Surgery, Gastric Cancer Center and Laboratory of Gastric Cancer, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
| | - Kai Xiao
- Department of Radiology, Department of Respiratory, Huaxi MR Research Center (HMRRC) and Critical Care Medicine, Institute of Respiratory Health, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
| | - Qiyong Gong
- Department of Radiology, Department of Respiratory, Huaxi MR Research Center (HMRRC) and Critical Care Medicine, Institute of Respiratory Health, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
- Precision Medicine Key Laboratory of Sichuan Province, Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China
- Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen, Fujian, 361000, China
| | - Zhongwei Gu
- Department of Radiology, Department of Respiratory, Huaxi MR Research Center (HMRRC) and Critical Care Medicine, Institute of Respiratory Health, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
| | - Kui Luo
- Department of Radiology, Department of Respiratory, Huaxi MR Research Center (HMRRC) and Critical Care Medicine, Institute of Respiratory Health, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
- Precision Medicine Key Laboratory of Sichuan Province, Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China
| | - Weimin Li
- Department of Radiology, Department of Respiratory, Huaxi MR Research Center (HMRRC) and Critical Care Medicine, Institute of Respiratory Health, Precision Medicine Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Chengdu, 610041, China
- Precision Medicine Key Laboratory of Sichuan Province, Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, 610041, China
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15
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Metro G, Baglivo S, Metelli N, Bonaiti A, Matocci R, Di Girolamo B, Mandarano M, Colafigli C, Bellezza G, Roila F, Ludovini V. Lorlatinib beyond progression plus platinum/pemetrexed for ALK-positive non-small cell lung cancer patients: report of two cases. J Chemother 2023; 35:576-582. [PMID: 36537289 DOI: 10.1080/1120009x.2022.2157611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 11/27/2022] [Accepted: 12/07/2022] [Indexed: 12/24/2022]
Abstract
Lorlatinib is an active treatment for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) pretreated with ALK-tyrosine kinase inhibitors (-TKIs). However, there is paucity of data on the activity of platinum/pemetrexed chemotherapy administered at the time of progression on lorlatinib. In addition, it is uncertain whether continuation of lorlatinib beyond progression (LBP) would provide any additional clinical benefit. Here, we describe two cases experiencing an exceptional response to platinum/pemetrexed chemotherapy plus LBP and make an attempt to identify which patients' characteristics and biologic profiles of the tumor could predict benefit from such an approach. In this report, presence of controlled brain metastases, rapidly progressing extracranial disease, and presence of ALK-dependent mechanisms of resistance were associated with benefit from platinum/pemetrexed chemotherapy plus lorlatinib beyond progression.
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Affiliation(s)
- Giulio Metro
- Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Sara Baglivo
- Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Niccolò Metelli
- Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Angelo Bonaiti
- Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Roberta Matocci
- Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Bruna Di Girolamo
- Oncologic Day Hospital, Santa Maria della Stella Hospital, Orvieto, Italy
| | - Martina Mandarano
- Section of Anatomic Pathology and Histology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Claudia Colafigli
- Diagnostic Imaging, Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Guido Bellezza
- Section of Anatomic Pathology and Histology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Fausto Roila
- Medical Oncology, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy
| | - Vienna Ludovini
- Santa Maria della Misericordia Hospital, Azienda Ospedaliera di Perugia, Perugia, Italy
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16
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Fukuda A, Yoshida T. Treatment of advanced ALK-rearranged NSCLC following second-generation ALK-TKI failure. Expert Rev Anticancer Ther 2023; 23:1157-1167. [PMID: 37772744 DOI: 10.1080/14737140.2023.2265566] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 09/27/2023] [Indexed: 09/30/2023]
Abstract
INTRODUCTION Anaplastic lymphoma kinase (ALK) gene rearrangement is detected in approximately 3-5% of non-small cell lung cancer (NSCLC) cases. Tyrosine kinase inhibitors (TKIs) targeting ALK rearrangement (ALK-TKIs) have shown significant efficacy and improved the survival of patients with NSCLC exhibiting ALK rearrangement. However, almost all patients exhibit disease progression during TKI therapy owing to resistance acquired through various molecular mechanisms, including both ALK-dependent and ALK-independent. AREAS COVERED Here, we review the mechanisms underlying resistance to second-generation ALK-TKIs, and the clinical management strategies following resistance in patients with ALK rearrangement-positive NSCLC. EXPERT OPINION Treatment strategies following the failure of second-generation ALK-TKIs failure should be based on resistant mechanisms. For patients with ALK mutations who exhibit resistance to second-generation ALK-TKIs, lorlatinib is the primary treatment option. However, the identification of resistance profiles of second-generation ALK-TKIs can aid in the selection of an appropriate treatment strategy. In cases of ALK-dependent resistance mutations, lorlatinib could be the first choice as it exhibits the broadest coverage of mutations that lead to resistance against second-generation ALK-TKIs, such as G1202R, and L1196M. In cases of no resistance mutations, atezolizumab, bevacizumab, and platinum-based chemotherapy could be the alternative treatment options.
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Affiliation(s)
- Akito Fukuda
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
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17
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Li Y, Lv Y, Zhang C, Fu B, Liu Y, Hu J. Recent advances in the development of dual ALK/ROS1 inhibitors for non-small cell lung cancer therapy. Eur J Med Chem 2023; 257:115477. [PMID: 37210839 DOI: 10.1016/j.ejmech.2023.115477] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 05/09/2023] [Accepted: 05/10/2023] [Indexed: 05/23/2023]
Abstract
As a member of the insulin-receptor superfamily, ALK plays an important role in regulating the growth, proliferation, and survival of cells. ROS1 is highly homologous with ALK, and can also regulate normal physiological activities of cells. The overexpression of both is closely related to the development and metastasis of tumors. Therefore, ALK and ROS1 may serve as important therapeutic targets in non-small cell lung cancer (NSCLC). Clinically, many ALK inhibitors have shown powerful therapeutic efficacy in ALK and ROS1-positive NSCLC patients. However, after some time, patients inevitably develop drug resistance, leading to treatment failure. There are no significant drug breakthroughs in solving the problem of drug-resistant mutations. In this review, we summarize the chemical structural features of several novel dual ALK/ROS1 inhibitors, their inhibitory effect on ALK and ROS1 kinases, and future treatment strategies for patients with ALK and ROS1 inhibitor-resistant mutations.
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Affiliation(s)
- Yingxue Li
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China
| | - Yanna Lv
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China
| | - Cheng Zhang
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China
| | - Binyu Fu
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China
| | - Yue Liu
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China.
| | - Jinxing Hu
- Weifang Medical University, No.7166 Baotong Road, Weifang, 261053, PR China.
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18
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Desai A, Lovly CM. Strategies to overcome resistance to ALK inhibitors in non-small cell lung cancer: a narrative review. Transl Lung Cancer Res 2023; 12:615-628. [PMID: 37057106 PMCID: PMC10087990 DOI: 10.21037/tlcr-22-708] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/20/2023] [Indexed: 04/15/2023]
Abstract
Background and Objective Anaplastic lymphoma kinase (ALK) rearrangements are detected in 3-7% of advanced non-small cell lung cancer (NSCLC). There are currently 5 U.S Food and Drug Administration (FDA)-approved ALK tyrosine kinase inhibitors (TKIs) for the treatment of patients with ALK-positive lung cancer in the advanced/metastatic disease setting. Despite these advances, most patients with ALK-positive lung cancer who are treated with ALK TKI therapy ultimately experience disease progression due to various mechanisms of drug resistance. In this review, we discuss strategies to address acquired therapeutic resistance to ALK inhibition, novel agents and combinatorial strategies in development for both on and off-target resistance, and some emerging approaches to prolong response to ALK inhibitors. Methods We performed a search of peer-reviewed literature in the English language, conference abstracts, and trial registrations from the MEDLINE (Ovid), Embase (Elsevier), and CENTRAL (Cochrane Library) databases and major international oncology meetings up to August 2022. We then screened for studies describing interventions to overcome ALK resistance based on review of each title and abstract. Key Content and Findings For patients with oligo-progression, treatment may include maintaining the same systemic treatment beyond progression while adding local therapies to progressing lesions. Strategies to combat ALK TKI resistance mediated by on-target resistance mechanisms include 4th generation TKIs (TPX-0131, NVL-655) and proteolysis-targeting chimeras (PROTACs) currently in development. While for those patients who develop tumor progression due to off-target (ALK independent) resistance, options may include combination therapies targeting ALK and other downstream or parallel pathways, novel antibody drug conjugates, or combinations of ALK inhibitors with chemotherapy and immunotherapy. Lastly, other potential strategies being explored in the clinic include circulating tumor DNA (ctDNA) surveillance to monitor for molecular mediators of drug resistance prior to frank progression on imaging studies and utilization of ALK TKIs in the adjuvant and neoadjuvant settings. Conclusions Strategies to overcome resistance to currently available ALK inhibitors are urgently needed. Given the variety of resistance mechanisms, tailormade approaches are required for disease control.
