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Arnaoutakis K, Wan Y, Elliott J, Young M, Yin Y, Leventakos K, Lin HM, Dimou A. Real-World Treatment Patterns and Outcomes Across Three Lines of Therapy in Patients with ALK+ NSCLC. Adv Ther 2024; 41:3217-3231. [PMID: 38916812 PMCID: PMC11263478 DOI: 10.1007/s12325-024-02899-6] [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: 03/14/2024] [Accepted: 05/10/2024] [Indexed: 06/26/2024]
Abstract
INTRODUCTION Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy. METHODS Flatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling. RESULTS Among patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41-0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33-0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19-0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24-0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37-1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33-0.98; p = 0.042). CONCLUSIONS Patients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs.
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Affiliation(s)
| | - Yin Wan
- Takeda Development Center Americas, Inc., 500 Kendall Street, Cambridge, MA, 02142, USA
| | | | - Matt Young
- Takeda Pharmaceuticals America, Inc., Lexington, MA, USA
| | - Yu Yin
- Takeda Development Center Americas, Inc., 500 Kendall Street, Cambridge, MA, 02142, USA
| | | | - Huamao M Lin
- Global Evidence and Outcomes Research, Takeda Development Center Americas, Inc., 500 Kendall Street, Cambridge, MA, 02142, USA.
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Zhang H, Zhang Y, Zhu Y, Dong T, Liu Z. Understanding the treatment response and resistance to targeted therapies in non-small cell lung cancer: clinical insights and perspectives. Front Oncol 2024; 14:1387345. [PMID: 39055566 PMCID: PMC11269125 DOI: 10.3389/fonc.2024.1387345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Lung cancer remains the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with a generally poor prognosis. In recent years, advances in targeted therapy and sequencing technology have brought significant improvement in the therapeutic outcomes of patients with advanced NSCLC. Targeted inhibitors directed against specific mutated or rearranged oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and receptor tyrosine kinase ROS proto-oncogene 1(ROS1) among others, exhibit promising anti-tumor activity. Unfortunately, some patients develop acquired resistance and disease progression soon after initial remission. Despite the continuous development of new drugs and strategies to overcome drug resistance, it is still a major challenge in the treatment of NSCLC. The landscape of targeted therapy for NSCLC is evolving rapidly in response to the pace of scientific research. This study aimed to provide a comprehensive review of tumor target antigens and agents related to targeted therapy in NSCLC.
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Affiliation(s)
- Hang Zhang
- Department of Hematology, Institute of Hematology, West China Hospital of Sichuan University, Chengdu, China
| | - Yingying Zhang
- Department of Neurology, West China Hospital of Sichuan University, Chengdu, China
| | - Yingying Zhu
- Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, China
| | - Tian Dong
- Department of Hematology, Institute of Hematology, West China Hospital of Sichuan University, Chengdu, China
| | - Zheng Liu
- Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, China
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Kumar A, Kapoor A, Noronha V, Patil V, Menon N, Singh AK, Joshi A, Janu A, Kaushal RK, Pai T, Chougule A, Shetty O, Prabhash K. Lorlatinib in the second line and beyond for ALK positive lung cancer: real-world data from resource-constrained settings. BJC REPORTS 2024; 2:35. [PMID: 39516655 PMCID: PMC11523971 DOI: 10.1038/s44276-024-00055-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 02/27/2024] [Accepted: 03/06/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND ALK-positive lung cancers are known to have favorable responses with oral tyrosine kinase inhibitors. Lorlatinib is an approved treatment option post first and second-line ALK inhibitors and is now also in first line. We present a retrospective observational study of the safety and efficacy of patients receiving Lorlatinib in second-line and beyond. METHODS We conducted a retrospective observational study of ALK-positive patients who received Lorlatinib post-progression or intolerance to initial therapy at the Medical Oncology department. The patients who were started on Lorlatinib between January 2018 to December 2019 were included. The patients underwent routine blood and radiological evaluation every two to three months. RESULTS A total of 38 patients received Lorlatinib in the specified period. The median age was 48 years (range 23-68), with 53% of patients being male, 37% having comorbidities; the most common being hypertension and diabetes and 79% of patients were of ECOG-PS1. Twenty-two patients (58%) had received two prior TKIs. The most common sites of metastasis before starting Lorlatinib were brain (55%) and bone (53%). All patients except one received prior whole-brain radiotherapy with 4 receiving radiation twice. The median follow-up period was 49 months (95% CI: 46.4-51.6). Eighty-four percent showed disease control with median progression-free survival (PFS) and overall survival (OS) of 16 months (95% CI 5.4-26.6) and 22 months (95% CI 9.9-34.1) respectively. Twelve patients died without documented progression. Five out of twelve with documented progression had brain involvement while six had lung involvement. Twelve out of twenty-four patients who progressed received subsequent chemotherapy. The most common grade 3 and above toxicities were hypercholesterolemia and hypertriglyceridemia. Three (7.8%) patients required dose reduction. CONCLUSION This real-world data confirms the efficacy of Lorlatinib in the second line and beyond with adverse effects matching that of registration studies.
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Affiliation(s)
- Amit Kumar
- Department of Medical Oncology, Homi Bhabha Cancer Hospital and Research Centre(A Unit of Tata Memorial Centre, Mumbai), Muzaffarpur-, 842001, Bihar, India
| | - Akhil Kapoor
- Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Center and Homi Bhabha Cancer Hospital (A Unit of Tata Memorial Centre, Mumbai), Varanasi, 221005, Uttar Pradesh, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Vijay Patil
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Nandini Menon
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Ajay Kumar Singh
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Amit Joshi
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Amit Janu
- Department of Radiology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Rajiv Kumar Kaushal
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Trupti Pai
- Department of Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Anuradha Chougule
- Department of Molecular Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Omshree Shetty
- Department of Molecular Pathology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, 400012, Maharashtra, India.
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Shukla S, Prasad KT, Ahuja CK, Muthu V, Singh N. Prevalence of asymptomatic brain metastases in metastatic nonsquamous nonsmall cell lung cancer: Treatment implications for resource-constrained settings. Indian J Cancer 2024; 61:29-36. [PMID: 38078444 DOI: 10.4103/ijc.ijc_878_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 02/24/2021] [Indexed: 07/10/2024]
Abstract
BACKGROUND Brain metastases (BM) are common in metastatic nonsmall cell lung cancer (NSCLC). However, routine neuroimaging in asymptomatic patients with metastatic NSCLC is controversial as there is no conclusive evidence of benefit from the detection and treatment of asymptomatic BM. Herein, we evaluated the prevalence of asymptomatic BM and its treatment implications in a resource-limited setting. METHODS Consecutive patients with newly diagnosed, treatment-naïve, metastatic, nonsquamous NSCLC (NS-NSCLC) were included. Subjects who already had clinical or radiological features suggestive of BM were excluded from the study. All eligible subjects underwent contrast-enhanced magnetic resonance imaging (MRI) of the brain. Management of the detected BM was at the discretion of the treating clinicians. RESULTS Among 809 subjects who were screened, 100 (12.4%) were included in the study and underwent MRI. BM was present in 30 (30%) of the subjects and absent in the remaining 70 subjects. A majority of BM were multiple (70%), involved the frontal lobe commonly (73.3%), and had a mean (standard deviation) size of 13.2 (7.3) mm. Detection of BM resulted in a treatment alteration in 17 (17%) of the study subjects (brain irradiation, n = 17, change in targeted therapy, n = 3) with BM. There was no difference in survival of patients who underwent treatment alteration for management of BM compared to those who did not ( P = 0.132). CONCLUSIONS About one-third of patients with metastatic NS-NSCLC had BM in MRI despite the absence of symptoms. Despite treatment of the majority of the patients with BM with brain irradiation, there was no demonstrable survival benefit. Hence, we conclude that although routine neuroimaging of asymptomatic patients with newly diagnosed metastatic NSCLC may result in treatment alteration (primarily brain irradiation) in a small proportion of patients, it may not influence outcomes in resource-constrained settings.
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Affiliation(s)
- Shubham Shukla
- Department of Internal Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Kuruswamy Thurai Prasad
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Chirag Kamal Ahuja
- Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Valliappan Muthu
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
| | - Navneet Singh
- Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
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Yang JCH, Liu G, Lu S, He J, Burotto M, Ahn MJ, Kim DW, Liu X, Zhao Y, Vincent S, Yin J, Ma X, Lin HM, Popat S. Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial. J Thorac Oncol 2023; 18:1743-1755. [PMID: 37574132 DOI: 10.1016/j.jtho.2023.08.010] [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: 08/04/2023] [Accepted: 08/07/2023] [Indexed: 08/15/2023]
Abstract
INTRODUCTION This open-label, phase 3 trial (ALTA-3; NCT03596866) compared efficacy and safety of brigatinib versus alectinib for ALK+ NSCLC after disease progression on crizotinib. METHODS Patients with advanced ALK+ NSCLC that progressed on crizotinib were randomized 1:1 to brigatinib 180 mg once daily (7-d lead-in, 90 mg) or alectinib 600 mg twice daily, aiming to test superiority. The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Interim analysis for efficacy and futility was planned at approximately 70% of 164 expected PFS events. RESULTS The population (N = 248; brigatinib, n = 125; alectinib, n = 123) was notable for long median duration of prior crizotinib (16.0-16.8 mo) and low rate of ALK fusion in baseline circulating tumor DNA (ctDNA; 78 of 232 [34%]). Median blinded independent review committee-assessed PFS was 19.3 months with brigatinib and 19.2 months with alectinib (hazard ratio = 0.97 [95% confidence interval: 0.66-1.42], p = 0.8672]). The study met futility criterion. Overall survival was immature (41 events [17%]). Exploratory analyses pooled across the treatment groups revealed median PFS of 11.1 versus 22.5 months in patients with versus without ctDNA-detectable ALK fusion at baseline (hazard ratio: 0.48 [95% confidence interval: 0.32-0.71]). Treatment-related adverse events in more than 30% of patients (brigatinib, alectinib) were elevated levels of blood creatine phosphokinase (70%, 29%), aspartate aminotransferase (53%, 38%), and alanine aminotransferase (40%, 36%). CONCLUSIONS Brigatinib was not superior to alectinib for PFS in crizotinib-pretreated ALK+ NSCLC. Safety was consistent with the well-established and unique profiles of each drug. The low proportion of patients with ctDNA-detectable ALK fusion may account for prolonged PFS with both drugs in ALTA-3.
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Affiliation(s)
- James Chih-Hsin Yang
- Department of Oncology, National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan
| | - Geoffrey Liu
- Department of Medical Oncology, Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada
| | - Shun Lu
- Shanghai Chest Hospital, Shanghai, People's Republic of China
| | - Jianxing He
- Thoracic Cardio Surgery Department, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People's Republic of China
| | | | - Myung-Ju Ahn
- Section of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Dong-Wan Kim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Hospital, Seoul, South Korea
| | - XiaoQing Liu
- Fifth Medical Center of PLA General Hospital, Beijing, People's Republic of China
| | - Yanqiu Zhao
- Affiliated Cancer Hospital of Zhengzhou University, Henan, People's Republic of China
| | - Sylvie Vincent
- Oncology Cell Therapy Precision and Translational Medicine, Takeda Development Center Americas, Inc., Lexington, Massachusetts
| | - Jiani Yin
- Oncology Statistics, Takeda Development Center Americas, Inc., Lexington, Massachusetts
| | - Xin Ma
- Clinical Science, Takeda Development Center Americas, Inc., Lexington, Massachusetts
| | - Huamao M Lin
- Global Evidence and Outcomes Oncology, Takeda Development Center Americas, Inc., Lexington, Massachusetts
| | - Sanjay Popat
- Lung Unit, Royal Marsden Hospital, London, England, United Kingdom.
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Dhamelincourt E, Descourt R, Rousseau-Bussac G, Doubre H, Decroisette C, Demontrond P, Le Garff G, Falchero L, Huchot E, Vieillot S, Corre R, Kazulinski L, Bizieux A, Bigay-Gamé L, Morel H, Molinier O, Chouaïd C, Guisier F. Clinical Characteristics of Patients with Advanced ALK-Translocated Non-small Cell Lung Cancers and Long-Term Responses to Crizotinib (CRIZOLONG GFPC 05-19 Study). Target Oncol 2023; 18:905-914. [PMID: 37966566 DOI: 10.1007/s11523-023-01014-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/21/2023] [Indexed: 11/16/2023]
Abstract
BACKGROUND Although ALK-translocated (ALK+) advanced non-small cell lung cancers (aNSCLCs) are currently treated with second- or third-generation ALK inhibitors (ALK-TKIs), some patients respond durably to the first-generation ALK-TKI crizotinib. OBJECTIVE This study aimed to describe the clinical characteristics of these long-term responders. PATIENTS AND METHODS This national, multicenter, retrospective, non-interventional study included patients with ALK+ aNSCLCs and long-term responses to first (L1)- or subsequent (≥ L2)-line crizotinib, defined, respectively, as treatments lasting > 18 and > 10 months. Median treatment duration (mDOT) was the primary endpoint. RESULTS A total of 85 patients (32 L1 and 53 ≥ L2 responders) from 23 centers were included (receiving crizotinib between 10/24/2011-10/02/2018): median age of 59 years, 83.6% non-smokers or ex-smokers, 85.9% performance status (PS) 0/1, 94.1% with adenocarcinomas, median of one metastatic site, and 22.4% with brain metastases (BMs). After median follow-up of 73.4 [95% confidence interval, 67.5-79.9] months, respective L1 and ≥ L2 mDOTs were 43.3 [26.7-56.8] and 29.6 [22.6-35.8] months, with overall survival (OS) not reached (NR) and 116.2 [83.4-NR] months. BM presence or absence did not affect mDOT (31.4 versus 32.9 months) but significantly impacted median OS (70.6 versus 158.6 months; p = 0.0008). Progression on crizotinib was paucisymptomatic (74.1%) and oligometastatic (34.8%), especially BMs (42.4%). After crizotinib discontinuation, 65 (76.5%) patients received subsequent systemic therapy: 57 (67.1%) with second-generation ALK-TKIs. Respective mDOTs of first- and second-line post-crizotinib ALK-TKIs lasted 19.4 [14.9-25.6] and 11.1 [4.8-17.9] months, respectively. CONCLUSIONS Most ALK+ aNSCLC patients with prolonged crizotinib efficacy had paucisymptomatic and oligometastatic disease without BMs. They subsequently benefited from a sequential strategy with other ALK-TKIs.
