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Journal of Nuclear Medicine DOI:Print ISSN 0161-5505
Authors: Sally Ayesa, Malinda Itchins, Anthony Gill and Geoff Schembri
KEY POINTS:
Non–small cell lung cancer with anaplastic lymphoma kinase (ALK) chromosomal rearrangement is
sensitive to treatment with tyrosine kinase inhibitors (TKIs).
Numerous TKIs have been developed in recent years, including alectinib, which is the current
preferred first-line agent for treatment-naı¨ve patients.
The development of resistance has led to next-generation ALK inhibitors that better penetrate the
central nervous system, which has improved the treatment of brain metastasis. READ ARTICLE
Thoracic Surgery Clinics DOI:10.1016/j.thorsurg.2019.12.001
Authors: Anthony V. Serritella, Christine M. Bestvina
There was a case report showed that a novel pleckstrin homology and RUN domain containing M2 (PLEKHM2)- anaplastic lymphoma kinase (ALK) gene rearrangement in small cell lung cancer (SCLC) patient had long-term benefit from ALK inhibitors [ [1] ]. Actually, the case report demonstrated that next generation sequence (NGS) maybe a very useful method for detecting a new subtype of ALK fusion and it may provide a better understanding of ALK- tyrosine kinase inhibitors (TKIs) treatment. Here, we identified a novel type of ALK rearrangement responding to ALK inhibitors in non-small cell lung cancer (NSCLC) by NGS. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.03.017
Authors: Li Ma, Quan Zhang, Yujie Dong, Haoyang Li, Jinghui Wang
Objectives: ... Our aim was to examine a unique atypical ALK FISH pattern, revealed during a systematic large-scale monitoring, which carries the great risk of misinterpretation, hence may result in loss of patients eligible for targeted therapy... Conclusion: Approximately 5% of the 59 ALK positive cases exhibited atypical attenuated isolated 3′ signal pattern. The immunohistochemistry and AMP-NGS examinations helped to clarify the presence of oncoprotein and the fusion gene, respectively. Our results emphasize the importance of extensive exploration of the genetic background of any unexpected FISH finding to avoid false diagnosis. This enables clinicians to indicate the adequate therapy with higher efficiency for patients suffering from NSCLC. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.03.007
Authors: Gábor Smuk, Gábor Pajor, Károly Szuhai, Hans Morreau, Ildikó Kocsmár, Éva Kocsmár, László Pajor, Béla Kajtár, Veronika Sárosi, Gábor Lotz, Tamás Tornóczky
Aims: To describe the real-world economic burden of patients with anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer (NSCLC) treated with post-crizotinib, second-line ALK inhibitor therapy.
Materials and methods: Retrospective analysis using data from US Optum: Clinformatics Data Mart administrative claims database. Adult patients with ALK + NSCLC treated with ceritinib or alectinib as second-line ALK inhibitors between 1 January 2011 and 30 September 2017 were included. Healthcare costs and resource utilization for up to 1 year of therapy were calculated on a per-patient-per-month (PPPM) basis and stratified by presence or absence of brain metastases (BM). Multivariate regression analysis was performed to identify factors associated with costs. Top ten cost drivers of non-inpatient procedure costs were recorded.
Results: One hundred and twelve patients received second-line ALK inhibitors. Total mean PPPM healthcare costs were $23,984 for all patients receiving up ..... READ ARTICLE
Journal of Medical Economics DOI:10.1080/13696998.2020.1762620
Authors: Huamao M. Lin, Xiaoyun Pan, Peijie Hou, Hui Huang, Yanyu Wu, Kaili Ren & Mohammad Jahanzeb
Introduction ALK gene rearrangement in NSCLC results from fusion with another partner gene, mainly EML4 gene, and is observed in less than 5% of adenocarcinoma tumors. Patients usually manifest a response to ALK tyrosine kinase inhibitors. Unfortunately, acquired resistance ineluctably occurs and has been associated with the emergence of secondary mutations.1 Here, we report the identification of an ALK resistance mutation in a patient with ALK tyrosine kinase inhibitor–naive multimetastatic NSCLC. Conclusions ALK secondary resistance mutations can be present in naive tumors and may be associated with aggressive presentation. Baseline NGS screening is very important to identify uncommon mutations and improve first-line targeted therapeutic strategies. READ ARTICLE
JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100047
Authors: Olfa Trabelsi-Grati, Elsy El-Alam, Samia Melaabi, Yves Allory, Ivan Bièche, Nicolas Girard, Céline Callens,
Introduction Ceritinib is a selective second-generation ALK inhibitor that is highly sensitive to echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) molecule. Case report In this paper, we report a 68-year-old female that was diagnosed with stage 4 ALK-positive non-small cell lung cancer (NSCLC) Management and outcome: She was treated with crizotinib first-line, cisplatin and gemcitabine as second-line. And for third-line, ceritinib was started. She had complete response over 3.5 years under ceritinib treatment. And she is still receiving ceritinib with no adverse event. Discussion Cases achieving complete response with ceritinib treatment are rare. In this paper, we aimed to emphasize the complete response in stage 4 NSCLC in an elderly patient. READ ARTICLE
Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220919172
Authors: Nilay Sengul Samanci, Emir Celik, Burak Akovalı, Sait Sager, Fuat Hulusi Demirelli
Background
ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.