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Affiliation(s)
- Aakash Desai
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Christine M. Lovly
- Division of Hematology-Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA
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19
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Smith S, Albuquerque de Almeida F, Inês M, Iadeluca L, Cooper M. Matching-Adjusted Indirect Comparisons of Lorlatinib Versus Chemotherapy for Patients With Second-Line or Later Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2023; 26:64-70. [PMID: 35985941 DOI: 10.1016/j.jval.2022.07.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 06/29/2022] [Accepted: 07/07/2022] [Indexed: 06/15/2023]
Abstract
OBJECTIVES This study aimed to compare the relative efficacy of lorlatinib, an anaplastic lymphoma kinase-tyrosine kinase inhibitor, with chemotherapy, for patients with second-line or later advanced anaplastic lymphoma kinase-positive non-small cell lung cancer. The endpoints of interest were overall survival (OS) and progression-free survival (PFS). METHODS Evidence for lorlatinib was informed by the single-arm phase I/II trial B7461001. A systematic literature review (SLR) was performed to identify OS and PFS data for chemotherapy. Unanchored matching-adjusted indirect comparisons (MAICs) between lorlatinib and chemotherapy (pemetrexed/docetaxel, platinum-based, or systemic therapy) were performed. RESULTS The SLR identified 3 relevant studies reporting PFS. Lorlatinib was associated with a significant decrease in the hazard of progression versus the 2 types of chemotherapy assessed. For PFS, the MAIC of lorlatinib versus the combined treatment arm of docetaxel or pemetrexed resulted in an adjusted hazard ratio (HR) of 0.22 (95% confidence interval [CI] 0.15-0.31). When lorlatinib was compared with platinum-based chemotherapy through an MAIC, the adjusted HR for PFS was 0.40 (95% CI 0.29-0.55). An exploratory comparison was performed for OS with evidence for systemic therapy (assumed equivalent to chemotherapy) not identified in the SLR. Lorlatinib provided a significant decrease in hazard of death (OS) versus systemic therapy, with HRs ranging from 0.12 (95% CI 0.05-0.27) to 0.43 (95% CI 0.27-0.60). CONCLUSIONS Lorlatinib demonstrated a significant improvement in PFS compared with chemotherapy, although limitations in the analyses were identified. The evidence informing OS comparisons was highly limited but suggested benefit of lorlatinib compared with systemic therapy.
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Affiliation(s)
- Sarah Smith
- BresMed Health Solutions, Sheffield, England, UK
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20
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Dayyani F, Lee W, Houshyar R, Fontaine P. Rapid and Deep Response to Lorlatinib in Pancreatic High-Grade Neuroendocrine Carcinoma With a Treatment Emergent Novel KANK1-ALK Fusion. JCO Precis Oncol 2023; 7:e2200230. [PMID: 36623237 DOI: 10.1200/po.22.00230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Affiliation(s)
- Farshid Dayyani
- Division of Hematology and Oncology, Department of Medicine, University of California, Orange, CA
| | - Whayoung Lee
- Department of Pathology and Laboratory Medicine, University of California, Orange, CA
| | - Roozbeh Houshyar
- Department of Radiological Sciences, University of California, Orange, CA
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21
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Itchins M, Pavlakis N. The quantum leap in therapeutics for advanced ALK+ non-small cell lung cancer and pursuit to cure with precision medicine. Front Oncol 2022; 12:959637. [PMID: 36003760 PMCID: PMC9393505 DOI: 10.3389/fonc.2022.959637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/08/2022] [Indexed: 11/13/2022] Open
Abstract
Since the discovery 15 years ago, we have seen a quantum leap in the treatment and survival for individuals diagnosed with ALK+ lung cancers. Unfortunately however, for most, the diagnosis is made in an incurable circumstance given the late presentation of symptoms. Through a revolutionary wave of therapeutics, individuals may remarkably live over a decade, however many fall short of this milestone, as the molecular profile of this disease is very heterogeneous, reflected in variable survival outcomes. Despite a significant improval in survival and quality of life with ALK-inhibitor monotherapies, now available across multiple-generations, drug resistance and disease relapse remains inevitable, and treatment is offered in an empiric, stepwise, non personalised biomarker informed fashion. A proposed future focus to treating ALK to improve the chronicity of this disease and even promote cure, is to deliver a personalised dynamic approach to care, with rational combinations of drugs in conjunction with local ablative therapies to prevent and constantly proactively alter clonal selection. Such an approach would be informed by precision imaging with MRI-brain and FDG-PETs sequentially, and by regular plasma sampling including for circulating tumour DNA sequencing with personalised therapeutic switches occurring prior to the emergence of radiological and clinical relapse. Such an approach to care will require a complete paradigm shift in the way we approach the treatment of advanced cancer, however evidence to date in ALK+ lung cancers, support this new frontier of investigation.
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Affiliation(s)
- Malinda Itchins
- Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, NSW, Australia
- Northern Clinical School, University of Sydney, Kolling Institute, St Leonards, NSW, Australia
- North Shore Health Hub, GenesisCare, St Leonards, NSW, Australia
- *Correspondence: Malinda Itchins,
| | - Nick Pavlakis
- Department of Medical Oncology, Northern Sydney Cancer Centre, Royal North Shore Hospital, St Leonards, NSW, Australia
- Northern Clinical School, University of Sydney, Kolling Institute, St Leonards, NSW, Australia
- North Shore Health Hub, GenesisCare, St Leonards, NSW, Australia
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22
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Cooper AJ, Sequist LV, Lin JJ. Third-generation EGFR and ALK inhibitors: mechanisms of resistance and management. Nat Rev Clin Oncol 2022; 19:499-514. [PMID: 35534623 PMCID: PMC9621058 DOI: 10.1038/s41571-022-00639-9] [Citation(s) in RCA: 266] [Impact Index Per Article: 88.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2022] [Indexed: 02/07/2023]
Abstract
The discoveries of EGFR mutations and ALK rearrangements as actionable oncogenic drivers in non-small-cell lung cancer (NSCLC) has propelled a biomarker-directed treatment paradigm for patients with advanced-stage disease. Numerous EGFR and ALK tyrosine kinase inhibitors (TKIs) with demonstrated efficacy in patients with EGFR-mutant and ALK-rearranged NSCLCs have been developed, culminating in the availability of the highly effective third-generation TKIs osimertinib and lorlatinib, respectively. Despite their marked efficacy, resistance to these agents remains an unsolved fundamental challenge. Both 'on-target' mechanisms (largely mediated by acquired resistance mutations in the kinase domains of EGFR or ALK) and 'off-target' mechanisms of resistance (mediated by non-target kinase alterations such as bypass signalling activation or phenotypic transformation) have been identified in patients with disease progression on osimertinib or lorlatinib. A growing understanding of the biology and spectrum of these mechanisms of resistance has already begun to inform the development of more effective therapeutic strategies. In this Review, we discuss the development of third-generation EGFR and ALK inhibitors, predominant mechanisms of resistance, and approaches to tackling resistance in the clinic, ranging from novel fourth-generation TKIs to combination regimens and other investigational therapies.
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Affiliation(s)
- Alissa J Cooper
- Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Lecia V Sequist
- Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Jessica J Lin
- Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA.
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23
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Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer. Cancers (Basel) 2022; 14:cancers14143452. [PMID: 35884511 PMCID: PMC9325236 DOI: 10.3390/cancers14143452] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/12/2022] [Accepted: 07/12/2022] [Indexed: 02/01/2023] Open
Abstract
EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance over time, emphasizing the need for alternative treatments. This review discusses recent advances in our understanding of the mechanisms behind EML4-ALK-driven NSCLC progression and the opportunities they present for alternative treatment options to ALK inhibitor monotherapy. Targeting ALK-dependent signalling pathways can overcome resistance that has developed due to mutations in the ALK catalytic domain, as well as through activation of bypass mechanisms that utilise the same pathways. We also consider evidence for polytherapy approaches that combine targeted inhibition of these pathways with ALK inhibitors. Lastly, we review combination approaches that use targeted inhibitors of ALK together with chemotherapy, radiotherapy or immunotherapy. Throughout this article, we highlight the importance of alternative breakpoints in the EML4 gene that result in the generation of distinct EML4-ALK variants with different biological and pathological properties and consider monotherapy and polytherapy approaches that may be selective to particular variants.