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Affiliation(s)
| | - Renaud Descourt
- Institut de Cancérologie, Hôpital Morvan, CHU de Brest, Brest, France
| | | | - Hélène Doubre
- Service d'Oncologie Thoracique, Hôpital Foch, Suresnes, France
| | | | | | | | - Lionel Falchero
- Service de Pneumologie, Hôpital Nord-Ouest de Villefranche-sur-Saône, Gleizé, France
| | - Eric Huchot
- Service de Pneumologie, CHU Saint-Pierre, La Réunion, France
| | - Sabine Vieillot
- Service d'Oncologie, Clinique Saint Pierre, Perpignan, France
| | - Romain Corre
- Service de Pneumologie, CH Quimper, Quimper, France
| | - Laure Kazulinski
- Service de Pneumologie, CH du Cotentin Cherbourg, Cherbourg, France
| | - Acya Bizieux
- Service de Pneumologie, CH La Roche-sur-Yon, La Roche-sur-Yon, France
| | | | - Hugues Morel
- Service de Pneumologie, CH Orléans, Orléans, France
| | | | - Christos Chouaïd
- Service de Pneumologie, Centre Hospitalier Intercommunal, Créteil, France
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Wang K, Xiang YJ, Yu HM, Cheng YQ, Feng JK, Liu ZH, Shan YF, Zheng YT, Ni QZ, Cheng SQ. Overall survival of patients with hepatocellular carcinoma treated with sintilimab and disease outcome after treatment discontinuation. BMC Cancer 2023; 23:1017. [PMID: 37867191 PMCID: PMC10591394 DOI: 10.1186/s12885-023-11485-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 10/06/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND The use of Anti-PD-1 therapy has yielded promising outcomes in hepatocellular carcinoma (HCC). However, limited research has been conducted on the overall survival (OS) of patients with varying tumor responses and treatment duration. METHODS This retrospective study analyzed HCC patients who received sintilimab between January 2019 and December 2020 at four centers in China. The evaluation of tumor progression was based on Response Evaluation Criteria in Solid Tumors version 1.1. The study investigated the correlation between tumor response and OS, and the impact of drug use on OS following progressive disease (PD). RESULTS Out of 441 treated patients, 159 patients satisfied the inclusion criteria. Among them, 77 patients with disease control exhibited a significantly longer OS compared to the 82 patients with PD (median OS 26.0 vs. 11.3 months, P < 0.001). Additionally, the OS of patients with objective response (OR) was better than that of patients with stable disease (P = 0.002). Among the 47 patients with PD who continued taking sintilimab, the OS was better than the 35 patients who discontinued treatment (median OS 11.4 vs. 6.9 months, P = 0.042). CONCLUSIONS In conclusion, the tumor response in HCC patients who received sintilimab affects OS, and patients with PD may benefit from continued use of sintilimab.
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Affiliation(s)
- Kang Wang
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yan-Jun Xiang
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Hong-Ming Yu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yu-Qiang Cheng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Jin-Kai Feng
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Zong-Han Liu
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yun-Feng Shan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Yi-Tao Zheng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China
| | - Qian-Zhi Ni
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Shu-Qun Cheng
- Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
- Department of Hepatic Surgery VI, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, 200433, China.
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, China.
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200083, China.
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Lee ATM, Ou SI. From ASCEND-5 to ALUR to ALTA-3, an Anti-Climactic End to the Era of Randomized Phase 3 Trials of Next-Generation ALK TKIs in the Crizotinib-Refractory Setting. LUNG CANCER (AUCKLAND, N.Z.) 2023; 14:57-62. [PMID: 37377783 PMCID: PMC10292622 DOI: 10.2147/lctt.s413091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Accepted: 05/30/2023] [Indexed: 06/29/2023]
Abstract
The competing roles of various next-generation ALK TKIs in the first and second line treatment setting of advanced ALK+ NSCLC were based on many phase 3 clinical trials in both the first-line and crizotinib-refractory settings. The approval of all next-generation ALK TKIs was first in the crizotinib-refractory setting, based on a large-scale Phase 2 trial, and was then followed by at least one global randomized phase 3 trial comparing to platinum-based chemotherapy (ASCEND-4) or to crizotinib (ALEX, ALTA-1L, eXalt3, CROWN). In addition, three randomized phase 3 trials in the crizotinib-refractory setting were also conducted by next-generation ALK TKIs that were developed earlier before the superiority of next-generation ALK TKIs was demonstrated in order to secure the approval of these ALK TKIs in the crizotinib-refractory setting. These three crizotinib-refractory randomized trials were: ASCEND-5 (ceritinib), ALUR (alectinib), and ALTA-3 (brigatinib). The outcome of the ATLA-3 trial was recently presented closing out the chapter where next-generation ALK TKIs were investigated in the crizotinib-refractory setting as they have replaced crizotinib as the standard of care first-line treatment of advanced ALK+ NSCLC. This editorial summarizes the results of next-generation ALK TKIs in randomized crizotinib-refractory trials and provides a perspective on how natural history of ALK+ NSCLC may potentially be altered with sequential treatment. ALTA-3 compared brigatinib to alectinib, showing that both achieved near identical blinded independent review committee (BIRC)-assessed progression-free survival (PFS) (19.2-19.3 months). Importantly, 4.8% of brigatinib-treated patients developed interstitial lung disease (ILD) while no alectinib-treated patients developed ILD. Dose reduction and discontinuation due to treatment-related adverse events were 21% and 5%, respectively, for brigatinib-treated patients compared to 11% and 2%, respectively, for alectinib-treated patients. Upon analysis of these findings, we speculate that brigatinib may have a diminishing role in the treatment of advanced ALK+ NSCLC.
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Affiliation(s)
- Alexandria T M Lee
- University of California Irvine School of Medicine, Department of Medicine, Orange, CA, USA
| | - Saihong Ignatius Ou
- University of California Irvine School of Medicine, Department of Medicine, Orange, CA, USA
- Chao Family Comprehensive Cancer Center, Orange, CA, USA
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Shi J, Jia Z, Zhou Z, Zhao L, Meng Q, Liu Y. Ineffectiveness of Crizotinib in a Non-Small-Cell Lung Cancer with Novel ALK- LIMS1 Fusion: A Case Report. Onco Targets Ther 2023; 16:109-114. [PMID: 36824323 PMCID: PMC9942507 DOI: 10.2147/ott.s388962] [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: 09/06/2022] [Accepted: 02/07/2023] [Indexed: 02/19/2023] Open
Abstract
Anaplastic lymphoma kinase (ALK) rearrangements have been reported in 3-7% of non-small-cell lung cancers (NSCLC). ALK has been reported to be fused with a variety of genes in NSCLC. Significant clinical activity was achieved by ALK inhibitors in patients with NSCLC harbouring ALK translocations. We reported on a 48-year-old male Chinese patient with advanced lung adenocarcinoma harboring a novel ALK-LIMS1 who showed no response to crizotinib. The tissue was assayed by immunohistochemistry (IHC) for ALK and showed diffuse expression of ALK. Next-generation sequencing (NGS) was performed on the peripheral blood and tissue. The previous tumor tissue showed diffuse expression of ALK. Tissue and the later peripheral blood revealed a ALK- LIMS1 fusion. The patient failed to benefit from crizotinib (250 mg, twice a day), with a progression-free survival of two months. We identified a new ALK-LIMS1 fusion from an advanced lung adenocarcinoma which was primary resistant to crizotinib. Our case suggested that the coexistence of mutations and the non-dominant clone, as well as the rearrangement of ALK fusion, did not result in expressed ALK kinase domain that might lead to no response to ALK-TKIs.
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Affiliation(s)
- Junmei Shi
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Zhaohui Jia
- Clinical Pharmacology, The First Affiliated Hospital of Xingtai Medical College, Xingtai, People’s Republic of China
| | - Zhiguo Zhou
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Liyan Zhao
- Clinical Pharmacology, The First Affiliated Hospital of Xingtai Medical College, Xingtai, People’s Republic of China
| | - Qingju Meng
- Clinical Pharmacology, The First Affiliated Hospital of Xingtai Medical College, Xingtai, People’s Republic of China,Qingju Meng, Department of Orthopedics, The First Affiliated Hospital of Xingtai Medical College, 376 Shun de Road, Qiaodong District, Xingtai, Hebei Province, People’s Republic of China, Tel +86-13780444436, Email
| | - Yibing Liu
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China,Correspondence: Yibing Liu, Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, 12 JianKang Road, Shijiazhuang, Hebei Province, People’s Republic of China, Tel +86-13831173220, Email
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10
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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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11
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Kapoor A, Noronha V, Patil V, Menon N, Joshi A, Kumar A, Singh AK, Mahajan A, Janu A, Kumar R, Pai T, Chougule A, Shetty O, Prabhash K. Clinical Profile, Practice Pattern, and Outcomes With First-Line Therapy in ALK-Positive Lung Cancer: Real-World Data From Resource-Constrained Settings. JTO Clin Res Rep 2023; 4:100443. [PMID: 36654881 PMCID: PMC9841022 DOI: 10.1016/j.jtocrr.2022.100443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 11/21/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022] Open
Abstract
Introduction ALK inhibitors are one of the success stories in precision medicine for treating patients with advanced ALK-positive NSCLC. Nevertheless, developing countries have substantial constraints in using ALK inhibitors, with limited data from India. Methods An audit of a prospectively collected database of patients with advanced ALK-positive NSCLC treated from January 2013 to March 2018 was conducted. The SPSS version 20.0 was used for statistical analysis. Results A total of 441 patients were available for analysis; 62.5% were males, median age was 50 (range: 19-75) years, and 78.3% had Eastern Cooperative Oncology Group performance status of 0 to 1. When all the lines of therapies were included in the analysis, ALK inhibitors could be used in 379 (85.9%) of the total ALK-positive patients and 292 patients (66.2%) received ALK inhibitors in the first line in any strategy. The major reason for not starting ALK inhibitors upfront was financial constraints in 69% of the patients. The median progression-free survival on first-line therapy for the entire cohort was 14.1 months (95% confidence interval [CI]: 12.2-15.9), with a significant difference between patients receiving ALK inhibitor in first line in any strategy versus not in first line (17.2 mo [95% CI: 14.5-19.9] versus 5.9 mo [95% CI: 4.2-7.6], p < 0.001). The median overall survival was 30.7 months (95% CI: 27.3-34.2), with 37.6 months (95% CI: 28.1-47.1) for ALK inhibitor in the first line versus 20.5 months (95% CI: 15.8-25.1) for subsequent lines of therapy (p < 0.001). Conclusions Most of our patients with ALK-positive NSCLC were exposed to ALK inhibitors through various support mechanisms. Those patients who could receive ALK inhibitors in the first line had a significant survival advantage as compared with others.
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Affiliation(s)
- Akhil Kapoor
- Department of Medical Oncology, Mahamana Pandit Madan Mohan Malviya Cancer Center and Homi Bhabha Cancer Hospital (A Unit of Tata Memorial Centre, Mumbai), Varanasi, India
| | - Vanita Noronha
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Vijay Patil
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Nandini Menon
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Amit Joshi
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Amit Kumar
- Department of Medical Oncology, Homi Bhabha Cancer Hospital (A Unit of Tata Memorial Centre, Mumbai), Muzaffarpur, India
| | - Ajay Kumar Singh
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Abhishek Mahajan
- Department of Radiology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Amit Janu
- Department of Radiology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Rajiv Kumar
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Trupti Pai
- Department of Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Anuradha Chougule
- Department of Molecular Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Omshree Shetty
- Department of Molecular Pathology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
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Phase II Trial of the Combination of Alectinib with Bevacizumab in Alectinib Refractory ALK-Positive Nonsquamous Non-Small-Cell Lung Cancer (NLCTG1501). Cancers (Basel) 2022; 15:cancers15010204. [PMID: 36612200 PMCID: PMC9818646 DOI: 10.3390/cancers15010204] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 12/22/2022] [Accepted: 12/27/2022] [Indexed: 12/31/2022] Open
Abstract
Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2-16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients.
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13
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Kuo WK, Weng CF, Lien YJ. Treatment beyond progression in non-small cell lung cancer: A systematic review and meta-analysis. Front Oncol 2022; 12:1023894. [PMID: 36465371 PMCID: PMC9713814 DOI: 10.3389/fonc.2022.1023894] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Accepted: 10/26/2022] [Indexed: 09/30/2023] Open
Abstract
OBJECTIVES Treatment beyond progression (TBP) is defined as treatment continuing in spite of disease progression, according to the Response Evaluation Criteria In Solid Tumors. We performed a systematic review and meta-analysis to provide evidence for the effects of TBP on lung cancer survival. MATERIALS AND METHODS This study has been conducted following the PRISMA guidelines. A systematic review of PubMed, MEDLINE, Embase, and Cochrane Collaboration Central Register of Controlled Clinical Trials from the inception of each database to December 2021 was conducted. Two authors independently reviewed articles for inclusion and extract data from all the retrieved articles. Random-effects meta-analysis was performed using Comprehensive Meta-Analysis software, version 3 (Biostat, Englewood, NJ, USA). Hazard ratios (HRs) with the corresponding 95% confidence intervals (CI) were used for survival outcomes. RESULTS We identified five (15.6%) prospective randomized trials and twenty-seven (84.4%) retrospective observational studies of a total of 9,631 patients for the meta-analysis. 3,941 patients (40.9%) were in a TBP group and 5,690 patients (59.1%) were in a non-TBP group. There is a statistically significant advantage for patients who received TBP compared with those who did not in post progression progression-free survival (ppPFS), post progression overall survival (ppOS), and overall survival (OS) from initiation of drugs (ppPFS: HR, 0.746; 95% CI, 0.644-0.865; P<0.001; ppOS: HR, 0.689; 95% CI, 0.596-0.797; P<0.001; OS from initiation of drugs: HR, 0.515; 95% CI, 0.387-0.685; P<0.001). CONCLUSION This study provides further evidence in support of TBP for NSCLC, however, these results require cautious interpretation. Large, randomized, controlled trials investigating the efficacy of TBP in lung cancer treatment are warranted. SYSTEMIC REVIEW REGISTRATION https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42021285147.