Methods
Comprehensive genomic profiling (CGP) of DNA isolated from formalin‐fixed paraffin‐embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.
Results
We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing i..... READ ARTICLE
Lung Cancer: Targets and Therapy DOI:10.2147/LCTT.S239675
Authors: Schrock AB, Madison R, Rosenzweig M, Allen JM, Erlich RL, Wang SY, Chidiac T, Reddy VS, Riess JW, Yassa AE, Shakir A, Miller VA, Alexander BM, Venstrom J, McGregor K, Ali SM
The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non–small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments. Conclusions This meta-analysis indicated that concurrent TP53 mutations was a negative prognostic factor and associated with poorer outcomes of patients with EGFR-TKIs or ALK-TKIs treatments in advanced NSCLC. In addition, our study provided evidence that TP53 mutations might be involved in primary resistance to EGFR-TKIs treatments in patients with sensitive EGFR mutations in advanced NSCLC. READ ARTICLE
BMC Cancer DOI:10.1186/s12885-020-06805-5
Authors: Kang Qin, Helei Hou, Yu Liang and Xiaochun Zhang
Background: The prognostic significance of TP53 concurrent mutations in patients with epidermal growth factor receptor (EGFR)- or anaplastic lymphoma kinase (ALK)- mutated advanced non–small-cell lung cancer (NSCLC) who received EGFR-tyrosine kinase inhibitors (TKIs) or ALK-TKIs based targeted therapy remains controversial. Therefore, the present meta-analysis was performed to investigate the association between TP53 concurrent mutations and prognosis of patients with advanced NSCLC undergoing EGFR-TKIs or ALK-TKIs treatments.
Methods: Eligible studies were identified by searching the online databases PubMed, Embase, Medline, The Cochrane library and Web of Science. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to clarify the correlation between TP53 mutation status and prognosis of patients. This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.
Results: In total, 15 studies wit..... READ ARTICLE
BMC Cancer DOI:10.1186/s12885-020-06805-5
Authors: Kang Qin, Helei Hou, Yu Liang and Xiaochun Zhang*
Although kinase-targeted drugs have achieved significant clinical success, they are frequently subject to the limitations of drug resistance, which has become a primary vulnerability to targeted drug therapy. Therefore, deciphering resistance mechanisms is an important step in designing more efficacious, anti-resistant, drugs. Here we studied two FDA-approved kinase drugs: Crizotinib and Ceritinib, which are first- and second-generation anaplastic lymphoma kinase (ALK) targeted inhibitors, to unravel drug-resistance mechanisms. We used an on-the-fly, function-site interaction fingerprint (on-the-fly Fs-IFP) approach by combining binding free energy surface calculations with the Fs-IFPs. Establishing the potentials of mean force and monitoring the atomic-scale protein-ligand interactions, before and after the L1196M-induced drug resistance, revealed insights into drug-resistance/anti-resistant mechanisms. Crizotinib prefers to bind the wild type ALK kinase domain, whereas Ceritinib bind..... READ ARTICLE
Journal of Chemical Theory and Computation DOI:10.1021/acs.jctc.9b01134
Authors: Zheng Zhao, Philip E. Bourne
Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer most commonly arises through EML4-ALK chromosomal fusion. We have previously demonstrated that combination of the ALK inhibitor crizotinib with the MEK inhibitor selumetinib was highly effective at reducing cell viability of ALK-positive NSCLC (H3122) cells. In this study, we further investigated the efficacy of crizotinib and selumetinib combination therapy in an in vivo xenograft model of ALK-positive lung cancer. Crizotinib decreased tumor volume by 52% compared to control, and the drug combination reduced tumor growth compared to crizotinib. In addition, MEK inhibition alone reduced tumor growth by 59% compared to control. Crizotinib, selumetinib, alone and in combination were non-toxic at the dose of 25 mg/kg with values for ALT (< 80 U/L) and creatinine (<2 mg/dL) within the normal range. Our results support the combined use of crizotinib with selumetinib in ALK-positive lung cancer but raise the possibility tha..... READ ARTICLE
Journal of Pharmacology and Experimental Therapeutics DOI:10.1124/jpet.120.266049