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24
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Abstract
Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, has been approved as a treatment for ALK-positive lung cancer. This review provides information regarding the pharmacology and clinical features of lorlatinib, including its efficacy and associated adverse events. Pivotal clinical trials are discussed along with the current status of lorlatinib as a treatment for ALK-positive lung cancer and future therapeutic challenges.
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Affiliation(s)
- Keisuke Baba
- Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Yasushi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
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25
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The Change in Paradigm for NSCLC Patients with EML4–ALK Translocation. Int J Mol Sci 2022; 23:ijms23137322. [PMID: 35806325 PMCID: PMC9266866 DOI: 10.3390/ijms23137322] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 06/24/2022] [Accepted: 06/28/2022] [Indexed: 02/01/2023] Open
Abstract
The severe prognosis linked with a lung cancer diagnosis has changed with the discovery of oncogenic molecularly driven subgroups and the use of tailored treatment. ALK-translocated advanced lung cancer is the most interesting model, having achieved the longest overall survival. Here, we report the most important paradigmatic shifts in the prognosis and treatment for this subgroup population occurred among lung cancer.
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26
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Peng L, Zhu L, Sun Y, Stebbing J, Selvaggi G, Zhang Y, Yu Z. Targeting ALK Rearrangements in NSCLC: Current State of the Art. Front Oncol 2022; 12:863461. [PMID: 35463328 PMCID: PMC9020874 DOI: 10.3389/fonc.2022.863461] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/08/2022] [Indexed: 12/25/2022] Open
Abstract
Anaplastic lymphoma kinase (ALK) alterations in non-small cell lung cancer (NSCLC) can be effectively treated with a variety of ALK-targeted drugs. After the approval of the first-generation ALK inhibitor crizotinib which achieved better results in prolonging the progression-free survival (PFS) compared with chemotherapy, a number of next-generation ALK inhibitors have been developed including ceritinib, alectinib, brigatinib, and ensartinib. Recently, a potent, third-generation ALK inhibitor, lorlatinib, has been approved by the Food and Drug Administration (FDA) for the first-line treatment of ALK-positive (ALK+) NSCLC. These drugs have manageable toxicity profiles. Responses to ALK inhibitors are however often not durable, and acquired resistance can occur as on-target or off-target alterations. Studies are underway to explore the mechanisms of resistance and optimal treatment options beyond progression. Efforts have also been undertaken to develop further generations of ALK inhibitors. This review will summarize the current situation of targeting the ALK signaling pathway.
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Affiliation(s)
- Ling Peng
- Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Liping Zhu
- Department of Medical Oncology, Shouguang Hospital of Traditional Chinese Medicine, Shouguang, China
| | - Yilan Sun
- Cancer Center, Department of Pulmonary and Critical Care Medicine, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China
| | - Justin Stebbing
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | | | - Yongchang Zhang
- Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, China
| | - Zhentao Yu
- Department of Thoracic Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
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Chen F, Zhang F, Wang Y, Peng J, Cao L, Mei Q, Ge M, Li L, Chen M, Dong WF, Chang Z. Biomimetic Redox-Responsive Mesoporous Organosilica Nanoparticles Enhance Cisplatin-Based Chemotherapy. Front Bioeng Biotechnol 2022; 10:860949. [PMID: 35372319 PMCID: PMC8966698 DOI: 10.3389/fbioe.2022.860949] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 02/10/2022] [Indexed: 11/13/2022] Open
Abstract
Cisplatin-based chemotherapy is dominated in several cancers; however, insufficient therapeutic outcomes and systemic toxicity hamper their clinical applications. Controlled release of cisplatin and reducing inactivation remains an urgent challenge to overcome. Herein, diselenide-bridged mesoporous organosilica nanoparticles (MON) coated with biomimetic cancer cell membrane were tailored for coordination responsive controlled cisplatin delivery and GSH depletion to strengthen Pt-based chemotherapy. Cisplatin-loaded MON (MON-Pt) showed high loading capacity due to robust coordination between selenium and platinum atoms and preventing premature leakage in normal tissue. MON-Pt exhibited a controlled release of activated cisplatin in response to the redox tumor microenvironment. Meanwhile, MON-Pt containing redox-responsive diselenide bonds could efficiently scavenge intracellular inactivation agents, such as GSH, to enhance Pt-based chemotherapy. 4T1 breast cancer cell membranes cloaked MON-Pt (MON-Pt@CM) performed efficient anticancer performance and low in vivo system toxicity due to long blood circulation time and high tumor accumulation benefiting from the tumor targeting and immune-invasion properties of the homologic cancer cell membrane. These results suggest a biomimetic nanocarrier to control release and reduce the inactivation of cisplatin for efficient and safe Pt-based chemotherapy by responding and regulating the tumor microenvironment.
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Affiliation(s)
- Fangman Chen
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Bio Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology Chinese Academy of Sciences, Suzhou, China
| | - Fan Zhang
- CAS Key Laboratory of Bio Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology Chinese Academy of Sciences, Suzhou, China
| | - Yanbin Wang
- Nephrology Department of the Fourth Affiliated Hospital of XinJiang Medical University, Macau, China
| | - Jiahui Peng
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Bio Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology Chinese Academy of Sciences, Suzhou, China
| | - Lei Cao
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Bio Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology Chinese Academy of Sciences, Suzhou, China
| | - Qian Mei
- CAS Key Laboratory of Bio Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology Chinese Academy of Sciences, Suzhou, China
| | - Mingfeng Ge
- CAS Key Laboratory of Bio Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology Chinese Academy of Sciences, Suzhou, China
| | - Li Li
- CAS Key Laboratory of Bio Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology Chinese Academy of Sciences, Suzhou, China
| | - Meiwan Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Wen-fei Dong
- School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- CAS Key Laboratory of Bio Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology Chinese Academy of Sciences, Suzhou, China
- *Correspondence: Wen-fei Dong, ; Zhimin Chang,
| | - Zhimin Chang
- CAS Key Laboratory of Bio Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology Chinese Academy of Sciences, Suzhou, China
- *Correspondence: Wen-fei Dong, ; Zhimin Chang,
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28
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Multiple Genetic Alterations as Resistance Mechanism during Second-Line Lorlatinib for Advanced ALK-Rearranged Lung Adenocarcinoma: A Case Report. Diagnostics (Basel) 2022; 12:diagnostics12030682. [PMID: 35328235 PMCID: PMC8947659 DOI: 10.3390/diagnostics12030682] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 02/28/2022] [Accepted: 03/07/2022] [Indexed: 12/12/2022] Open
Abstract
Second and third-generation ALK-TKI inhibitors have showed better activity and have replaced crizotinib in most of cases of advanced ALK-rearranged lung adenocarcinoma. The emergence of resistance adversely affects also the activity of these newer drugs; in particular, lorlatinib often shows multiple and complex resistance mechanisms. The case reported here highlights the importance of reassessing the biomolecular profile during the disease course, both by tissutal and liquid biopsy, with the aim of improving the knowledge of these resistance mechanisms, and so identifying new drugs or sequences able to optimize the management of these patients.
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29
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Takeyasu Y, Yoshida T, Masuda K, Matsumoto Y, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Yamamoto N, Ohe Y. Lorlatinib versus Pemetrexed-based chemotherapy in patients with ALK-rearranged non-small cell lung cancer previously treated with Alectinib. JTO Clin Res Rep 2022; 3:100311. [PMID: 35498380 PMCID: PMC9046446 DOI: 10.1016/j.jtocrr.2022.100311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 03/11/2022] [Accepted: 03/14/2022] [Indexed: 11/25/2022] Open
Abstract
Introduction Lorlatinib (LOR) or pemetrexed-based chemotherapy (PEM) is the standard treatment after failure of a second-generation ALK tyrosine kinase inhibitor, such as alectinib, in patients with ALK-positive NSCLC. Nevertheless, there have been few data on the clinical outcomes of these treatments after alectinib failure. Methods We retrospectively analyzed patients with ALK-rearranged NSCLC who received LOR (LOR group) or PEM (PEM group) as post-treatment after alectinib failure between December 2012 and August 2020. Results Among 90 patients who experienced disease progression during alectinib treatment, 38 of them received either PEM (n = 22) or LOR (n = 16) as subsequent treatment. The objective response rate and the median progression-free survival were similar in the PEM and LOR groups (objective response rate: 45% versus 44%, p = 0.92; median progression-free survival: 6.9 mo versus 6.2 mo, p = 0.83, respectively). Disease progression during treatment occurred in 22 patients with PEM and 14 patients with LOR. The central nervous system (CNS) was the most common site of progression in both groups. In patients without CNS metastasis at baseline, the cumulative incidence rate of CNS progression was lower over time in the LOR group compared with the PEM group (p = 0.045), whereas in patients with CNS metastasis at baseline, there were no significant differences in cumulative incidence rate of CNS progression between both groups (p = 0.43). Conclusions Clinical outcomes of PEM and LOR after failure of alectinib were similar in patients with ALK-positive NSCLC.