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Affiliation(s)
- Wei-Ke Kuo
- Division of Respiratory Therapy and Chest Medicine, Sijhih Cathay General Hospital, Taipei, Taiwan
| | - Ching-Fu Weng
- Division of Pulmonary Medicine, Department of Internal Medicine, Hsinchu Cathay General Hospital, Hsinchu, Taiwan
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan
| | - Yin-Ju Lien
- Department of Health Promotion and Health Education, National Taiwan Normal University, Taipei, Taiwan
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14
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Hubbeling H, Choudhury N, Flynn J, Zhang Z, Falcon C, Rusch VW, Park BJ, Ziv E, Shaverdian N, Gelblum DY, Shepherd AF, Simone CB, Wu AJ, Gomez DR, Drilon A, Rimner A. Outcomes With Local Therapy and Tyrosine Kinase Inhibition in Patients With ALK/ ROS1/ RET-Rearranged Lung Cancers. JCO Precis Oncol 2022; 6:e2200024. [PMID: 36201714 PMCID: PMC9848570 DOI: 10.1200/po.22.00024] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 05/08/2022] [Accepted: 08/08/2022] [Indexed: 11/06/2022] Open
Abstract
PURPOSE Local therapy prolongs progression-free survival in patients with oligometastatic non-small-cell lung cancers treated with chemotherapy. We previously reported that local therapy also prolongs survival and time to next therapy in patients on tyrosine kinase inhibitors (TKIs) for EGFR-mutant lung adenocarcinomas. Here, we investigate the role of local therapy in patients progressing on TKIs for ALK/ROS1/RET-rearranged lung adenocarcinomas. MATERIALS AND METHODS Patients with advanced ALK/ROS/RET-rearranged lung adenocarcinomas who underwent radiation, surgery, or percutaneous thermal ablation from 2012 to 2020 for progression on an ALK/ROS1/RET TKI were included. Progression patterns were identified. Times from local therapy to progression, next therapy, and death were measured. RESULTS Sixty-one patients with ALK (n = 37), ROS1 (n = 12), and RET (n = 12) fusions were identified. Patients received radiotherapy (92%), surgery (13%), and percutaneous thermal ablation (8%). Local therapy was administered for solitary/oligoprogressive (94%) or polyprogressive (6%) disease. For most patients (85%), local therapy addressed all progressing sites. The median times from any local therapy to subsequent progression and next systemic therapy were 6.8 months (95% CI, 5.1 to 8.1) and 10 months (95% CI, 8.4 to 15.3), respectively. Third or greater local therapy was associated with shorter time to progression and next therapy than first/second local therapies (hazard ratio, 4.97; P < .001 and hazard ratio, 2.48; P < .001). The median overall survival from first local therapy was 34 months (95% CI, 26 to not reached). CONCLUSION Local therapy for progression on ALK, ROS1, or RET TKIs is associated with clinically meaningful time on continued TKI therapy beyond progression, especially earlier in the course of disease.
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Affiliation(s)
- Harper Hubbeling
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Noura Choudhury
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jessica Flynn
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Zhigang Zhang
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Christina Falcon
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Valerie W. Rusch
- Department of Thoracic Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Bernard J. Park
- Department of Thoracic Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Etay Ziv
- Department of Interventional Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Narek Shaverdian
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Daphna Y. Gelblum
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Annemarie F. Shepherd
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Charles B. Simone
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Abraham J. Wu
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Daniel R. Gomez
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alexander Drilon
- Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Andreas Rimner
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
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15
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Ignatius Ou SH. In Response to Continuation of Lorlatinib Beyond Progressive Disease. J Thorac Oncol 2022; 17:e86-e88. [PMID: 36031299 DOI: 10.1016/j.jtho.2022.07.1149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 11/26/2022]
Affiliation(s)
- Sai-Hong Ignatius Ou
- Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, California.
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Beaudet MÉ, Lacasse Y, Labbé C. Palliative Systemic Therapy Given near the End of Life for Metastatic Non-Small Cell Lung Cancer. Curr Oncol 2022; 29:1316-1325. [PMID: 35323312 PMCID: PMC8947187 DOI: 10.3390/curroncol29030112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Revised: 02/12/2022] [Accepted: 02/21/2022] [Indexed: 12/26/2022] Open
Abstract
Background: The use of chemotherapy near end of life (EOL) for various cancers is increasing and has been shown to be associated with delayed access to palliative care (PC) and increased aggressiveness in EOL care, without any benefit on survival. Methods: This retrospective study included 90 patients with metastatic non-small cell lung cancer (NSCLC) who received at least one line of palliative systemic anticancer therapy (SACT) and died between 1 November 2014, and 31 October 2016, at Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ). Our primary objective was to evaluate the proportion of patients with NSCLC receiving SACT within 30 days of death. Secondary outcomes were to determine the mean and median delays between the administration of the last treatment and death, and to evaluate if there were differences in characteristics and outcomes (including overall survival (OS)) between patients treated or not within 30 days of death. Results: In our cohort, 22% of patients received SACT within 30 days of death. For the entire cohort, the mean delay between the last treatment and death was 94 days, and the median was 57 days. There were no statistically significant differences between the two groups in terms of baseline characteristics. Use of SACT near EOL was associated with decreased access to PC, higher rates of in hospital death, decreased use of medical aid in dying (MAiD), and a shorter median OS (4.0 vs. 9.0 months). Conclusions: In this retrospective cohort of patients with metastatic NSCLC, 22% of patients received SACT within 30 days of death, with a negative impact on access to PC, higher rates of in hospital death, decreased use of MAiD and palliative sedation, and a shorter median OS.
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Continuation of Lorlatinib in ALK-positive NSCLC Beyond Progressive Disease. J Thorac Oncol 2022; 17:568-577. [PMID: 35026476 DOI: 10.1016/j.jtho.2021.12.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 11/11/2021] [Accepted: 12/22/2021] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Lorlatinib, a potent, selective third-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK TKI), showed overall and intracranial anti-tumor activity in patients with ALK-positive non-small cell lung cancer (NSCLC). METHODS Retrospective analyses in the ongoing phase II trial (NCT01970865) investigated clinical benefit of continuing lorlatinib beyond progressive disease (LBPD). Patients with prior crizotinib as the only ALK TKI were Group A (n = 28); those with ≥1 prior second-generation ALK TKIs were Group B (n = 74). LBPD was defined as >3 weeks of lorlatinib treatment after investigator-assessed progressive disease. Only patients with a best overall response of complete or partial response or stable disease were included. RESULTS There were no major differences in baseline characteristics between groups. Median duration of treatment for LBPD patients was 32.4 months (Group A) and 16.4 months (Group B) versus 12.5 months (Group A) and 7.7 months (Group B) for non-LBPD patients. Median overall survival (OS) in Group A was not reached (NR) in LBPD patients versus 24.4 months (95% confidence interval [CI] 12.1-NR); Group B median was 26.5 months (95% CI 18.7-35.5) in LBPD patients versus 14.7 months (95% CI 9.3-38.5) in non-LBPD patients. Median OS post-progression for Groups A and B was NR (95% CI 21.4-NR) and 14.6 months (95% CI 11.2-19.2) in LBPD patients, and 8.0 months (95% CI 1.5-NR) versus 5.3 months (95% CI 2.8-14.3) in non-LBPD patients. CONCLUSIONS Continuing LBPD is a viable treatment option for select patients with ALK-positive NSCLC who progressed on lorlatinib.
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18
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王 可, 李 娟, 孙 建, 李 力, 张 西, 张 建, 余 敏, 叶 贤, 张 明, 张 瑜, 姚 文, 黄 媚. [Recommendations from Experts in the Management of Adverse Reactions
to ALK Inhibitors (2021 Version)]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2021; 24:815-828. [PMID: 34670356 PMCID: PMC8695243 DOI: 10.3779/j.issn.1009-3419.2021.102.32] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Anaplastic lymphoma kinase (ALK) fusion gene, as a tumor driver gene, was crucial for the occurrence and development of non-small cell lung cancer (NSCLC). Recently, targeted ALK fusion gene has become the main treatment method for ALK-positive NSCLC. The first and second generation ALK inhibitors (ALKi), such as crizotinib, ceritinib, alectinib and ensartinib have been approved in China. However, there was no guidance for the management of ALKi adverse reactions. Therefore, this "Recommendations from experts in the management of adverse reactions to ALK inhibitors (2021 version)" has been summarized, led by Lung Cancer Professional Committee of Sichuan Cancer Society and Sichuan Medical Quality Control Center for Tumor Diseases, to provide practical and feasible strategies for clinical ALKi management specification of adverse reactions.
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Affiliation(s)
- 可 王
- 610041 成都，四川大学华西医院呼吸与危重症医学科Department of Respiratory and Critical Care Medicine, West China Hospital of Sichuan University, Chengdu 610041, China
| | - 娟 李
- 610041 成都，四川省肿瘤医院肿瘤内科Department of Oncology, Sichuan Cancer Hospital, Chengdu 610041, China
| | - 建国 孙
- 400037 重庆，陆军军医大学新桥医院肿瘤科Department of Oncology, Xinqiao Hospital, Army Military Medical University, Chongqing 400037, China
| | - 力 李
- 400042 重庆，陆军特色医学中心（大坪医院）呼吸与危重症医学科Department of Respiratory and Critical Care Medicine, Army Special Medical Center (Daping Hospital), Chongqing 400042, China
| | - 西 张
- 610000 成都，成都市第三人民医院肿瘤科Department of Oncology, Chengdu Third People's Hospital, Chengdu 610000, China
| | - 建勇 张
- 563000 遵义，呼吸与危重症医学科，遵义医科大学附属医院Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi 563000, China
| | - 敏 余
- 610041 成都，四川大学华西医院胸部肿瘤科Department of Thoracic Oncology, West China Hospital of Sichuan University, Chengdu 610041, China
| | - 贤伟 叶
- 550002 贵阳，贵州省人民医院呼吸与危重症医学科Department of Respiratory and Critical Care Medicine, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - 明 张
- 650118 昆明，云南省肿瘤医院放射治疗科Department of Radiation Therapy, Yunnan Cancer Hospital, Kunming 650118, China
| | - 瑜 张
- 550002 贵阳，贵州省人民医院肿瘤科Department of Oncology, Guizhou Provincial People's Hospital, Guiyang 550002, China
| | - 文秀 姚
- 610041 成都，四川省肿瘤医院肿瘤内科Department of Oncology, Sichuan Cancer Hospital, Chengdu 610041, China
| | - 媚娟 黄
- 610041 成都，四川大学华西医院胸部肿瘤科Department of Thoracic Oncology, West China Hospital of Sichuan University, Chengdu 610041, China
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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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Barry E, Walsh JA, Weinrich SL, Beaupre D, Blasi E, Arenson DR, Jacobs IA. Navigating the Regulatory Landscape to Develop Pediatric Oncology Drugs: Expert Opinion Recommendations. Paediatr Drugs 2021; 23:381-394. [PMID: 34173206 PMCID: PMC8275539 DOI: 10.1007/s40272-021-00455-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/21/2021] [Indexed: 11/30/2022]
Abstract
Regulatory changes have been enacted in the United States (US) and European Union (EU) to encourage the development of new treatments for pediatric cancer. Here, we review some of the factors that have hampered the development of pediatric cancer treatments and provide a comparison of the US and EU regulations implemented to address this clinical need. We then provide some recommendations for each stage of the oncology drug development pathway to help researchers maximize their chance of successful drug development while complying with regulations. A key recommendation is the engagement of key stakeholders such as regulatory authorities, pediatric oncologists, academic researchers, patient advocacy groups, and a Pediatric Expert Group early in the drug development process. During drug target selection, sponsors are encouraged to consult the Food and Drug Administration (FDA), European Medicines Agency (EMA), and the FDA target list, in addition to relevant US and European consortia that have been established to characterize and prioritize oncology drug targets. Sponsors also need to carefully consider the resourcing requirements for preclinical testing, which include ensuring appropriate access to the most relevant databases, clinical samples, and preclinical models (cell lines and animal models). During clinical development, sponsors can account for the pharmacodynamic (PD)/pharmacokinetic (PK) considerations specific to a pediatric population by developing pediatric formulations, selecting suitable PD endpoints, and employing sparse PK sampling or modeling/simulation of drug exposures where appropriate. Additional clinical considerations include the specific design of the clinical trial, the potential inclusion of children in adult trials, and the value of cooperative group trials.