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30
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Zheng Y, Guo Z, Li Y. Long non-coding RNA prostate cancer-associated transcript 6 inhibited gefitinib sensitivity of non-small cell lung cancer by serving as a competing endogenous RNA of miR-326 to up-regulate interferon-alpha receptor 2. Bioengineered 2022; 13:3785-3796. [PMID: 35081872 PMCID: PMC8974150 DOI: 10.1080/21655979.2022.2031416] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
The critical roles of lncRNAs in drug resistance of malignancies have been widely recognized. This investigation aims to study the function of lncRNA PCAT6 in the resistance of non-small cell lung cancer (NSCLC) to gefitinib. In our study, we demonstrated that prostate cancer-associated transcript 6 (PCAT6) was upregulated in gefitinib-resistant NSCLC. PCAT6 knockdown inhibited gefitinib resistance of NSCLC, as indicated by decreased IC50 value, proliferation, and metastasis, and increased cell apoptosis. Besides, PCAT6 could directly target miR-326 in gefitinib-resistant NSCLC cells and augment NSCLC resistance to gefitinib by serving as ceRNA of miR-326. Furthermore, interferon-alpha receptor 2 (IFNAR2) was validated as a downstream target of miR-326 and miR-326 reduced resistance to gefitinib by inhibiting IFNAR2 expression. Our investigation identified that PCAT6 enhanced gefitinib resistance of NSCLC via miR-326/IFNAR2 axis, which might offer a new therapeutic strategy against gefitinib resistance of NSCLC patients.
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Affiliation(s)
- Yu Zheng
- Department of General Medicine, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Ziyi Guo
- Intervention Centre, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Ying Li
- Department of Outpatient, The First Affiliated Hospital of Jinzhou Medical University Jinzhou, Liaoning, China
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Ou SHI, Nagasaka M, Brazel D, Hou Y, Zhu VW. Will the clinical development of 4th-generation "double mutant active" ALK TKIs (TPX-0131 and NVL-655) change the future treatment paradigm of ALK+ NSCLC? Transl Oncol 2021; 14:101191. [PMID: 34365220 PMCID: PMC8353359 DOI: 10.1016/j.tranon.2021.101191] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/29/2021] [Accepted: 07/29/2021] [Indexed: 12/27/2022] Open
Abstract
Our current treatment paradigm of advanced anaplastic lymphoma kinase fusion (ALK+) non-small cell lung cancer (NSCLC) classifies the six currently approved ALK tyrosine kinase inhibitors (TKIs) into three generations. The 2nd-generation (2G) and 3rd-generation (3G) ALK TKIs are all "single mutant active" with varying potencies across a wide spectrum of acquired single ALK resistance mutations. There is a vigorous debate among clinicians which is the best upfront ALK TKI is for the first-line (1L) treatment of ALK+ NSCLC and the subsequent sequencing strategies whether it should be based on the presence of specific on-target ALK resistance mutations or not. Regardless, sequential use of "single mutant active" ALK TKIs will eventually lead to double ALK resistance mutations in cis. This has led to the creation of fourth generation (4G) "double mutant active" ALK TKIs such as TPX-0131 and NVL-655. We discuss the critical properties 4G ALK TKIs must possess to be clinically successful. We proposed conceptual first-line, second-line, and molecularly-based third-line registrational randomized clinical trials designed for these 4G ALK TKIs. How these 4G ALK TKIs would be used in the future will depend on which line of treatment the clinical trial design(s) is adopted provided the trial is positive. If approved, 4G ALK TKIs may usher in a new treatment paradigm for advanced ALK+ NSCLC that is based on classifying ALK TKIs based on the intrinsic functional capabilities ("singe mutant active" versus "double mutant active") rather than the loosely-defined "generational" (first-, second-,third-,fourth-) classification and avoid the current clinical approaches of seemingly random sequential use of 2G and 3G ALK TKIs.
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Affiliation(s)
- Sai-Hong Ignatius Ou
- University of California Irvine School of Medicine, 200 South Manchester Avenue, Suite 400, Orange, CA, United States; Chao Family Comprehensive Cancer Center, Orange, California, United States.
| | - Misako Nagasaka
- University of California Irvine School of Medicine, 200 South Manchester Avenue, Suite 400, Orange, CA, United States; Chao Family Comprehensive Cancer Center, Orange, California, United States; St. Marianna University, School of Medicine, Kawasaki, Japan
| | - Danielle Brazel
- University of California Irvine School of Medicine, 200 South Manchester Avenue, Suite 400, Orange, CA, United States
| | - Yujie Hou
- Samuel Curtis Johnson Graduate School of Management, Cornell University, Ithaca, New York, United States
| | - Viola W Zhu
- University of California Irvine School of Medicine, 200 South Manchester Avenue, Suite 400, Orange, CA, United States; Chao Family Comprehensive Cancer Center, Orange, California, United States
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A Novel Sequentially Evolved EML4-ALK Variant 3 G1202R/S1206Y Double Mutation In Cis Confers Resistance to Lorlatinib: A Brief Report and Literature Review. JTO Clin Res Rep 2021; 2:100116. [PMID: 34589977 PMCID: PMC8474455 DOI: 10.1016/j.jtocrr.2020.100116] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 10/08/2020] [Accepted: 10/25/2020] [Indexed: 11/30/2022] Open
Abstract
Lorlatinib is a third-generation ALK inhibitor that can overcome the largest number of acquired ALK resistance mutations, including the solvent-front mutation G1202R. Here, we report, for the first time, a novel, sequentially-evolved EML4-ALK variant 3 G1202R/S1206Y double mutation in cis detected in a patient with ALK-positive NSCLC after disease progression on sequential crizotinib, alectinib, and then lorlatinib. Three-dimensional computer modeling of this double mutation and other G1202R-based double mutations with lorlatinib (ALK G1202R/L1196M, ALK G1202R/F1174C, ALK G1202R/l1198F, ALK G1202R/G1269A) were provided to reveal how these double mutations may confer resistance to lorlatinib through diverse steric hindrances in the ALK kinase domain. In addition, we performed a comprehensive literature review on published acquired double or triple ALK mutations that are resistant to lorlatinib from both patient samples and in vitro mutagenesis experiments.
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Wu JY, Weng YS, Chiou YC, Hsu FT, Chiang IT. Induction of Apoptosis and Inhibition of EGFR/NF-κB Signaling Are Associated With Regorafenib-sensitized Non-small Cell Lung Cancer to Cisplatin. In Vivo 2021; 35:2569-2576. [PMID: 34410944 DOI: 10.21873/invivo.12539] [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: 05/19/2021] [Revised: 06/04/2021] [Accepted: 06/15/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND/AIM The combination of regorafenib with cisplatin/pemetrexed has indicated controllable safety and encouraging antitumor activity in non-small cell lung cancer (NSCLC) patients. However, the anti-NSCLC effects and action mechanisms of regorafenib combined with cisplatin is ambiguous. The major goal of the study was to study the inhibitory effects and action mechanisms of regorafenib combined with cisplatin in NSCLC cells. MATERIALS AND METHODS Cell viability, flow cytometry, immunofluorescence staining, western blotting, migration, and invasion assays were employed to verify the anti-NSCLC effects and mechanisms of regorafenib in combination with cisplatin. RESULTS Cisplatin-induced epidermal growth factor receptor (EGFR)/nuclear factor κB (NF-κB) signaling was effectively inhibited by regorafenib treatment. Regorafenib, erlotinib (EGFR inhibitor) and QNZ (NF-κB inhibitor) may all enhance the cytotoxicity effect of cisplatin. The invasion ability was effectively decreased by combination treatment. Caspase-dependent and -independent apoptosis was activated by cisplatin combined with regorafenib. CONCLUSION Apoptosis induction and EGFR/NF-κB inactivation correlate with regorafenib-enhanced anti-NSCLC efficacy of cisplatin. This study provides evidence of the therapeutic efficacy of regorafenib in combination with cisplatin on NSCLC.