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21
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Clinical benefit of continuing pembrolizumab treatment beyond progression in patients with metastatic urothelial carcinoma. Cancer Immunol Immunother 2021; 71:229-236. [PMID: 34100985 DOI: 10.1007/s00262-021-02980-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 06/02/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND There has been no clinical evidence to justify continued pembrolizumab therapy beyond progression in patients with metastatic urothelial carcinoma (UC). MATERIALS AND METHODS We conducted a multicenter retrospective study evaluating the clinical efficacy of continued use of pembrolizumab beyond progression in patients with metastatic UC. Data from 51 patients with metastatic UC, who developed progression during second-line pembrolizumab therapy, were analyzed. Progression was defined based on the Immunotherapy Response Evaluation Criteria in Solid Tumors. The outcome was overall survival (OS). The association between continued treatment, OS, and the risk of all-cause mortality was tested using log-rank test, conventional and time-dependent Cox regression models. RESULTS No significant difference in patient characteristics was noted between patients continuing pembrolizumab beyond progression (N = 21) and those discontinuing pembrolizumab (N = 30). Median OS was significantly longer in the continuation group (17.8 vs. 8.8 months; P = 0.038). A multivariable conventional Cox regression model identified continued pembrolizumab administration as a significant independent prognostic factor of all-cause mortality (hazard ratio [HR]: 0.21, 95% confidence interval [CI]: 0.05-0.90, P = 0.036), irrespective of the time from treatment initiation to progression and concurrent clinical progression. Further, longer duration of pembrolizumab treatment beyond progression was independently associated with a reduced risk of all-cause mortality in a multivariable time-dependent Cox regression model, when used as a time-dependent variable (HR: 0.07, 95% CI: 0.01-0.45, P = 0.006). CONCLUSIONS Continued pembrolizumab administration beyond progression might be beneficial in patients with metastatic UC who were clinically stable.
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Melosky B, Wheatley-Price P, Juergens RA, Sacher A, Leighl NB, Tsao MS, Cheema P, Snow S, Liu G, Card PB, Chu Q. The rapidly evolving landscape of novel targeted therapies in advanced non-small cell lung cancer. Lung Cancer 2021; 160:136-151. [PMID: 34353680 DOI: 10.1016/j.lungcan.2021.06.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/25/2021] [Accepted: 06/02/2021] [Indexed: 01/15/2023]
Abstract
Lung cancer is a highly heterogeneous disease often driven by well-characterized driver mutations. Although the best studied are common alterations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) oncogenes, rapid advances in molecular characterization has led to the development of novel therapeutics that inhibit additional oncogenic alterations in advanced NSCLC. The literature search identified 62 eligible phase I/II clinical trials or integrated analyses of assessing novel targeted agents against the following molecular alterations: ROS1-rearranged, BRAF V600E-mutant, NTRK-rearranged, MET-altered, uncommon EGFR-mutant, RET-rearranged, HER2-positive, KRAS G12C-mutant and NRG1-rearranged. This rapidly evolving field has produced many new targeted treatment options and promising outcomes have led to the FDA approval of seven novel agents for use in ROS1-rearranged, BRAF V600E-mutant, NTRK-rearranged, MET exon 14 skipping-mutant or RET-rearranged advanced NSCLC. Research continues at a rapid pace, with a number of phase III trials underway to fully evaluate new promising agents under development for improving outcomes in patients with NSCLC harboring distinct molecular subtypes. This review will provide a comprehensive summary of existing data as well as a user-friendly guide on the current status of novel targeted therapy in oncogene-driven advanced NSCLC.
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Affiliation(s)
- Barbara Melosky
- Medical Oncology, BCCA - 600 W 10th Ave, Vancouver, BC, V5Z 4E6, Canada.
| | - Paul Wheatley-Price
- Ottawa Hospital Research Institute, University of Ottawa, 501 Smyth Box 511, Ottawa, ON, K1H 8L6, Canada
| | - Rosalyn A Juergens
- Juravinski Cancer Centre, McMaster University, 699 Concession Street, Hamilton, ON, L8V5C2, Canada
| | - Adrian Sacher
- Princess Margaret Cancer Centre, University of Toronto, 101 College Street, Toronto, ON, M5G1L7, Canada
| | - Natasha B Leighl
- Princess Margaret Cancer Centre, University of Toronto, 7-913 700 University Avenue, Toronto, ON, M5G1Z5, Canada
| | - Ming-Sound Tsao
- Princess Margaret Cancer Centre, University of Toronto, 101 College Street, Toronto, ON, M5G1L7, Canada
| | - Parneet Cheema
- William Osler Health System, University of Toronto, 101 Humber College Blvd, Etobicoke, ON, M9V 1R8, Canada
| | - Stephanie Snow
- QEII Health Sciences Centre, Dalhousie University, 1276 South Park Street Halifax, NS, B3H 2Y9, Canada
| | - Geoffrey Liu
- Princess Margaret Cancer Centre, University of Toronto, 101 College Street, Toronto, ON, M5G1L7, Canada
| | - Paul B Card
- Kaleidoscope Strategic Inc., 146 Marion St., Toronto, ON, M6R 1E7, Canada
| | - Quincy Chu
- Cross Cancer Institute, University of Alberta, 11560 University Ave, 2nd Floor, Edmonton, AB, T6G 1Z2, Canada
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Pan Y, Xiao W, Ye F, Wang H, Shen Y, Yu X, Han X, Chu Q, Zhou C, Zhang Z, Ren S. Outcomes of switching from crizotinib to alectinib in patients with advanced non-small cell lung cancer with anaplastic lymphoma kinase fusion. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1014. [PMID: 34277814 PMCID: PMC8267309 DOI: 10.21037/atm-21-2769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 06/16/2021] [Indexed: 01/15/2023]
Abstract
BACKGROUND Alectinib and crizotinib have been approved as first-line therapies for advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) gene fusion. However, the therapeutic efficacy and side effects are still largely unknown of patients who switched to next-generation ALK tyrosine kinase inhibitors (ALK-TKIs), such as alectinib, after experiencing no disease progression with initial crizotinib treatment. METHODS This prospective real-world study enrolled patients who were treated with alectinib after experiencing no disease progression with initial crizotinib treatment. The patients' baseline characteristics, objective response rate (ORR) of crizotinib and alectinib, size change of target tumor lesions, treatment regimen and adverse events (AEs) were collected and analyzed. RESULTS The study included 53 patients, the majority of whom (96.2%) had non-squamous NSCLC. The median age was 51 (range, 31-80) years old. The ORR of first-line crizotinib was 54.7%. The ORR of sequential alectinib was 73.6%, and 90.5% of patients showed further tumor shrinkage after the alectinib treatment. The median progression-free survival was not reached, and 90.5% of patients were still enrolled in the study at the last follow-up. Among them, 34.0% of patients switched to alectinib treatment due to the toxicity. Crizotinib was associated with a higher frequency of AEs of grades 3 and 4 than alectinib (15.1% vs. 0%). Neither group had any AEs resulting in death. CONCLUSIONS Switching to alectinib might be an option for patients who do not experience disease progression with initial crizotinib therapy, and may promote better treatment compliance.
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Affiliation(s)
- Yingying Pan
- Department of Medical Oncology, Shanghai Pulmonary Hospital &Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Wenjing Xiao
- Department of Tumor Radiotherapy, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Feng Ye
- Xiamen Key Laboratory of Antitumor Drug Transformation Research, The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Huijuan Wang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yihong Shen
- Department of Respiratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xinmin Yu
- Department of Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou, China
| | - Xiao Han
- Department of Internal Medicine-Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Caicun Zhou
- Department of Medical Oncology, Shanghai Pulmonary Hospital &Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
| | - Zhihong Zhang
- Department of Respiratory Oncology, Anhui Provincial Cancer Hospital (The First Affiliated Hospital of USTC West District), Hefei, China
| | - Shengxiang Ren
- Department of Medical Oncology, Shanghai Pulmonary Hospital &Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China
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Wiest NE, Tzou KS, Olson MT, Herchko SM, Bajalia EM, Thiel DD, Lou Y, Zhao Y, Manochakian R. Crizotinib-associated renal cyst development may be associated with prolonged progression-free survival in patients with ALK-positive non-small-cell lung cancer: Case report and review of the literature. Clin Case Rep 2021; 9:e04278. [PMID: 34136235 PMCID: PMC8190584 DOI: 10.1002/ccr3.4278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/02/2021] [Accepted: 04/14/2021] [Indexed: 12/13/2022] Open
Abstract
Non-small cell lung cancer patients with anaplastic lymphoma kinase or c-ros oncogene 1 mutations who are treated with the tyrosine kinase inhibitor crizotinib rarely develop crizotinib-associated renal cysts (CARCs). Here, we present a case report and review of the literature supporting the hypothesis that CARCs may correlate positively with progression-free survival.
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Affiliation(s)
| | - Katherine S. Tzou
- Department of Radiation OncologyMayo Clinic FloridaJacksonvilleFLUSA
| | | | - Steven M. Herchko
- Department of Radiation OncologyMayo Clinic FloridaJacksonvilleFLUSA
| | | | - David D. Thiel
- Department of UrologyMayo Clinic FloridaJacksonvilleFLUSA
| | - Yanyan Lou
- Division of Hematology/OncologyDepartment of MedicineMayo Clinic FloridaJacksonvilleFLUSA
| | - Yujie Zhao
- Division of Hematology/OncologyDepartment of MedicineMayo Clinic FloridaJacksonvilleFLUSA
| | - Rami Manochakian
- Division of Hematology/OncologyDepartment of MedicineMayo Clinic FloridaJacksonvilleFLUSA
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Sun S, Fei K, Zhang G, Wang J, Yang Y, Guo W, Yang Z, Wang J, Xue Q, Gao Y, He J. Construction and Comprehensive Analyses of a METTL5-Associated Prognostic Signature With Immune Implication in Lung Adenocarcinomas. Front Genet 2021; 11:617174. [PMID: 33679869 PMCID: PMC7933593 DOI: 10.3389/fgene.2020.617174] [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: 10/14/2020] [Accepted: 12/21/2020] [Indexed: 12/24/2022] Open
Abstract
For lung adenocarcinoma (LUAD), patients of different stages have strong heterogeneity, and their overall prognosis varies greatly. Thus, exploration of novel biomarkers to better clarify the characteristics of LUAD is urgent. Multi-omics information of LUAD patients were collected form TCGA. Three independent LUAD cohorts were obtained from gene expression omnibus (GEO). A multi-omics correlation analysis of METTL5 was performed in TCGA dataset. To build a METTL5-associated prognostic score (MAPS). Spathial and random forest methods were first applied for feature selection. Then, LASSO was implemented to develop the model in TCGA cohort. The prognostic value of MAPS was validated in three independent GEO datasets. Finally, functional annotation was conducted using gene set enrichment analysis (GSEA) and the abundances of infiltrated immune cells were estimated by ImmuCellAI algorithm. A total of 901 LUAD patients were included. The expression of METTL5 in LUAD was significantly higher than that in normal lung tissue. And high expression of METTL5 indicated poor prognosis in all different stages (P < 0.001, HR = 1.81). Five genes (RAC1, C11of24, METTL5, RCCD1, and SLC7A5) were used to construct MAPS and MAPS was significantly correlated with poor prognosis (P < 0.001, HR = 2.15). Furthermore, multivariate Cox regression analysis suggested MAPS as an independent prognostic factor. Functional enrichment revealed significant association between MAPS and several immune components and pathways. This study provides insights into the potential significance of METTL5 in LUAD and MAPS can serve as a promising biomarker for LUAD.
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Affiliation(s)
- Sijin Sun
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kailun Fei
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guochao Zhang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Juhong Wang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yannan Yang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Guo
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhenlin Yang
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Wang
- State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qi Xue
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yibo Gao
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Frost N, Christopoulos P, Kauffmann-Guerrero D, Stratmann J, Riedel R, Schaefer M, Alt J, Gütz S, Christoph DC, Laack E, Faehling M, Fischer R, Fenchel K, Haen S, Heukamp L, Schulz C, Griesinger F. Lorlatinib in pretreated ALK- or ROS1-positive lung cancer and impact of TP53 co-mutations: results from the German early access program. Ther Adv Med Oncol 2021; 13:1758835920980558. [PMID: 33613692 PMCID: PMC7876585 DOI: 10.1177/1758835920980558] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 11/17/2020] [Indexed: 01/31/2023] Open
Abstract
Introduction: We report on the results of the German early access program (EAP) with the third-generation ALK- and ROS1-inhibitor lorlatinib. Patients and Methods: Patients with documented treatment failure of all approved ALK/ROS1-specific therapies or with resistance mutations not covered by approved inhibitors or leptomeningeal carcinomatosis were enrolled and analyzed. Results: In total, 52 patients were included [median age 57 years (range 32–81), 54% female, 62% never smokers, 98% adenocarcinoma]; 71% and 29% were ALK- and ROS1-positive, respectively. G1202R and G2032R resistance mutations prior to treatment with lorlatinib were observed in 10 of 26 evaluable patients (39%), 11 of 39 patients showed TP53 mutations (28%). Thirty-six patients (69%) had active brain metastases (BM) and nine (17%) leptomeningeal carcinomatosis when entering the EAP. Median number of prior specific TKIs was 3 (range 1–4). Median duration of treatment, progression-free survival (PFS), response rate and time to treatment failure were 10.4 months, 8.0 months, 54% and 13.0 months. Calculated 12-, 18- and 24-months survival rates were 65, 54 and 47%, overall survival since primary diagnosis (OS2) reached 79.6 months. TP53 mutations were associated with a substantially reduced PFS (3.7 versus 10.8 month, HR 3.3, p = 0.003) and were also identified as a strong prognostic biomarker (HR for OS2 3.0 p = 0.02). Neither prior treatments with second-generation TKIs nor BM had a significant influence on PFS and OS. Conclusions: Our data from real-life practice demonstrate the efficacy of lorlatinib in mostly heavily pretreated patients, providing a clinically meaningful option for patients with resistance mutations not covered by other targeted therapies and those with BM or leptomeningeal carcinomatosis.
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Affiliation(s)
- Nikolaj Frost
- Department of Infectious Diseases and Respiratory Medicine, Charité Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, D-13353, Germany Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Infectious Diseases and Pulmonary Medicine, Berlin, Germany
| | - Petros Christopoulos
- Department of Thoracic Oncology, Thoraxklinik at Heidelberg University Hospital, Heidelberg, Germany, and Translational Research Center Heidelberg, Member of the German Center for Lung Research (DZL)
| | - Diego Kauffmann-Guerrero
- Division of Respiratory Medicine and Thoracic Oncology, Department of Internal Medicine V University of Munich (LMU), Thoracic Oncology Centre Munich (TOM), Comprehensive Pneumology Center Munich (CPC-M), Member of the German Center for Lung Research (DZL), Munich, Bayern, Germany
| | - Jan Stratmann
- Department of Internal Medicine II, University Clinic of Frankfurt, Frankfurt, Germany
| | - Richard Riedel
- Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany
| | - Monica Schaefer
- HELIOS Klinikum Emil-von-Behring, Lungenklinik Heckeshorn, Berlin, Germany
| | - Jürgen Alt
- Department of Internal Medicine III (Hematology, Oncology, Pneumology), University Medical Center Mainz, Mainz, Germany
| | - Sylvia Gütz
- Department of Respiratory Medicine and Cardiology, Evangelisches Diakonissenkrankenhaus Leipzig, Leipzig, Germany
| | - Daniel C Christoph
- Department of Hematology and Oncology, Evang. Kliniken Essen-Mitte, Essen, Germany
| | | | - Martin Faehling
- Department of Cardiology, Angiology and Pneumonology, Klinikum Esslingen, Esslingen, Germany
| | | | - Klaus Fenchel
- Private Practice for Hematology and Oncology, Saalfeld, Germany
| | - Sebastian Haen
- Department of Hematology and Oncology, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
| | | | - Christian Schulz
- Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany
| | - Frank Griesinger
- Department Internal Medicine-Oncology, Pius Hospital, Oldenburg, Germany
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Rybarczyk-Kasiuchnicz A, Ramlau R, Stencel K. Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma. Int J Mol Sci 2021; 22:ijms22020593. [PMID: 33435596 PMCID: PMC7826874 DOI: 10.3390/ijms22020593] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 02/07/2023] Open
Abstract
Lung cancer is one of the most common malignant neoplasms. As a result of the disease's progression, patients may develop metastases to the central nervous system. The prognosis in this location is unfavorable; untreated metastatic lesions may lead to death within one to two months. Existing therapies-neurosurgery and radiation therapy-do not improve the prognosis for every patient. The discovery of Epidermal Growth Factor Receptor (EGFR)-activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPK, AKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, the cancer progresses. These activating gene mutations for the EGFR are present in 10-20% of lung adenocarcinomas. Approximately 3-7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway, stimulates the proliferation of tumor cells, and inhibits apoptosis. A new group of drugs-small-molecule tyrosine kinase inhibitors-has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irreversibly. Clinical trials with TKI in patients with non-small cell lung adenocarcinoma with central nervous system (CNS) metastases have shown prolonged, progression-free survival, a high percentage of objective responses, and improved quality of life. Resistance to treatment with this group of drugs emerging during TKI therapy is the basis for the detection of resistance mutations. The T790M mutation, present in exon 20 of the EGFR gene, is detected in patients treated with first- and second-generation TKI and is overcome by Osimertinib, a third-generation TKI. The I117N resistance mutation in patients with the ALK mutation treated with alectinib is overcome by ceritinib. In this way, sequential therapy ensures the continuity of treatment. In patients with CNS metastases, attempts are made to simultaneously administer radiation therapy and tyrosine kinase inhibitors. Patients with lung adenocarcinoma with CNS metastases, without activating EGFR mutation and without ALK rearrangement, benefit from immunotherapy. This therapeutic option blocks the PD-1 receptor on the surface of T or B lymphocytes or PD-L1 located on cancer cells with an applicable antibody. Based on clinical trials, pembrolizumab and all antibodies are included in the treatment of non-small cell lung carcinoma with CNS metastases.
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Prabhash K. Treatment of advanced nonsmall cell lung cancer: First line, maintenance and second line - Indian consensus statement update. South Asian J Cancer 2020; 8:1-17. [PMID: 30766843 PMCID: PMC6348782 DOI: 10.4103/sajc.sajc_227_18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
The management of advanced nonsmall cell lung cancer (NSCLC) patients is becoming increasingly complex with the identification of driver mutations/rearrangements and development/availability of appropriate targeted therapies. In 2017, an expert group of medical oncologists with expertise in treating lung cancer used data from published literature and experience to arrive at practical consensus recommendations on treatment of advanced NSCLC for use by the community oncologists. This was published subsequently in the Indian Journal of Cancer with a plan to be updated annually. The present document is an update to the 2017 document.
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Affiliation(s)
- Kumar Prabhash
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
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Nagano T, Tachihara M, Nishimura Y. Molecular Mechanisms and Targeted Therapies Including Immunotherapy for Non-Small Cell Lung Cancer. Curr Cancer Drug Targets 2020; 19:595-630. [PMID: 30526458 DOI: 10.2174/1568009619666181210114559] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/21/2018] [Accepted: 11/28/2018] [Indexed: 12/21/2022]
Abstract
Lung cancer is the leading cause of cancer death worldwide. Molecular targeted therapy has greatly advanced the field of treatment for non-small cell lung cancer (NSCLC), which accounts for the majority of lung cancers. Indeed, gefitinib, which was the first molecular targeted therapeutic agent, has actually doubled the survival time of NSCLC patients. Vigorous efforts of clinicians and researchers have revealed that lung cancer develops through the activating mutations of many driver genes including the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1), v-Raf murine sarcoma viral oncogene homolog B (BRAF), and rearranged during transfection (RET) genes. Although ALK, ROS1, and RET are rare genetic abnormalities, corresponding tyrosine kinase inhibitors (TKIs) can exert dramatic therapeutic effects. In addition to anticancer drugs targeting driver genes, bevacizumab specifically binds to human vascular endothelial growth factor (VEGF) and blocks the VEGF signaling pathway. The VEGF signal blockade suppresses angiogenesis in tumor tissues and inhibits tumor growth. In this review, we also explore immunotherapy, which is a promising new NSCLC treatment approach. In general, antitumor immune responses are suppressed in cancer patients, and cancer cells escape from the immune surveillance mechanism. Immune checkpoint inhibitors (ICIs) are antibodies that target the primary escape mechanisms, immune checkpoints. Patients who respond to ICIs are reported to experience longlasting therapeutic effects. A wide range of clinical approaches, including combination therapy involving chemotherapy or radiation plus adjuvant therapy, are being developed.
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Affiliation(s)
- Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Motoko Tachihara
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yoshihiro Nishimura
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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An International Real-World Analysis of the Efficacy and Safety of Lorlatinib Through Early or Expanded Access Programs in Patients With Tyrosine Kinase Inhibitor–Refractory ALK-Positive or ROS1-Positive NSCLC. J Thorac Oncol 2020; 15:1484-1496. [DOI: 10.1016/j.jtho.2020.04.019] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 04/18/2020] [Accepted: 04/20/2020] [Indexed: 11/19/2022]
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31
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De Giglio A, Lamberti G, Facchinetti F, Genova C, Andrini E, Dal Bello MG, Tiseo M, Metro G, Chiari R, Ricciuti B. Treatment Patterns and Clinical Outcomes Among Patients With ROS1-rearranged Non–small-cell Lung Cancer Progressing on Crizotinib. Clin Lung Cancer 2020; 21:e478-e487. [DOI: 10.1016/j.cllc.2020.03.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 03/23/2020] [Accepted: 03/26/2020] [Indexed: 10/24/2022]
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32
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Singh A, Chen H. Optimal Care for Patients with Anaplastic Lymphoma Kinase (ALK)-Positive Non-Small Cell Lung Cancer: A Review on the Role and Utility of ALK Inhibitors. Cancer Manag Res 2020; 12:6615-6628. [PMID: 32821158 PMCID: PMC7425086 DOI: 10.2147/cmar.s260274] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 07/09/2020] [Indexed: 12/17/2022] Open
Abstract
The treatment of advanced non–small-cell lung cancer (NSCLC) has undergone a paradigm shift in the last decade. Molecular characterization of the disease has led to the rapid development of personalized medicine and swift delivery of targeted therapies to patients. The discovery of the anaplastic lymphoma kinase (ALK) gene in patients with NSCLC has resulted in rapid bench–bedside transition of several active drugs, with several others currently in clinical trials. After the first-generation ALK inhibitor crizotinib, next-generation ALK inhibitors have entered clinical applications for ALK-rearranged NSCLC. Ceritinib, alectinib, and brigatinib have all received approval for ALK-positive patients who have failed prior crizotinib, as well as first-line therapy in treatment-naïve patients based on favorable efficacy. Most recently, lorlatinib, a potent, newer-generation ALK inhibitor, has been approved as second- or third-line treatment. These advances have led to better patient outcomes, but concurrently have led to several crucial unanswered questions about optimal care for ALK-positive NSCLC patients. The ultimate acquisition of resistance to ALK-inhibitor therapy poses a challenge to ongoing research efforts, in addition to the routine management of these patients in the clinic. This review provides a summary of the clinical development of crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib and highlights current management paradigms, current and evolving clinical information, emerging clinical decision-making and sequencing of therapy in advanced, metastatic, or recurrent ALK-positive NSCLC.
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Affiliation(s)
- Abhay Singh
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Hongbin Chen
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
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Chu P, Antoniou M, Bhutani MK, Aziez A, Daigl M. Matching-adjusted indirect comparison: entrectinib versus crizotinib in ROS1 fusion-positive non-small cell lung cancer. J Comp Eff Res 2020; 9:861-876. [PMID: 32648475 DOI: 10.2217/cer-2020-0063] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Aim: To perform indirect treatment comparisons of entrectinib versus alternative ROS1 fusion-positive non-small cell lung cancer treatments. Methods: Relevant studies with crizotinib and chemotherapy as comparators of interest identified by systematic literature review were selected for matching-adjusted indirect comparison by feasibility assessment. Matching was based on known prognostic/predictive factors and scenario analyses were used for unreported confounders in comparator trials. Results: Entrectinib yielded significantly better responses versus crizotinib in all scenarios (odds ratio [OR]: 2.43-2.74). Overall survival (hazard ratio: 0.47-0.61) and adverse event-related discontinuation (OR: 0.79-0.90) favored entrectinib. Progression-free survival was similar across treatments, except in one scenario. Conclusion: These results suggested improved outcomes with entrectinib versus crizotinib/chemotherapy and may help to make better informed treatment decisions.
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Affiliation(s)
- Paula Chu
- Global Access, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
| | - Miranta Antoniou
- Global Access, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
| | - Mohit K Bhutani
- Health Economics & Outcomes Research and Real World Evidence, BresMed Ltd, Gurugram Haryana, 122018, India
| | - Amine Aziez
- Product Development Medical Affairs, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
| | - Monica Daigl
- Global Access, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
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34
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Metro G, Baglivo S, Moretti R, Bellezza G, Sidoni A, Roila F. Is There a Role for Multiple Lines of Anti-HER2 Therapies Administered Beyond Progression in HER2-Mutated Non-Small Cell Lung Cancer? A Case Report and Literature Review. Oncol Ther 2020; 8:341-350. [PMID: 32700047 PMCID: PMC7683654 DOI: 10.1007/s40487-020-00121-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Indexed: 12/17/2022] Open
Abstract
Oncogene-addicted non-small cell lung cancer (NSCLC) comprises a number of distinct disease subtypes, each of which is characterised by druggable genetic alterations. Among them, the receptor tyrosine kinase protein human epidermal receptor 2 (HER2) is occasionally found deregulated via gene mutation and/or amplification and/or protein overexpression. HER2 mutation, in particular, is a relatively rare condition which occurs in 1-4% of NSCLC patients, especially in those with adenocarcinoma histology and a never/light smoking history. However, the clinical relevance of a HER2 mutation in NSCLC relies on the fact that this genetic alteration has been associated with sensitivity to anti-HER2 therapies such as the monoclonal antibody trastuzumab or the pan-HER-tyrosine kinase inhibitor poziotinib. Here we describe the case of a NSCLC patient with an activating exon 20 G776VinsC mutation in the HER2 gene who responded well to multiple lines of trastuzumab-based therapies administered beyond progression and poziotinib given sequentially. In this specific case, the discovery of a druggable genetic alteration such as a mutation in the HER2 gene allowed for long-term control of the disease through the use of highly effective anti-HER2 therapies.