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Affiliation(s)
- Jeng-Yuan Wu
- Department of Thoracic Surgery, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, Taiwan, R.O.C.,School of Medicine, Tzu Chi University, Hualien, Taiwan, R.O.C
| | - Yueh-Shan Weng
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C
| | - Yi-Chou Chiou
- Chest Medicine Department, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan, R.O.C
| | - Fei-Ting Hsu
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan, R.O.C
| | - I-Tsang Chiang
- Department of Radiation Oncology, Show Chwan Memorial Hospital, Changhua, Taiwan, R.O.C.; .,Department of Radiation Oncology, Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan, R.O.C.,Department of Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung, Taiwan, R.O.C
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Nilsson FOL, Asanin ST, Masters ET, Iadeluca L, Almond C, Cooper M, Smith S. The Cost-Effectiveness of Lorlatinib Versus Chemotherapy as a Second- or Third-Line Treatment in Anaplastic Lymphoma Kinase (ALK)-Positive Non-small-cell Lung Cancer in Sweden. PHARMACOECONOMICS 2021; 39:941-952. [PMID: 34080140 PMCID: PMC8298221 DOI: 10.1007/s40273-021-01015-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 03/06/2021] [Indexed: 05/03/2023]
Abstract
BACKGROUND Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with efficacy in patients with ALK-rearranged non-small-cell lung cancer (NSCLC) previously treated with a second-generation ALK inhibitor or with first- and second-generation ALK inhibitors. We examined the cost-effectiveness of second- or third-line+ (2L+ or 3L+) lorlatinib in Sweden, versus chemotherapy. METHODS A partitioned survival model with three health states (progression free, progressed, or death) was used. Lorlatinib relative efficacy versus chemotherapy was derived using unanchored matching adjusted indirect treatment comparisons from a phase 2 clinical trial. Utility data were derived from the same trial and published studies. Costs (year 2019) were obtained from Swedish national data. Costs and benefits were discounted at 3% per annum using a societal perspective (base case). Model robustness was evaluated with deterministic and probabilistic sensitivity analyses. RESULTS For 2L+, the average discounted total quality-adjusted life year (QALY) gain was 1.29 years. Total incremental costs were Swedish krona (SEK) 731,791, resulting in an incremental cost-effectiveness ratio (ICER) of SEK 566,278 per QALY gained. Non-discounted survival gain amounted to 1.94 years. For 3L+, the average discounted total QALY gain was 1.25 years. Total incremental costs were SEK 754,801, resulting in an ICER of SEK 603,934 per QALY gained. Non-discounted survival gain was 1.88 years. Sensitivity analyses were consistent. CONCLUSIONS ICERs ranged from SEK 421,000 to SEK 384,066 less than the boundary for a cost-effective treatment for a high-severity disease in Sweden (SEK 988,000), suggesting 2L+ or 3L+ lorlatinib is a cost-effective treatment for ALK-positive NSCLC versus chemotherapy.
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Affiliation(s)
- Fredrik O L Nilsson
- Pfizer Innovations AB, Stockholm, Sweden.
- , Vetenskapsvägen 10 SE-191 90, Sollentuna, Sweden.
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Nensi S, Ashton J. ALK-positive non-small cell lung cancer; potential combination drug treatments. Curr Cancer Drug Targets 2021; 21:737-748. [PMID: 34325640 DOI: 10.2174/1568009621666210729100647] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/31/2021] [Accepted: 06/07/2021] [Indexed: 11/22/2022]
Abstract
Advances in chromosomally rearranged ALK positive non-small cell lung cancer have been dramatic in only the last few years. Survival times have improved dramatically due to the introduction of ever more efficacious ALK inhibitors. These improvements have been due largely to improvements in blood-brain barrier penetration and the breadth of ligand binding pocket mutations against which the drugs are effective. However, the advances maybe slow as compared to the frequency of cancers with compound resistance mutations are appearing, suggesting the need to develop multiple ALK inhibitors to target different compound mutations.Another research area that promises to provide further gains is the use of drug combinations, with an ALK inhibitor combined with a drug targeting a "second driver" to overcome resistance. In this review, the range of secondary targets for ALK+ lung cancer and the potential for their clinical success are reviewed.
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Affiliation(s)
- Shrestha Nensi
- Department of Pharmacology & Toxicology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - John Ashton
- Department of Pharmacology & Toxicology, Otago School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
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Zhang C. Case Report: Treatment of Alectinib in NSCLC With Brain Metastasis Patient Refractory to Radiotherapy After Resistance to Crizotinib. Front Oncol 2021; 11:709188. [PMID: 34262876 PMCID: PMC8273575 DOI: 10.3389/fonc.2021.709188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 06/10/2021] [Indexed: 11/25/2022] Open
Abstract
Background Brain metastasis is the most common form of tumor recurrence after resistance to crizotinib in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). The treatment of brain metastasis in patients with ALK-positive NSCLC requires a multidisciplinary approach, including targeted therapy, chemotherapy, and radiotherapy. At present, no optimal treatment for these patients has been identified, although radiotherapy has remained a vital treatment. Case Presentation We experienced a patient with ALK-positive NSCLC who developed brain metastasis after crizotinib therapy. ALK rearrangement was not detected in a blood sample using next-generation sequencing. In accordance with National Comprehensive Cancer Network guidance, the patient underwent whole-brain radiotherapy. However, the number of metastatic sites unexpectedly increased. In desperation, the patient was empirically given alectinib after radiotherapy failure, and unanticipated success was achieved. Conclusions This case revealed some new insights. First, liquid biopsy is complementary to tissue biopsy in patients with NSCLC, mainly in those with EGFR mutation. However, ALK rearrangement should be assessed using tissue biopsy as much as possible. Second, brain metastasis of NSCLC might respond to second-generation tyrosine kinase inhibitors (TKIs), such as alectinib and ceritinib, after resistance to crizotinib regardless of the presence or absence of ALK rearrangement in liquid biopsy. Finally, combined radiotherapy and TKI therapy appears optimal in patients with brain metastasis of NSCLC after resistance to crizotinib in the absence of a definitive driver gene.
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Affiliation(s)
- Chunzhi Zhang
- Department of Radiation Oncology, Tianjin Hospital, Tianjin, China
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Su PL, Tsai JS, Yang SC, Wu YL, Tseng YL, Chang CC, Yen YT, Lin CY, Lin CC, Wang CC, Lin MC, Su WC. Survival benefit of osimertinib combination therapy in patients with T790M-positive non-small-cell lung cancer refractory to osimertinib treatment. Lung Cancer 2021; 158:137-145. [PMID: 34214933 DOI: 10.1016/j.lungcan.2021.06.014] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 04/27/2021] [Accepted: 06/16/2021] [Indexed: 01/10/2023]
Abstract
OBJECTIVES Osimertinib is the main treatment choice for pretreated patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) T790M mutations. However, the choice of subsequent therapy when progressive disease has developed after osimertinib treatment remains a major therapeutic challenge. This study evaluated the efficacy of osimertinib-based combination therapies in patients who developed progressive disease after treatment with osimertinib. MATERIAL AND METHODS We enrolled NSCLC patients harbouring T790M mutations pretreated with first- or second-generation EGFR tyrosine-kinase inhibitors and were receiving osimertinib at two tertiary referral centres between August 2015 and July 2019, and the subsequent treatment efficacy was assessed. RESULTS Osimertinib-based combination therapy yielded better overall survival (OS) than chemotherapy alone (not achieved vs. 7.8 months; hazard ratio, 0.39; 95 % confidence interval 0.17-0.89; P = 0.025) according to the Cox proportional hazards model adjusted for possible confounders. Synergism (combination index <1) between AZD9291 and chemotherapy and a higher proportion of apoptosis cells in combination treatment were also demonstrated in the T790M-positive PC9 cell line with acquired resistance to AZD9291. CONCLUSION Our data supported the hypothesis that osimertinib-based combination therapy is associated with improved OS among patients with clinical progression following the use of osimertinib. These findings warrant further validation in a randomised controlled study.