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Affiliation(s)
- Giulio Metro
- Medical Oncology, Santa Maria Della Misericordia Hospital, Azienda Ospedaliera Di Perugia, Perugia, Italy.
| | - Sara Baglivo
- Laboratory of Oncology, Medical Oncology, Santa Maria Della Misericordia Hospital, Azienda Ospedaliera Di Perugia, Perugia, Italy
| | - Riccardo Moretti
- Department of Radiology, Santa Maria Della Misericordia Hospital, Azienda Ospedaliera Di Perugia, Perugia, Italy
| | - Guido Bellezza
- Division of Pathology and Histology, Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
| | - Angelo Sidoni
- Division of Pathology and Histology, Department of Experimental Medicine, University of Perugia Medical School, Perugia, Italy
| | - Fausto Roila
- Medical Oncology, Santa Maria Della Misericordia Hospital, Azienda Ospedaliera Di Perugia, Perugia, Italy
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Breadner D, Blanchette P, Shanmuganathan S, Boldt RG, Raphael J. Efficacy and safety of ALK inhibitors in ALK-rearranged non-small cell lung cancer: A systematic review and meta-analysis. Lung Cancer 2020; 144:57-63. [PMID: 32371261 DOI: 10.1016/j.lungcan.2020.04.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 03/30/2020] [Accepted: 04/13/2020] [Indexed: 12/22/2022]
Abstract
OBJECTIVES No overall survival (OS) benefit has been reported from a mature randomized trial with the use of ALK inhibitors. We conducted a systematic review and meta-analysis to assess the efficacy of ALK inhibitors compared to chemotherapy (ALK vs. chemo) and 2nd generation ALK inhibitors compared to 1 st generation ALK inhibitors (ALK-2 G vs. ALK-1 G). METHODS The electronic databases Medline (PubMed), EMBASE, and the Cochrane Database of Systematic Reviews were searched for relevant randomized trials. Pooled hazard ratios (HR) for OS and progression free survival (PFS), and pooled risk ratios for objective response rates (ORR) and toxicity were meta-analyzed using the generic inverse variance and the Mantel-Haenszel methods. To account for between-studies heterogeneity, random-effect models were used. Subgroup analyses compared PFS by gender, smoking status, brain metastases, race and age. RESULTS Six trials were included in the analysis of ALK vs. chemo and four in the analysis of ALK-2 G vs. ALK-1 G. Treatment with ALK inhibitors improved OS compared to chemotherapy (HR: 0.84, 95 %CI 0.72-0.97) while a trend toward a better OS was seen with ALK-2 G vs. ALK-1 G (HR: 0.66, 95 %CI 0.43-1.02). PFS was improved with ALK vs. chemo and ALK-2 G vs. ALK-1 G (HR: 0.44, 95 %CI 0.35-0.54 and HR: 0.38, 95 %CI-0.29-0.51, respectively). ORR was improved with ALK vs. chemo and ALK-2 G vs. ALK-1 G. No difference in toxicity was observed. CONCLUSIONS This meta-analysis is the first, to our knowledge, to report an OS and PFS benefit with the use of ALK inhibitors compared to chemotherapy from randomized trial data. A trend toward a better OS was also seen with ALK-2 G vs. ALK-1 G and this is likely because of crossover effects and limited OS follow-up. Longer follow up and further research are warranted to directly compare ALK inhibitor sequences and to understand the outcomes of second generation ALK inhibitors as initial therapy.
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Affiliation(s)
- Daniel Breadner
- Department of Oncology, London Regional Cancer Program, Schulich School of Medicine and Dentistry, 800 Commissioners Road East, London, Ontario, N6A5W9, Canada.
| | - Phillip Blanchette
- Department of Oncology, London Regional Cancer Program, Schulich School of Medicine and Dentistry, 800 Commissioners Road East, London, Ontario, N6A5W9, Canada.
| | - Sumugan Shanmuganathan
- Department of Medicine, Schulich School of Medicine and Dentistry, E6-117 Victoria Hospital, London, Ontario, N6A5A5, Canada.
| | - Ronald Gabriel Boldt
- Department of Oncology, London Regional Cancer Program, Schulich School of Medicine and Dentistry, 800 Commissioners Road East, London, Ontario, N6A5W9, Canada.
| | - Jacques Raphael
- Department of Oncology, London Regional Cancer Program, Schulich School of Medicine and Dentistry, 800 Commissioners Road East, London, Ontario, N6A5W9, Canada.
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Xu H, Zhang Q, Liang L, Li J, Liu Z, Li W, Yang L, Yang G, Xu F, Ying J, Zhang S, Wang Y. Crizotinib vs platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer with different ROS1 fusion variants. Cancer Med 2020; 9:3328-3336. [PMID: 32168429 PMCID: PMC7221311 DOI: 10.1002/cam4.2984] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 02/21/2020] [Accepted: 02/27/2020] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND ROS1 gene fusion represents a specific subtype of non-small cell lung cancer (NSCLC). Crizotinib is recommended for ROS1-positive NSCLC due to its favorable outcome in published clinical trials. However, due to the low incidence of ROS1-positive NSCLC, there is limited information on real-world clinical outcomes in patients treated with either crizotinib or platinum-based doublet chemotherapy. METHODS Outcomes were recorded in 102 patients with stage Ⅲb or Ⅳ NSCLC who were treated at four Chinese hospitals between April, 2010 and June, 2019. RESULTS Of the 102 patients followed, 71.6% were females, 81.4% were non-smokers, and 98.0% had adenocarcinoma. First-line treatment with crizotinib achieved a significantly longer median progression-free survival (PFS) compared with platinum-based chemotherapy (14.9 months vs 8.5 months, respectively; P < .001). Next-generation sequencing (NGS) identified 61 patients who had ROS1 fusion variants, including CD74 (n = 33) and non-CD74 (n = 28) variants. In patients harboring CD74 fusion variants, the median PFS with first-line crizotinib treatment was significantly longer than in those harboring non-CD74 fusion variants (20.1 months vs 12.0 months, respectively; P = .046). However, in patients treated with platinum-based chemotherapy, there was no significant difference in PFS between the CD74 and non-CD74 variant groups (8.6 months vs 4.3 months, respectively; P = .115). Overall survival (OS) was not reached. CONCLUSIONS First-line therapy with crizotinib is more beneficial than platinum-based chemotherapy in patients with advanced NSCLC with different ROS1 fusion variants. Patients harboring CD74 fusion variants appear to respond better to crizotinib.
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Affiliation(s)
- Haiyan Xu
- Department of Comprehensive Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Quan Zhang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Li Liang
- Cancer Chemotherapy and Radiation Department, Peking University Third Hospital, Beijing, China
| | - Junling Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Zhefeng Liu
- Department of Medical Oncology, Chinese PLA General Hospital, Beijing, China
| | - Weihua Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Lu Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Guangjian Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Fei Xu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Jianming Ying
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Shucai Zhang
- Department of Medical Oncology, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
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Wang M, Wang G, Ma H, Shan B. Crizotinib Versus Chemotherapy on ALK-positive NSCLC: A Systematic Review of Efficacy and Safety. Curr Cancer Drug Targets 2020; 19:41-49. [PMID: 28669346 DOI: 10.2174/1568009617666170623115846] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 05/09/2017] [Accepted: 06/01/2017] [Indexed: 11/22/2022]
Abstract
INTRODUCTION Crizotinib was approved to treat anaplastic lymphoma kinase (ALK)- positive non-small cell lung cancer (NSCLC) by the Food and Drug Administration in 2011.We conducted a systematic review of clinical trials and retrospective studies to compare the efficacy and safety of crizotinib with chemotherapy. METHODS We searched electronic databases from inception to Dec. 2016. Clinical trials and retrospective studies regarding crizotinib and crizotinib versus chemotherapy in treatment of NSCLC were eligible. The primary outcomes were the objective response rate (ORR) and disease control rate (DCR). RESULTS Nine studies (five clinical trials and four retrospective studies) including 729 patients met the inclusion criteria. Crizotinib treatment revealed 1-year OS of 77.1% and PFS of 9.17 months. And crizotinib had a better performance than chemotherapy in ORR (OR: 4.97, 95%CI: 3.16 to 7.83, P<0.00001, I2=35%). DCR revealed superiority with crizotinib than chemotherapy (OR: 3.42, 95% CI: 2.33 to 5.01, P<0.00001, I2=0%). PR (partial response) were significant superior to that of chemotherapy through direct systematic review. No statistically significant difference in CR (complete response) was found between crizotinib-treated group and chemotherapy-treated group. Regarding SD (stable disease), chemotherapy-treated group had a better performance than crizotinib-treated group. Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, nausea, and hematologic toxicity. CONCLUSION This systematic review revealed improved objective response rate and increased disease control rate in crizotinib group comparing with chemotherapy group. Crizotinib treatment would be a favorable treatment option for patients with ALK-positive NSCLC. ALK inhibitors may have future potential applications in other cancers driven by ALK or c-MET gene mutations.
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Affiliation(s)
- Mingxia Wang
- Hebei Medical University Affiliated Fourth Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China
| | - Guanqi Wang
- Hebei Medical University Affiliated Fourth Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China
| | - Haiyan Ma
- Hebei Medical University Affiliated Fourth Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China
| | - Baoen Shan
- Hebei Medical University Affiliated Fourth Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, 050011, China
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Liu C, Yu H, Chang J, Chen H, Li Y, Zhao W, Zhao K, Zhu Z, Sun S, Fan M, Wang J. Crizotinib in Chinese Patients with ROS1-Rearranged Advanced Non‒Small-Cell Lung Cancer in Routine Clinical Practice. Target Oncol 2020; 14:315-323. [PMID: 30976989 PMCID: PMC6602983 DOI: 10.1007/s11523-019-00636-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background Approximately 1–2% of patients with non‒small-cell lung cancer (NSCLC) harbor ROS1 rearrangements. Crizotinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets anaplastic lymphoma kinase (ALK), MET, and ROS1, has shown marked antitumor activity in patients with ROS1-positive advanced NSCLC. Objective Our objective was to analyze the efficacy and safety of crizotinib treatment in Chinese patients with advanced NSCLC with ROS1 rearrangement in real-world clinical practice. Methods We included 35 patients with ROS1-positive NSCLC in this retrospective analysis. All received crizotinib 250 mg twice daily between March 2016 and April 2018 at the Fudan University Shanghai Cancer Center. All had histologically or cytologically confirmed locally advanced or metastatic NSCLC with ROS1 rearrangements, which were identified by fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, or next-generation sequencing. The main outcome measures were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse events. Results The median age of the patients was 51.0 years; 23 (65.7%) were female and 28 (80.0%) were never smokers. All were diagnosed as having adenocarcinoma; eight patients (22.9%) had brain metastases at baseline. The ORR and DCR were 71.4% and 94.3%, respectively. The estimated median PFS was 11.0 months (95% confidence interval [CI] 7.8–14.2). The estimated median OS was 41.0 months (95% CI 22.5–59.5). Elevated transaminases (54.3%), vision disorder (25.7%), elevated blood creatinine (22.9%), diarrhea (20.0%), and vomiting (20.0%) were the most commonly reported adverse effects. Conclusion Crizotinib was effective and well tolerated in Chinese patients with ROS1-positive advanced NSCLC in real-world clinical practice. The progression sites and patterns, as well as treatments after first disease progression on crizotinib were diverse. Crizotinib beyond progressive disease and local therapy after failure of crizotinib treatment were feasible and effective in clinical practice.
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Affiliation(s)
- Chang Liu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China
| | - Hui Yu
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China
| | - Jianhua Chang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China
| | - Haiquan Chen
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China.,Department of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, China
| | - Yuan Li
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China.,Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Weixin Zhao
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China.,Department of Radiotherapy, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Kuaile Zhao
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China.,Department of Radiotherapy, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Zhengfei Zhu
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China.,Department of Radiotherapy, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Si Sun
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China
| | - Min Fan
- Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China.,Department of Radiotherapy, Fudan University Shanghai Cancer Center, Shanghai, 200032, China
| | - Jialei Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. .,Department of Oncology, Shanghai Medical College, Fudan University, No. 270 Dong-An Road, Shanghai, 200032, China.
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Passiglia F, Pilotto S, Facchinetti F, Bertolaccini L, Del Re M, Ferrara R, Franchina T, Malapelle U, Menis J, Passaro A, Ramella S, Rossi G, Trisolini R, Novello S. Treatment of advanced non-small-cell lung cancer: The 2019 AIOM (Italian Association of Medical Oncology) clinical practice guidelines. Crit Rev Oncol Hematol 2020; 146:102858. [PMID: 31918343 DOI: 10.1016/j.critrevonc.2019.102858] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 12/03/2019] [Indexed: 01/10/2023] Open
Abstract
The Italian Association of Medical Oncology (AIOM) has developed clinical practice guidelines for the treatment of patients with advanced non-small cell lung cancer (NSCLC). In the current paper a panel of AIOM experts in the field of thoracic malignancies discussed the available scientific evidences, with the final aim of providing a summary of clinical recommendations, which may guide physicians in their current practice.
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Affiliation(s)
- F Passiglia
- Department of Oncology, University of Turin, San Luigi Hospital, Orbassano (TO), Italy
| | - S Pilotto
- U.O.C. Oncology, University of Verona, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - F Facchinetti
- INSERM U981, Gustave Roussy Cancer Campus, Université Paris Saclay, Villejuif, France
| | - L Bertolaccini
- Division of Thoracic Surgery, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - M Del Re
- Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Italy
| | - R Ferrara
- Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - T Franchina
- Department of Human Pathology "G. Barresi", University of Messina, Italy
| | - U Malapelle
- Department of Public Health, University of Naples "Federico II", Naples, Italy
| | - J Menis
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Medical Oncology Department, Istituto Oncologico Veneto IRCCS, Padova, Italy
| | - A Passaro
- Division of Thoracic Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - S Ramella
- Radiotherapy Unit, Campus Bio-Medico University, Rome, Italy
| | - G Rossi
- Pathologic Anatomy, Azienda USL della Romagna, S. Maria delle Croci Hospital of Ravenna and Degli Infermi Hospital of Rimini, Italy
| | - R Trisolini
- Interventional Pulmonology Unit, Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - S Novello
- Department of Oncology, University of Turin, San Luigi Hospital, Orbassano (TO), Italy.