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Affiliation(s)
- Po-Lan Su
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Jeng-Shiuan Tsai
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Szu-Chun Yang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Yi-Lin Wu
- Department of Nursing, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Yau-Lin Tseng
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Chao-Chun Chang
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Yi-Ting Yen
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Chia-Ying Lin
- Department of Medical Imaging, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Chien-Chung Lin
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
| | - Chin-Chou Wang
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi, Taiwan.
| | - Meng-Chih Lin
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan; Department of Respiratory Therapy, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan.
| | - Wu-Chou Su
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department of Medical Imaging, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Center of Applied Nanomedicine, National Cheng Kung University, Tainan, Taiwan.
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Combination of Chemotherapy and ALK Inhibitors in ALK-Positive NSCLC. J Thorac Oncol 2021; 16:e31-e32. [PMID: 33896577 DOI: 10.1016/j.jtho.2021.01.1612] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 01/10/2021] [Accepted: 01/11/2021] [Indexed: 11/23/2022]
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Chevallier M, Borgeaud M, Addeo A, Friedlaender A. Oncogenic driver mutations in non-small cell lung cancer: Past, present and future. World J Clin Oncol 2021; 12:217-237. [PMID: 33959476 PMCID: PMC8085514 DOI: 10.5306/wjco.v12.i4.217] [Citation(s) in RCA: 140] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/05/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Lung cancer, of which non-small lung cancer is the most common subtype, represents the leading cause of cancer related-death worldwide. It is now recognized that a significant proportion of these patients present alterations in certain genes that drive oncogenesis. In recent years, more of these so-called oncogenic drivers have been identified, and a better understanding of their biology has allowed the development new targeted agents. This review aims to provide an update about the current landscape of driver mutation in non-small-cell lung cancer. Alterations in Kirsten rat sarcoma, epidermal growth factor receptor, MET, anaplastic lymphoma kinase, c-ROS oncogene 1, v-raf murine sarcoma viral oncogene homolog B, neurotrophic receptor tyrosine kinase, human epidermal growth factor 2, neuregulin-1 and rearranged during transfection are discussed, as well as agents targeting these alterations. Current standards of treatment as well as promising future strategies are presented. Currently, more than fifteen targeted agents are food and Drug administration-approved for seven oncogenic drivers in non-small-cell lung cancer, highlighting the importance of actively searching for these mutations. Continuous and future efforts made in defining the biology of each of these alterations will help to elucidate their respective resistance mechanisms, and to define the best treatment strategy and therapeutic sequence.
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Affiliation(s)
- Mathieu Chevallier
- Department of Oncology, University Hospital Geneva, Geneva 1205, Switzerland
| | - Maxime Borgeaud
- Department of Oncology, University Hospital Geneva, Geneva 1205, Switzerland
| | - Alfredo Addeo
- Department of Oncology, University Hospital Geneva, Geneva 1205, Switzerland
| | - Alex Friedlaender
- Department of Oncology, University Hospital Geneva, Geneva 1205, Switzerland
- Department of Oncology, Clinique Générale Beaulieu, Geneva 1206, Switzerland
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Nagasaka M, Ou SHI. Lorlatinib Should Be Considered as the Preferred First-Line Option in Patients With Advanced ALK-Rearranged NSCLC. J Thorac Oncol 2021; 16:532-536. [DOI: 10.1016/j.jtho.2020.12.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 12/18/2020] [Indexed: 01/24/2023]
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Current treatment and future challenges in ROS1- and ALK-rearranged advanced non-small cell lung cancer. Cancer Treat Rev 2021; 95:102178. [PMID: 33743408 DOI: 10.1016/j.ctrv.2021.102178] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/23/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022]
Abstract
Non─small cell lung cancer (NSCLC) presents different druggable genetic abnormalities, including ROS1 and ALK rearrangements, which share relevant clinical features and therapeutic strategies. The homology between the tyrosine kinase domains of ROS1 and ALK defines unique subsets of patients highly sensitive to targeted tyrosine kinase inhibitors (TKIs). Genomic profiling in advanced NSCLC is standard, immunohistochemistry and fluorescence in situ hybridization being the main techniques used to detect genomic rearrangements. Personalized treatment with TKIs in ROS1- and ALK-positive NSCLC patients has dramatically improved patients' outcomes. Crizotinib has been the first-line standard of care treatment in ALK-rearranged NSCLC patients for a long time, while crizotinib still represents the best upfront therapeutic option in ROS1-positive NSCLC patients, followed by next-generation TKIs at the time of disease progression. However, the improved intracranial efficacy of next-generation TKIs has led to these drugs becoming first-line options, widening treatment opportunities for these patients. Since all patients will develop disease progression under TKI therapy, understanding the mechanisms of acquired resistance is crucial to define the optimal sequential therapeutic strategy. Despite the positive correlation between personalized treatment and patients' outcome, access to next-generation TKIs and genomic profiling at the time of disease progression are major challenges to achieving this goal. In this review, we present updated evidence on ROS1- and ALK-rearranged NSCLC regarding epidemiology and diagnostics, current therapies and the most suitable sequential treatment approaches, as well as mechanisms of acquired resistance and strategies to overcome them.
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Nishio M, Yoshida T, Kumagai T, Hida T, Toyozawa R, Shimokawaji T, Goto K, Nakagawa K, Ohe Y, Seto T, Kudou K, Asato T, Zhang P, Yamamoto N. Brigatinib in Japanese Patients With ALK-Positive NSCLC Previously Treated With Alectinib and Other Tyrosine Kinase Inhibitors: Outcomes of the Phase 2 J-ALTA Trial. J Thorac Oncol 2021; 16:452-463. [DOI: 10.1016/j.jtho.2020.11.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/28/2020] [Accepted: 11/02/2020] [Indexed: 10/22/2022]
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Felip E, Shaw AT, Bearz A, Camidge DR, Solomon BJ, Bauman JR, Bauer TM, Peters S, Toffalorio F, Abbattista A, Thurm H, Peltz G, Wiltshire R, Besse B. Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs. Ann Oncol 2021; 32:620-630. [PMID: 33639216 DOI: 10.1016/j.annonc.2021.02.012] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 02/12/2021] [Accepted: 02/16/2021] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has substantial activity against ALK-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in ALK-positive NSCLC that progressed on second-generation ALK TKIs. PATIENTS AND METHODS In the ongoing phase II study (NCT01970865), patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial and extracranial antitumor activity were assessed independently per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6 months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6 (5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5). CONCLUSIONS Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy.
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Affiliation(s)
- E Felip
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), UVic-UCC, IOB-Quiron, Barcelona, Spain.
| | - A T Shaw
- Massachusetts General Hospital, Boston, USA
| | - A Bearz
- National Institute for Cancer Research, Aviano, Italy
| | | | - B J Solomon
- Peter MacCallum Cancer Centre, Melbourne, Australia
| | - J R Bauman
- Fox Chase Cancer Center, Philadelphia, USA
| | - T M Bauer
- Sarah Cannon Cancer Research Institute and Tennessee Oncology, PLLC, Nashville, USA
| | - S Peters
- Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | | | | | - H Thurm
- Pfizer Oncology, La Jolla, USA
| | - G Peltz
- Pfizer Oncology, Groton, USA
| | | | - B Besse
- Gustave Roussy Cancer Campus, Villejuif, France; Paris-Sud University, Orsay, France
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Xia B, Nagasaka M, Zhu VW, Ou SHI, Soo RA. How to select the best upfront therapy for metastatic disease? Focus on ALK-rearranged non-small cell lung cancer (NSCLC). Transl Lung Cancer Res 2021; 9:2521-2534. [PMID: 33489815 PMCID: PMC7815371 DOI: 10.21037/tlcr-20-331] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Anaplastic lymphoma kinase (ALK) inhibitors have demonstrated robust clinical activity in patients with ALK-rearranged lung cancers. The echinoderm microtubule-associated protein-like (EML)-ALK translocation was first discovered in 2007 and 4 years later, crizotinib, a first-generation ALK inhibitor was approved. Since then, subsequent generations of ALK inhibitors have demonstrated superior efficacy and better CNS activity compared to crizotinib. Alectinib and brigatinib, both second-generation ALK inhibitors have been compared directly to crizotinib in the first-line setting and has demonstrated improved progression free survival (PFS) and intracranial response. Ceritinib, another second-generation ALK inhibitor has been shown to be superior to chemotherapy in ALK-rearranged disease with good CNS activity. Initial responses to ALK inhibitors are not always durable and resistance can occur as on-target or off-target alterations. Lorlatinib, a third-generation ALK inhibitor, has demonstrated activity in the treatment naïve setting and in resistance to crizotinib and second-generation ALK inhibitors. Lorlatinib has also shown improved PFS in patients harboring EML4-ALK variant 3, which is associated with the development of ALK resistance mutations, specifically G1202R. Another new ALK inhibitor, ensartinib, has demonstrated efficacy in the first-line setting and in alectinib refractory disease. Additional studies are underway examining mechanisms of resistance and best treatment options post resistance.
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Affiliation(s)
- Bing Xia
- USC Norris Comprehensive Cancer Center, Keck School of Medicine of USC, Los Angeles, CA, USA
| | - Misako Nagasaka
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.,St. Marianna University Graduate School of Medicine, Kawaski, Japan
| | - Viola W Zhu
- Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, USA
| | - Sai-Hong Ignatius Ou
- Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, CA, USA
| | - Ross A Soo
- Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore, Singapore
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Elsayed M, Christopoulos P. Therapeutic Sequencing in ALK + NSCLC. Pharmaceuticals (Basel) 2021; 14:ph14020080. [PMID: 33494549 PMCID: PMC7912146 DOI: 10.3390/ph14020080] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/14/2021] [Accepted: 01/16/2021] [Indexed: 12/17/2022] Open
Abstract
Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. Of particular interest are cases with off-target resistance, for example MET, HER2 or KRAS alterations, which require special therapeutic maneuvers, e.g., inclusion in early clinical trials or off-label administration of respectively targeted drugs. On the other hand, up to approximately half of the patients failing TKI, develop anatomically restricted progression, which can be initially tackled with local ablative measures without switch of systemic therapy. Among the overall biologically favorable ALK+ tumors, with a mean tumor mutational burden uniquely below 3 mutations per Mb and the longest survival among NSCLC currently, presence of the EML4-ALK fusion variant 3 and/or TP53 mutations identify high-risk cases with earlier treatment failure and a need for more aggressive surveillance and treatment strategies. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a currently a matter of intense investigation. Major pharmaceutical challenges for the field are the development of more potent, fourth-generation TKI and effective immuno-oncological interventions, especially ALK-directed cell therapies, which will be essential for further improving survival and achieving cure of ALK+ tumors.
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Affiliation(s)
- Mei Elsayed
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, 69126 Heidelberg, Germany;
| | - Petros Christopoulos
- Department of Thoracic Oncology, Thoraxklinik and National Center for Tumor Diseases (NCT) at Heidelberg University Hospital, 69126 Heidelberg, Germany;
- Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), 69126 Heidelberg, Germany
- Correspondence: ; Tel.: +49-6221-396-1371
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Gristina V, La Mantia M, Iacono F, Galvano A, Russo A, Bazan V. The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2020; 13:E474. [PMID: 33352844 PMCID: PMC7766858 DOI: 10.3390/ph13120474] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/03/2020] [Accepted: 12/16/2020] [Indexed: 12/11/2022] Open
Abstract
The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs. Several compounds are currently under investigation to achieve the optimal strategy of therapy. Additionally, the results of ongoing clinical trials with novel-generation TKI will provide more evidence on the best sequence in the treatment of ALK-positive NSCLC patients. In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized.
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Affiliation(s)
- Valerio Gristina
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; (V.G.); (M.L.M.); (F.I.); (A.G.); (A.R.)
| | - Maria La Mantia
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; (V.G.); (M.L.M.); (F.I.); (A.G.); (A.R.)
| | - Federica Iacono
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; (V.G.); (M.L.M.); (F.I.); (A.G.); (A.R.)
| | - Antonio Galvano
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; (V.G.); (M.L.M.); (F.I.); (A.G.); (A.R.)
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, University of Palermo, 90127 Palermo, Italy; (V.G.); (M.L.M.); (F.I.); (A.G.); (A.R.)
| | - Viviana Bazan
- Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Section of Medical Oncology, University of Palermo, 90127 Palermo, Italy
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Russo A, Cardona AF, Caglevic C, Manca P, Ruiz-Patiño A, Arrieta O, Rolfo C. Overcoming TKI resistance in fusion-driven NSCLC: new generation inhibitors and rationale for combination strategies. Transl Lung Cancer Res 2020; 9:2581-2598. [PMID: 33489820 PMCID: PMC7815353 DOI: 10.21037/tlcr-2019-cnsclc-06] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 08/18/2020] [Indexed: 12/27/2022]
Abstract
During the last several years, multiple gene rearrangements with oncogenic potential have been described in NSCLC, identifying specific clinic-pathological subgroups of patients that benefit from a targeted therapeutic approach, including anaplastic lymphoma kinase (ALK), c-ros protooncogene 1 (ROS1) and, more recently, REarranged during Transfection (RET) and neurotrophic tyrosine receptor kinases (NTRK) genes. Despite initial impressive antitumor activity, the use of targeted therapies in oncogene-addicted NSCLC subgroups is invariably associated with the development of acquired resistance through multiple mechanisms that can include both on-target and off-target mechanisms. However, the process of acquired resistance is a rapidly evolving clinical scenario that constantly evolves under the selective pressure of tyrosine kinase inhibitors. The development of increasingly higher selective and potent inhibitors, traditionally used to overcome resistance to first generation inhibitors, is associated with the development of novel mechanisms of resistance that encompass complex resistance mutations, highly recalcitrant to available TKIs, and bypass track mechanisms. Herein, we provide a comprehensive overview on the therapeutic strategies for overcoming acquired resistance to tyrosine kinase inhibitors (TKIs) targeting the most well-established oncogenic gene fusions in advanced NSCLC, including ALK, ROS1, RET, and NTRK rearrangements.
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Affiliation(s)
| | - Andrés F. Cardona
- Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia
- Molecular Oncology and Biology Systems Research Group (FOX-G), Universidad el Bosque, Bogotá, Colombia
- Clinical and Translational Oncology Group, Institute of Oncology, Clínica del Country, Bogotá, Colombia
| | - Christian Caglevic
- Head of Cancer Research Department, Instituto Oncologico Fundacion Arturo Lopez Perez, Santiago, Chile
| | - Paolo Manca
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alejandro Ruiz-Patiño
- Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia
- Molecular Oncology and Biology Systems Research Group (FOX-G), Universidad el Bosque, Bogotá, Colombia
| | - Oscar Arrieta
- Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), México City, México
| | - Christian Rolfo
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA
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Mustachio LM, Roszik J. Current Targeted Therapies for the Fight against Non-Small Cell Lung Cancer. Pharmaceuticals (Basel) 2020; 13:ph13110374. [PMID: 33182254 PMCID: PMC7695293 DOI: 10.3390/ph13110374] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/01/2020] [Accepted: 11/05/2020] [Indexed: 12/12/2022] Open
Abstract
Lung cancers contribute to the greatest number of cancer-related deaths worldwide and still pose challenges in response to current treatment strategies. Non-small cell lung cancer (NSCLC) accounts for over 85% of lung cancers diagnosed in the United States and novel therapeutics are needed for the treatment of this disease. First and second generation targeted therapies against specific mutated or rearranged oncogenes in NSCLCs show anti-tumor activity and also increase survival. However, many NSCLC patients eventually develop resistance to these therapies or do not properly respond if they have central nervous system metastases. Thus, this review summarizes recent developments and findings related to the generation of novel targeted therapies recently or currently being developed to tackle hurdles that prior therapies were not able to overcome.
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Affiliation(s)
- Lisa Maria Mustachio
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Center for Cancer Epigenetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: (L.M.M.); (J.R.); Tel.: +1-832-750-4367 (L.M.M.); +1-713-745-2641 (J.R.)
| | - Jason Roszik
- Department of Genomic Medicine, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
- Correspondence: (L.M.M.); (J.R.); Tel.: +1-832-750-4367 (L.M.M.); +1-713-745-2641 (J.R.)