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40
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Huang M, Tian Y, He M, Liu J, Ren L, Gong Y, Peng F, Wang Y, Ding Z, Wang J, Zhu J, Xu Y, Liu Y, Li L, Lu Y. Crizotinib versus chemotherapy: a real-world cost-effectiveness study in China. J Comp Eff Res 2020; 9:93-102. [PMID: 31958984 DOI: 10.2217/cer-2019-0075] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Aim: To assess the cost-effectiveness of crizotinib verses platinum-based doublet chemotherapy as the first-line treatment for anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) in the real-world setting. Methods: Data from 163 advanced ALK positive NSCLC patients were collected from West China Hospital, Sichuan University (Chengdu, China). They were categorized into two groups as treated with crizotinib (n = 83) or chemotherapy (n = 80) as a first-line therapy. The progression-free survival (PFS) as the primary clinical outcome, and the direct medical costs were collected from hospital information systems. Incremental cost-effectiveness ratio (ICER) was calculated with costs, quality-adjusted life-years, as well as the costs discounted at 3% annually. Additionally, two different kinds of medical insurance (MI) for pharma-economic assessment were considered. Results: Crizotinib improved PFS versus chemotherapy in ALK positive patients (median PFS 19.67 m vs 5.47 m; p < 0.001). Moreover, crizotinib obtained an ICER of US$36,285.39 before the end of 2016, when crizotinib, pemetrexed and anti-angiogenesis drugs were not MI covered. This is more than the willingness to pay threshold (three-times of gross domestic product per capita in mainland China or Sichuan Province). However, ICER was US$7321.16, which is less than willingness to pay, when crizotinib and all chemotherapy drugs were covered by MI from the end of 2016. Sensitivity analysis demonstrated a 99.7% probability for crizotinib to be more cost-effective than chemotherapy, when crizotinib and all anticancer drugs were MI covered. One-way sensitivity analysis for the reimbursement ratio of crizotinib indicated that cost-effective tendency for crizotinib increased as reimbursement ratio increased. Conclusion: Crizotinib could be an effective, and cost-effective first-line treatment for ALK positive advanced NSCLC with the MI coverage currently available in Chengdu, Sichuan Province, China.
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Affiliation(s)
- Meijuan Huang
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yuke Tian
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingmin He
- Fengling Clinic, Wuhou, Chengdu 610041, China
| | - Juan Liu
- Fengling Clinic, Wuhou, Chengdu 610041, China
| | - Li Ren
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Youling Gong
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Feng Peng
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongsheng Wang
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhenyu Ding
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jin Wang
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jiang Zhu
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yong Xu
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yongmei Liu
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lanting Li
- Shanghai Palan DataRx Co. Ltd, Shanghai 200051, China
| | - You Lu
- Department of Thoracic Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China
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Abstract
Thoracic tumors are a leading cause of cancer-related morbidity and mortality. In recent years, developments in oncologic treatments for these tumors have ushered in an era of targeted therapy, and, in many cases, these novel treatments have replaced conventional strategies to become standard therapeutic options, particularly in those with lung cancer. Targeted medical therapies for lung cancer now include angiogenesis inhibitors, tyrosine kinase inhibitors, and immunotherapeutic agents. Several novel ablative therapies have also gained widespread acceptance as alternatives to conventional surgical options in appropriately selected patients. Tumors treated with targeted medical therapies can respond to treatment differently when compared with conventional therapies. For example, pseudoprogression is a well-described phenomenon in patients receiving checkpoint inhibitor immunotherapy in which an initial increase in tumor burden is followed by a decrease in tumor burden and sometimes partial or complete response, while the frequent cavitating responses seen when antiangiogenic agents are used can be difficult to quantify using existing response assessment criteria. In some cases, novel response assessment criteria are needed to adequately capture response. In addition, numerous treatment-related side effects have been described, which are important to recognize, both to ensure appropriate treatment and to avoid misclassification as worsening tumor. Imaging plays a vital role in the assessment of patients receiving targeted medical therapy, and it is essential that thoracic radiologists are familiar with the rationale underpinning these treatments and the expected posttherapy findings.
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Novello S, Mazières J, Oh IJ, de Castro J, Migliorino MR, Helland Å, Dziadziuszko R, Griesinger F, Kotb A, Zeaiter A, Cardona A, Balas B, Johannsdottir HK, Das-Gupta A, Wolf J. Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Ann Oncol 2019; 29:1409-1416. [PMID: 29668860 PMCID: PMC6005013 DOI: 10.1093/annonc/mdy121] [Citation(s) in RCA: 234] [Impact Index Per Article: 39.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Background This is the first trial to directly compare efficacy and safety of alectinib versus standard chemotherapy in advanced/metastatic anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC) patients who have progressed on, or were intolerant to, crizotinib. Patients and methods ALUR (MO29750; NCT02604342) was a randomized, multicenter, open-label, phase III trial of alectinib versus chemotherapy in advanced/metastatic ALK-positive NSCLC patients previously treated with platinum-based doublet chemotherapy and crizotinib. Patients were randomized 2 : 1 to receive alectinib 600 mg twice daily or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, both every 3 weeks) until disease progression, death, or withdrawal. Primary end point was investigator-assessed progression-free survival (PFS). Results Altogether, 107 patients were randomized (alectinib, n = 72; chemotherapy, n = 35) in 13 countries across Europe and Asia. Median investigator-assessed PFS was 9.6 months [95% confidence interval (CI): 6.9–12.2] with alectinib and 1.4 months (95% CI: 1.3–1.6) with chemotherapy [hazard ratio (HR) 0.15 (95% CI: 0.08–0.29); P < 0.001]. Independent Review Committee-assessed PFS was also significantly longer with alectinib [HR 0.32 (95% CI: 0.17–0.59); median PFS was 7.1 months (95% CI: 6.3–10.8) with alectinib and 1.6 months (95% CI: 1.3–4.1) with chemotherapy]. In patients with measurable baseline central nervous system (CNS) disease (alectinib, n = 24; chemotherapy, n = 16), CNS objective response rate was significantly higher with alectinib (54.2%) versus chemotherapy (0%; P < 0.001). Grade ≥3 adverse events were more common with chemotherapy (41.2%) than alectinib (27.1%). Incidence of AEs leading to study-drug discontinuation was lower with alectinib (5.7%) than chemotherapy (8.8%), despite alectinib treatment duration being longer (20.1 weeks versus 6.0 weeks). Conclusion Alectinib significantly improved systemic and CNS efficacy versus chemotherapy for crizotinib-pretreated ALK-positive NSCLC patients, with a favorable safety profile. Trial registration ClinicalTrials.gov NCT02604342; Roche study MO29750
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Affiliation(s)
- S Novello
- Department of Oncology, University of Turin, Turin, Italy
| | - J Mazières
- Department of Pneumology, Toulouse University Hospital, Paul Sabatier University, Toulouse, France
| | - I-J Oh
- Department of Internal Medicine, Chonnam National University Hwasun Hospital, Hwasun-gun Jeollanam-do, Republic of Korea
| | - J de Castro
- Department of Translational Oncology, La Paz University Hospital, Madrid, Spain
| | - M R Migliorino
- Azienda Ospedaliera San Camillo Forlanini Hospital, Rome, Italy
| | - Å Helland
- Department of Cancer Genetics and Department of Oncology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
| | - R Dziadziuszko
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland
| | - F Griesinger
- Department of Hematology and Oncology, Pius Hospital, Medical Campus University of Oldenburg, Oldenburg, Germany
| | - A Kotb
- F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - A Zeaiter
- F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - A Cardona
- F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - B Balas
- F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | | | - A Das-Gupta
- F. Hoffmann-La Roche Ltd., Basel, Switzerland
| | - J Wolf
- Department I of Internal Medicine, Center for Integrated Oncology, University Hospital Cologne, Cologne, Germany.
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Tiotiu A, Billon Y, Vaillant P, Menard O, Hofman P, Mascaux C. [Therapeutic strategies in advanced ALK positive non-small cell lung cancer]. Rev Mal Respir 2019; 36:1107-1116. [PMID: 31727555 DOI: 10.1016/j.rmr.2019.02.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 02/19/2019] [Indexed: 11/30/2022]
Abstract
Anaplastic lymphoma kinase (ALK) rearrangement is a therapeutically targetable oncogenic driver found in 5% of patients with non-small-cell lung cancer (NSCLC). The objective of this paper is to synthesise current knowledge on ALK rearrangement and its impact on the management of advanced NSCLC. Several inhibitors of the tyrosine kinase of ALK (crizotinib, ceritinib, alectinib) have been approved as first line therapies in patients with advanced ALK positive NSCLC, which are associated with a better median progression-free survival than conventional chemotherapy. Unfortunately, the emergence of drug resistance leads to tumor progression. In patients with oligoprogressive disease if local ablative therapy can be effected, continuing with the same ALK tyrosine kinase inhibitor is one option. In patients with progression, clinicians may consider switching to another therapy. Rebiopsy of the tumor or liquid biopsy could be attempted to identify the mechanisms of resistance and to customize ALK-target therapy. The emergence of crizotinib drug resistance has prompted the development of next generation drugs including ceritinb, alectinib, brigatinib and lorlatinib. The ability to quickly develop targeted therapies against specific oncogenic drivers will require close co-operation between pathologists, pulmonologists and oncologists in the future to keep pace with drug discoveries and to define optimal therapeutic strategies.
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Affiliation(s)
- A Tiotiu
- Département de pneumologie, CHRU Nancy site Brabois, bâtiment de spécialités médicales, 9, rue du Morvan, 54511 Vandœuvre-lès-Nancy, France.
| | - Y Billon
- Département de pneumologie, CHRU Nancy site Brabois, bâtiment de spécialités médicales, 9, rue du Morvan, 54511 Vandœuvre-lès-Nancy, France
| | - P Vaillant
- Département de pneumologie, CHRU Nancy site Brabois, bâtiment de spécialités médicales, 9, rue du Morvan, 54511 Vandœuvre-lès-Nancy, France
| | - O Menard
- Département de pneumologie, CHRU Nancy site Brabois, bâtiment de spécialités médicales, 9, rue du Morvan, 54511 Vandœuvre-lès-Nancy, France
| | - P Hofman
- Laboratoire de pathologie clinique et expérimentale, CHU de Nice, 06000 Nice, France; Centre IRCAN, Inserm U1081 et CNRS/UMR 7284, Centre de lutte contre le cancer Antoine-Lacassagne, 06000 Nice, France; Université Côte d'Azur, 06000 Nice, France
| | - C Mascaux
- Département d'oncologie multidisciplinaire et Innovations thérapeutiques, Assistance Publique-Hôpitaux de Marseille, 13354 Marseille, France; Aix Marseille université, CNRS, Inserm, CRCM, 13354 Marseille, France
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Delmonte A, Burgio MA, Verlicchi A, Bronte G, Cravero P, Ulivi P, Martinelli G, Crinò L. New generation anaplastic lymphoma kinase inhibitors. Transl Lung Cancer Res 2019; 8:S280-S289. [PMID: 31857951 PMCID: PMC6894988 DOI: 10.21037/tlcr.2019.09.14] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 09/18/2019] [Indexed: 11/06/2022]
Abstract
Anaplastic lymphoma kinase (ALK) gene translocations are pro-tumoral driver alterations that encompass 3-7% of non-squamous non-small cell lung cancer (NSCLC) with specific, clinic and histologic features. The therapeutic strategy depends on anti-ALK tyrosine kinase inhibitors (TKIs) of which crizotinib was the first approved for clinical use. Despite its use improved significantly progression-free survival, overall response rate and duration of response of this illness, after a median period of 10.9 months all patients progress due to the development of acquired resistance mutations in the ALK tyrosine kinase domain in approximately one third of patients. Moreover, 60-90% of patients treated with crizotinib has a progression in the central nervous system (CNS) in absence of extracranial worsening of the disease. This is primarily attributed to poor CNS penetration by crizotinib as many pre-clinical and clinical models suggest. For instance, in order to overtake acquired resistance to crizotinib, prolong the control of the disease and manage CNS localizations, several II and III generation TKIs have been developed. Some of them were approved after the failure of crizotinib (ceritinib, alectinib, brigatinib and lorlatinib) and in first line setting (ceritinib, alectinib and brigatinib) while others are still under evaluation for TKI-naive patients such as lorlatinib, ensartinib and entrectinib. In this review we will discuss the most recent results of new TKIs in order to describe a fast growing therapeutic landscape in this setting.
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Affiliation(s)
- Angelo Delmonte
- Thoracic Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Marco Angelo Burgio
- Thoracic Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Alberto Verlicchi
- Thoracic Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Giuseppe Bronte
- Thoracic Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Paola Cravero
- Thoracic Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Paola Ulivi
- Thoracic Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Giovanni Martinelli
- Thoracic Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
| | - Lucio Crinò
- Thoracic Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy
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Zhao Y, Zhang B, Wang S, Qiao R, Xu J, Zhang L, Zhang Y, Han B. Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer During Crizotinib Treatment. Clin Lung Cancer 2019; 20:e631-e637. [DOI: 10.1016/j.cllc.2019.06.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/16/2019] [Accepted: 06/07/2019] [Indexed: 10/26/2022]
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Iwama E, Goto Y, Murakami H, Tsumura S, Sakashita H, Mori Y, Nakagaki N, Fujita Y, Seike M, Bessho A, Ono M, Nishitsuji M, Akamatsu H, Morinaga R, Akagi T, Shimose T, Tokunaga S, Yamamoto N, Nakanishi Y, Sugio K, Okamoto I. Survival Analysis for Patients with ALK Rearrangement-Positive Non-Small Cell Lung Cancer and a Poor Performance Status Treated with Alectinib: Updated Results of Lung Oncology Group in Kyushu 1401. Oncologist 2019; 25:306-e618. [PMID: 32297438 DOI: 10.1634/theoncologist.2019-0728] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 09/15/2019] [Indexed: 11/17/2022] Open
Abstract
LESSONS LEARNED Alectinib confers a pronounced survival benefit in patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status. Survival benefit of alectinib for patients with a poor performance status was consistent regardless of the presence of central nervous system metastases. BACKGROUND We previously reported a marked objective response rate (ORR) and safety for alectinib treatment in patients with ALK rearrangement-positive non-small cell lung cancer (NSCLC) and a poor performance status (PS) in the Lung Oncology Group in Kyushu (LOGiK) 1401 study. It remained unclear, however, whether alectinib might also confer a long-term survival benefit in such patients. METHODS Eighteen patients with ALK rearrangement-positive advanced NSCLC and a PS of 2, 3, or 4 (n = 12, 5, and 1, respectively) were enrolled in LOGiK1401 between September 2014 and December 2015 and received alectinib. We have now updated the survival data for the study. RESULTS The median follow-up time for all patients was 27.3 months. The median progression-free survival (PFS) was 16.2 months (95% confidence interval [CI], 7.1-30.8 months), and the median survival time (MST) and the 3-year overall survival rate were 30.3 months (95% CI, 11.5 months to not reached) and 43.8% (95% CI, 20.8-64.7%), respectively. This survival benefit was similarly manifest in patients with a PS of 2 (MST, 20.5 months) and those with a PS of ≥3 (MST, not reached). PFS did not differ between patients with or without central nervous system (CNS) metastases at baseline (median of 17.5 and 16.2 months, respectively, p = .886). CONCLUSION Alectinib showed a pronounced survival benefit for patients with ALK rearrangement-positive NSCLC and a poor PS regardless of the presence of CNS metastases, a patient population for which chemotherapy is not indicated.
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Affiliation(s)
- Eiji Iwama
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasushi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Haruyasu Murakami
- Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Shinsuke Tsumura
- Department of Respiratory Medicine, Kumamoto Regional Medical Center, Kumamoto, Japan
| | - Hiroyuki Sakashita
- Department of Clinical Oncology, Tokyo Medical and Dental University, Tokyo, Japan
- Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yoshiaki Mori
- Department of Respiratory Medicine, Iwate Prefectural Central Hospital, Morioka, Japan
| | - Noriaki Nakagaki
- Department of Respiratory Medicine, Steel Memorial Yawata Hospital, Kita-Kyushu, Japan
| | - Yuka Fujita
- Department of Respiratory Medicine, National Hospital Organization Asahikawa Medical Center, Asahikawa, Japan
| | - Masahiro Seike
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
| | - Akihiro Bessho
- Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan
| | - Manabu Ono
- Department of Respiratory Medicine, Kesen-numa City Hospital, Kesen-numa, Japan
| | - Masaru Nishitsuji
- Division of Respiratory Medicine, Ishikawa Prefectural Central Hospital, Kanazawa, Japan
| | - Hiroaki Akamatsu
- Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Ryotaro Morinaga
- Department of Thoracic Medical Oncology, Oita Prefectural Hospital, Oita, Japan
| | - Takanori Akagi
- Department of Respiratory Medicine, Fukuoka University Chikushi Hospital, Chikushino, Japan
| | | | - Shoji Tokunaga
- Medical Information Center, Kyushu University Hospital, Fukuoka, Japan
| | - Nobuyuki Yamamoto
- Third Department of Internal Medicine, Wakayama Medical University, Wakayama, Japan
| | - Yoichi Nakanishi
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenji Sugio
- Department of Thoracic and Breast Surgery, Oita University, Oita, Japan
| | - Isamu Okamoto
- Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Couñago F, Luna J, Guerrero LL, Vaquero B, Guillén-Sacoto MC, González-Merino T, Taboada B, Díaz V, Rubio-Viqueira B, Díaz-Gavela AA, Marcos FJ, del Cerro E. Management of oligometastatic non-small cell lung cancer patients: Current controversies and future directions. World J Clin Oncol 2019; 10:318-339. [PMID: 31799148 PMCID: PMC6885452 DOI: 10.5306/wjco.v10.i10.318] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 08/30/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
Oligometastatic non-small cell lung cancer (NSCLC) describes an intermediate stage of NSCLC between localized and widely-disseminated disease. This stage of NSCLC is characterized by a limited number of metastases and a more indolent tumor biology. Currently, the management of oligometastatic NSCLC involves radical treatment (radiotherapy or surgery) that targets the metastatic lesions and the primary tumor to achieve disease control. This approach offers the potential to achieve prolonged survival in patients who, in the past, would have only received palliative measures. The optimal therapeutic strategies for the different scenarios of oligometastatic disease (intracranial vs extracranial disease, synchronous vs metachronous) remain undefined. Given the lack of head-to-head studies comparing radiotherapy to surgery in these patients, the decision to apply surgery or radiotherapy (with or without systemic treatment) must be based on prognostic factors that allow us to classify patients. This classification will allow us to select the most appropriate therapeutic strategy on an individualized basis. In the future, the molecular or microRNA profiles will likely improve the treatment selection process. The objective of the present article is to review the most relevant scientific evidence on the management of patients with oligometastatic NSCLC, focusing on the role of radiotherapy and surgery. We also discuss areas of controversy and future directions.
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Affiliation(s)
- Felipe Couñago
- Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Pozuelo de Alarcón, Madrid 28223, Spain
- Department of Radiation Oncology, Hospital La Luz, Madrid 28003, Spain
- Clinical Department, Faculty of Biomedicine, Universidad Europea, Madrid 28223, Spain
| | - Javier Luna
- Department of Radiation Oncology, Hospital Fundación Jiménez Díaz, Madrid 28040, Spain
| | | | - Blanca Vaquero
- Department of Radiation Oncology, Hospital La Luz, Madrid 28003, Spain
| | | | | | - Begoña Taboada
- Department of Radiation Oncology, Complexo Hospitalario Universitario Santiago de Compostela, Santiago de Compostela 15706, Spain
| | - Verónica Díaz
- Department of Radiation Oncology, Hospital Universitario Puerta del Mar, Cádiz 11009, Spain
| | - Belén Rubio-Viqueira
- Department of Medical Oncology, Hospital Universitario Quirónsalud Madrid, Pozuelo de Alarcón, Madrid 28223, Spain
| | - Ana Aurora Díaz-Gavela
- Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Pozuelo de Alarcón, Madrid 28223, Spain
- Department of Radiation Oncology, Hospital La Luz, Madrid 28003, Spain
- Clinical Department, Faculty of Biomedicine, Universidad Europea, Madrid 28223, Spain
| | - Francisco José Marcos
- Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Pozuelo de Alarcón, Madrid 28223, Spain
- Department of Radiation Oncology, Hospital La Luz, Madrid 28003, Spain
- Clinical Department, Faculty of Biomedicine, Universidad Europea, Madrid 28223, Spain
| | - Elia del Cerro
- Department of Radiation Oncology, Hospital Universitario Quirónsalud Madrid, Pozuelo de Alarcón, Madrid 28223, Spain
- Department of Radiation Oncology, Hospital La Luz, Madrid 28003, Spain
- Clinical Department, Faculty of Biomedicine, Universidad Europea, Madrid 28223, Spain
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Wang W, Sun X, Hui Z. Treatment Optimization for Brain Metastasis from Anaplastic Lymphoma Kinase Rearrangement Non-Small-Cell Lung Cancer. Oncol Res Treat 2019; 42:599-606. [PMID: 31527380 DOI: 10.1159/000502755] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Accepted: 08/14/2019] [Indexed: 01/30/2023]
Abstract
BACKGROUND Brain metastasis is common in non-small-cell lung cancer (NSCLC) with driver gene mutations. Anaplastic lymphoma kinase (ALK) gene rearrangement is one of the common driver mutations in NSCLC. Tyrosine kinase inhibitor (TKI) has been the research hotspot at present. However, there are relatively few studies specified on the treatment of brain metastasis from ALK gene rearrangement NSCLC. The prognosis of these patients, the role of ALK-TKI, and the proper combination model of ALK-TKI with radiotherapy are worth further exploring. This review focuses on new data on the prognosis of ALK-TKI and the proper combination model of ALK-TKI with radiotherapy. SUMMARY According to some retrospective trials, for ALKi-naïve ALK rearrangement NSCLC patients with brain metastasis, crizotinib together with radiotherapy seem to improve intracranial control rate, progression-free survival, and very likely improve overall survival; next-generation ALK-TKIs are now replacing crizotinib as first-line treatment. For patients with central nervous system progression during crizotinib application, combining radiotherapy could improve the local control rate while continuing crizotinib to control systemic disease. Second-/third-generation ALK inhibitors had higher intracranial ORR and DCR even after crizotinib-refractory situations, and they alone had a strong efficacy against intracranial tumors, in which situation radiotherapy might be omitted. Stereotactic radiosurgery (SRS) and whole-brain radiotherapy (WBRT) were both local treatment options for brain metastasis, and the preferred choice was hard to make. ALK resistance is complicated with a wide range of molecular changes, and future studies are needed to solve these problems. Anyway, further and larger prospective studied are worth exploring to offer a confirmed preferred choice of drugs and radiation. Key Messages: Next-generation ALK-TKIs are now replacing crizotinib as first-line treatment in ALKi-naïve ALK rearrangement NSCLC patients with brain metastasis, and they alone might have a strong efficacy against intracranial tumors in crizotinib-refractory situations in which occasion radiotherapy might be omitted. SRS and WBRT are both local treatment options for brain metastasis.
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Affiliation(s)
- Wenhui Wang
- Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academic of Medical Science and Peking Union Medical College, Beijing, China
| | - Xin Sun
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academic of Medical Science and Peking Union Medical College, Beijing, China
| | - Zhouguang Hui
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academic of Medical Science and Peking Union Medical College, Beijing, China, .,Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academic of Medical Science and Peking Union Medical College, Beijing, China,
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Ock CY, Yoo SH, Keam B, Kim M, Kim TM, Jeon YK, Kim DW, Chung DH, Heo DS. Clinical factors affecting progression-free survival with crizotinib in ALK-positive non-small cell lung cancer. Korean J Intern Med 2019; 34:1116-1124. [PMID: 29950554 PMCID: PMC6718771 DOI: 10.3904/kjim.2018.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Accepted: 03/27/2018] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND/AIMS Although crizotinib is standard chemotherapy for advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), clinical factors affecting progression-free survival (PFS) have not been reported. The purpose of this study was to identify clinical factors affecting PFS of crizotinib and develop a prognostic model for advanced ALK-positive NSCLC. METHODS Clinicopathologic features of patients enrolled in PROFILE 1001, 1005, 1007, and 1014 (training cohort) were reviewed. We conducted multivariate Cox analysis for PFS and overall survival (OS) in the training cohort (n = 159) and generated a proportional hazards model based on significant clinicopathologic factors, and then validated the model in an independent validation cohort (n = 40). RESULTS In the training cohort, the objective response rate was 81.5%. Median PFS and OS from the start of crizotinib were 12.4 and 31.3 months, respectively. Multivariate Cox analysis showed poor performance status, number of metastatic organs (≥ 3), and no response to crizotinib independently associated shorter PFS. Based on a score derived from these three factors, median PFS and OS of patients with one or two factors were significantly shorter compared to those without these factors (median PFS, 22.4 months vs. 10.5 months vs. 6.5 months; median OS, not reached vs. 29.1 months vs. 11.8 months, respectively; p < 0.001 for each group). This model also had validated in an independent validation cohort. CONCLUSION Performance status, number of metastatic organs, and response to crizotinib affected PFS of crizotinib in ALK-positive NSCLC. Based on these factors, we developed a simple and useful prediction model for PFS.
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Affiliation(s)
- Chan-Young Ock
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Shin-Hye Yoo
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Bhumsuk Keam
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
- Correspondence to Bhumsuk Keam, M.D. Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: +82-2-2072-7215 Fax: +82-2-2072-7379 E-mail:
| | - Miso Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Tae Min Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yoon Kyung Jeon
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Dong-Wan Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Doo Hyun Chung
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Dae Seog Heo
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Del Valle MFF, Chang AYC. Real world experience on treatment, outcome and toxicity of crizotinib in patients with anaplastic lymphoma kinase positive advanced non-small cell lung cancer. J Thorac Dis 2019; 11:3864-3873. [PMID: 31656659 DOI: 10.21037/jtd.2019.09.15] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Background Crizotinib has been the standard treatment for patients with anaplastic lymphoma kinase (ALK)-rearranged advanced non-small cell lung cancer (NSCLC). It demonstrated superior progression-free survival (PFS) and higher objective response rates (ORRs) vs. chemotherapy in previously treated and untreated patients with ALK-positive advanced NSCLC. This retrospective analysis reports real-world experience in treatment outcome and toxicity of crizotinib in this group of patients, with a focus on the cardiac toxicity and its management. Methods Twenty-two patients diagnosed with ALK-positive NSCLC, either by immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH), treated at Johns Hopkins Singapore International Medical Centre (JHSIMC) and Tan Tock Seng Hospital (TTSH) in Singapore, were identified and followed for a median of 18 months. Data were collected and analyzed for baseline demographics, PFS, ORR, duration of response, toxicity and overall survival (OS). Results Clinical profile of patients included in the study was similar with clinical trials on crizotinib. Most patients were young of mean age 42, non-smokers and with good performance status. Fifty-nine percent had prior chemotherapy. Fifty percent of patients had brain metastases (BM), either de novo or on progression. ORR of crizotinib was 64% with median total duration of treatment of 8.5 months (range, 2-73+ months). Median PFS for patients treated with first-line crizotinib was 15 months. Most patients with BM had brain radiation. Median time for intracranial progression from the start of crizotinib was 11 months. Those with stable or responding extracranial disease continued crizotinib after radiotherapy to the brain. Median duration of response in this group of patients was 14 months (range, 2-31 months). Median OS among patients treated with upfront crizotinib was not reached, with 7 out of 11 patients still alive at the time of data analysis (n=11, range, 1-73+). Toxicity was manageable with moderate rate of grade 3 or worse toxicity (n=7, 31.8%). Three patients had grade 3-4 neutropenia. Eighteen percent (n=4) of patients developed cardiotoxicities such as bradycardia, prolonged QTc interval and complete heart block. One patient who developed complete heart block required pacemaker insertion. Two patients are long term responders who have been on crizotinib for 68+ and 73+ months. Conclusions This retrospective analysis of a real-world experience confirms the therapeutic benefit of crizotinib in advanced ALK-positive NSCLC. Our data showed crizotinib is tolerable and effective, comparable with literature report. Occasional serious cardiac toxicity requires attention.
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Affiliation(s)
| | - Alex Yuang-Chi Chang
- Department of Medical Oncology, Tan Tock Seng Hospital, Johns Hopkins Singapore Pte Ltd., Singapore
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