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Stinchcombe TE, Doebele RC, Wang X, Gerber DE, Horn L, Camidge DR. Preliminary Clinical and Molecular Analysis Results From a Single-Arm Phase 2 Trial of Brigatinib in Patients With Disease Progression After Next-Generation ALK Tyrosine Kinase Inhibitors in Advanced ALK+ NSCLC. J Thorac Oncol 2020; 16:156-161. [PMID: 33039599 DOI: 10.1016/j.jtho.2020.09.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/21/2020] [Accepted: 09/23/2020] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor (TKI) with activity against ALK resistance mutations and central nervous system activity. We prospectively studied the activity and safety of brigatinib in patients with disease progression after other next-generation ALK TKIs. METHODS Patients with stage IIIB or IV ALK+ NSCLC and progressive disease after next-generation ALK TKIs were eligible. Patients were required to undergo tumor biopsy less than or equal to 60 days before enrollment, and circulating tumor DNA was collected at baseline. Brigatinib treatment was 90 mg daily for 7 days and then escalated to 180 mg daily. Primary end point was objective response rate, and two-stage design was used. RESULTS Between March 2017 and November 2018, a total of 20 patients were treated in stage 1; median age was 55 years (range: 32-71), median number of previous therapies was three (range: 1-6), median number of previous ALK TKIs was two (range: 1-4), and 11 had central nervous system disease at baseline. The objective response rate was 40% (95% confidence interval [CI]: 19%-62%), and the duration of response was 5.3 months (95% CI: 3.6-nonassessable). With follow-up of 22 months, the median progression-free survival was 7.0 months (95% CI: 4.6-10.1). Grade 3 or 4 adverse events were consistent with those of previous studies. CONCLUSIONS Brigatinib has activity in ALK+ NSCLC after previous next-generation ALK TKIs. Further study in patients with disease progression on next-generation ALK TKI is warranted. National Clinical Trials #: NCT02706626.
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Affiliation(s)
- Thomas E Stinchcombe
- Division of Medical Oncology, Duke Cancer Institute, Duke University School of Medicine, Durham, North Carolina.
| | - Robert C Doebele
- Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado
| | - Xiaofei Wang
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
| | - David E Gerber
- Division of Hematology-Oncology, Department of Internal Medicine, Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Leora Horn
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - D Ross Camidge
- Division of Medical Oncology, University of Colorado Cancer Center, Aurora, Colorado
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50
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Itchins M, Lau B, Hudson AL, Westman H, Xia CY, Hayes SA, Howell VM, Rodriguez M, Cooper WA, Wei H, Buckland M, Li BT, Li M, Rathi V, Fox SB, Gill AJ, Clarke SJ, Boyer MJ, Pavlakis N. ALK-Rearranged Non-Small Cell Lung Cancer in 2020: Real-World Triumphs in an Era of Multigeneration ALK-Inhibitor Sequencing Informed by Drug Resistance Profiling. Oncologist 2020; 25:641-649. [PMID: 32558067 PMCID: PMC7418351 DOI: 10.1634/theoncologist.2020-0075] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Accepted: 05/13/2020] [Indexed: 12/13/2022] Open
Abstract
Since its discovery in 2007, we have seen the lives of patients diagnosed with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancers (NSCLC) transform with the advent of molecular therapies with first-, second-, and third-generation ALK inhibitors now available in the clinic. Despite great gains in patient survival now measured in years and preserved quality of life with targeted therapies, drug resistance is unfortunately inevitably encountered in this rare and unique molecular subset of lung cancer, and patients will eventually succumb to the disease. As these patients are often young, fit, and never smokers, the clinical and scientific communities have aligned to expedite drug development and access. Drug resistance profiling and further strategies are being explored through clinical trials, including the evaluation of specific drug sequencing and combinations to overcome such resistance and promote patient longevity. The cases of this report focus on precision medicine and aim to portray the pertinent aspects to consider when treating ALK-rearranged NSCLC in 2020, an ever-shifting space. By way of case examples, this report offers valuable information to the treating clinician, including the evolution of systemic treatments and the management of oligo-progression and multisite drug resistance. With the maturation of real-world data, we are fortunate to be experiencing quality and length of life for patients with this disease surpassing prior expectations in advanced lung cancer. KEY POINTS: This report focuses on the importance of genetic analysis of serial biopsies to capture the dynamic therapeutic vulnerabilities of a patient's tumor, providing a perspective on the complexity of ALK tyrosine kinase inhibitor (ALKi) treatment sequencing. These case examples contribute to the literature on ALK-rearranged and oncogene addicted non-small cell lung cancer (NSCLC), providing a framework for care in the clinic. In oligo-progressive disease, local ablative therapy and continuation of ALKi postprogression should be considered with potential for sustained disease control. ALK G1202R kinase domain mutations (KDM), highly prevalent at resistance to second-generation ALKi resistances, may emerge in non-EML4-ALK variant 3 cases and is sensitive to third-generation lorlatinib. When in compound with one or more ALK KDMs, resistance to lorlatinib is expected. In the case of rampantly progressive disease, rebiopsy and redefining biology in a timely manner may be informative.
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Affiliation(s)
- Malinda Itchins
- Department of Medical Oncology, Royal North Shore HospitalSt LeonardsNew South WalesAustralia
- Bill Walsh Translational Research Laboratory, Kolling InstituteSt LeonardsNew South WalesAustralia
- Northern Clinical School, Faculty of Medicine and Health, University of SydneySt LeonardsNew South WalesAustralia
| | - Brandon Lau
- Chris O'Brien LifehouseCamperdownNew South WalesAustralia
| | - Amanda L. Hudson
- Bill Walsh Translational Research Laboratory, Kolling InstituteSt LeonardsNew South WalesAustralia
- Northern Clinical School, Faculty of Medicine and Health, University of SydneySt LeonardsNew South WalesAustralia
| | - Helen Westman
- Department of Medical Oncology, Royal North Shore HospitalSt LeonardsNew South WalesAustralia
| | - Cathy Yi Xia
- Department of Medical Oncology, Royal North Shore HospitalSt LeonardsNew South WalesAustralia
| | - Sarah A. Hayes
- Bill Walsh Translational Research Laboratory, Kolling InstituteSt LeonardsNew South WalesAustralia
- Northern Clinical School, Faculty of Medicine and Health, University of SydneySt LeonardsNew South WalesAustralia
| | - Viive M. Howell
- Bill Walsh Translational Research Laboratory, Kolling InstituteSt LeonardsNew South WalesAustralia
- Northern Clinical School, Faculty of Medicine and Health, University of SydneySt LeonardsNew South WalesAustralia
| | - Michael Rodriguez
- Bill Walsh Translational Research Laboratory, Kolling InstituteSt LeonardsNew South WalesAustralia
- Northern Clinical School, Faculty of Medicine and Health, University of SydneySt LeonardsNew South WalesAustralia
- Department of Anatomical Pathology, Douglas Hanly MoirMacquarie ParkNew South WalesAustralia
| | - Wendy A. Cooper
- Central Clinical School, School of Medicine, University of SydneySt LeonardsNew South WalesAustralia
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred HospitalSydneyNew South WalesAustralia
- School of Medicine, Western Sydney UniversitySydneyNew South WalesAustralia
| | - Heng Wei
- Brain and Mind Centre, University of SydneySt LeonardsNew South WalesAustralia
| | - Michael Buckland
- Brain and Mind Centre, University of SydneySt LeonardsNew South WalesAustralia
- Department of Neuropathology, Royal Prince Alfred HospitalSydneyNew South WalesAustralia
| | - Bob T. Li
- Northern Clinical School, Faculty of Medicine and Health, University of SydneySt LeonardsNew South WalesAustralia
- Memorial Sloan Kettering Cancer Center, and Weill Cornell Medical CollegeNew YorkNew YorkUSA
| | - Mark Li
- Resolution BioscienceRedmondWashingtonUSA
| | - Vivek Rathi
- Department of Anatomical Pathology, St Vincent's, Victoria ParadeFitzroyVictoriaAustralia
| | - Stephen B. Fox
- Department of Pathology, Peter MacCallum Cancer Centre, and University of MelbourneVictoriaAustralia
| | - Anthony J. Gill
- Department of Anatomical Pathology, Royal North Shore HospitalSt LeonardsNew South WalesAustralia
- Northern Clinical School, Faculty of Medicine and Health, University of SydneySt LeonardsNew South WalesAustralia
| | - Stephen J. Clarke
- Department of Medical Oncology, Royal North Shore HospitalSt LeonardsNew South WalesAustralia
- Bill Walsh Translational Research Laboratory, Kolling InstituteSt LeonardsNew South WalesAustralia
- Northern Clinical School, Faculty of Medicine and Health, University of SydneySt LeonardsNew South WalesAustralia
| | - Michael J. Boyer
- Chris O'Brien LifehouseCamperdownNew South WalesAustralia
- Department of Pathology, Peter MacCallum Cancer Centre, and University of MelbourneVictoriaAustralia
| | - Nick Pavlakis
- Department of Medical Oncology, Royal North Shore HospitalSt LeonardsNew South WalesAustralia
- Bill Walsh Translational Research Laboratory, Kolling InstituteSt LeonardsNew South WalesAustralia
- Northern Clinical School, Faculty of Medicine and Health, University of SydneySt LeonardsNew South WalesAustralia
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