Authors: Nensi Shrestha, Abigail R Bland, Rebecca L Bower, Rhonda Rosengren, John Ashton
What is known and objective: Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-re-sistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC.Methods: We searched articles published from January 1980 to March 2019 in PubMed, EMBASE, Cochrane Library and Web of Science. The pooled estimate and 95% CI were calculated with DerSimonian-Laird method and the random effect model.Results and discussion: From 15 articles, 2,598 patients were included in the meta-analysis. Eleven studies reported the ORR, and the DCR was presented in 10 stud-ies. The ORR and DCR of ceritinib were 0.48 (95% CI, 0.39-0.57) and 0.76 (95% CI, 0.69-0.82), respectively. The PFS and OS were presented in nine and ..... READ ARTICLE
Journal of Clinical Pharmacy and Therapeutics DOI:10.1111/jcpt.13157
Authors: Wei Tian, Ping Zhang, Yuan Yuan, Xiao-Hui Deng, Rui Yue, Xiao-Zhu Ge
To date, no head-to-head trials have compared the e cacy of brigatinib and alectinib
against anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p), ALK-inhibitor-naïve,
advanced non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis.
We conducted an indirect treatment comparison (ITC) between brigatinib and alectinib, with crizotinib
as a common comparator, using a Bayesian model with non-informative prior distribution and assessed
the between-study heterogeneity of the studies. The primary e cacy endpoint was progression-free
survival (PFS), and e cacy was ranked using the surface under the cumulative ranking (SUCRA)
curve values. ITC analysis showed that there were no significant di erences in PFS between the
brigatinib and alectinib arms. However, the SUCRA values revealed that alectinib ranked the highest
by e cacy in the overall patient population, whereas brigatinib ranked the highest by e cacy in
the CNS metastasis sub-group. Although there wer..... READ ARTICLE
Cancers DOI:10.3390/cancers12040942
Authors: Koichi Ando, Kaho Akimoto, Hiroki Sato, Ryo Manabe, Yasunari Kishino,
Tetsuya Homma, Sojiro Kusumoto, Toshimitsu Yamaoka , Akihiko Tanaka,
Tohru Ohmori,Hironori Sagara
Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint
inhibitor (ICI) treatment e cacy. The clinical e cacy of ICIs for non-small-cell lung cancer (NSCLC)
patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped
190 patients with advanced lung adenocarcinomas who received nivolumab or pembrolizumab
monotherapy, and examined the e cacy in NSCLC patients with or without major mutations.
Among the patients enrolled in the genotyping study, 47 patients harbored EGFR mutations, 25 patients
had KRAS mutations, 5 patients had a HER2 mutation, 6 patients had a BRAF mutation, and 7 patients
had ALK rearrangement. The status of PD-L1 expression was evaluated in 151 patients, and the
rate of high PD-L1 expression ( 50%) was significantly higher in patients with ALK mutations.
The progression-free survival was 0.6 (95% CI: 0.2–2.1) months for ALK-positive patients and 1.8 (95%
CI: 1.2–2.1) months for EGFR-positive patients. All patients..... READ ARTICLE
International Journal of Molecular Sciences DOI:10.3390/ijms21072623
Authors: Yuko Oya, Hiroaki Kuroda, Takeo Nakada, Yusuke Takahashi, Noriaki Sakakura, Toyoaki Hida
ALK (Anaplastic lymphoma kinase) rearrangement is the second most common targetable oncogene-dirven gene in NSCLC (non-small cell lung cancer). It is identified in approximately 3–7% of NSCLC patients [ [1] ], and is highly sensitive to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib, ceritinib, brigatinib [ [2] ]. EML4-ALK rearrangement was firstly identified by Soda et al. in 2007 [ [3] ]. With the development of NGS (Next Generation Sequencing), more and more novel ALK fusion partners have been identified, such as KIF5B, STRN, KLC1, TPR, HIP1, DCTN1, CMTR1, GCC2, SEC31A and so on. A liquid biopsy by amplicon-based NGS analysis has been considered as an accurate and reliable tool to detect and monitor clinically relevant molecular alterations. Herein, using NGS and malignant pleural effusion (MPE) cfDNA, we report a novel latent transforming growth factor β binding protein 1 (LTBP1)-ALK fusion in a patient with NSCLC. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.03.025
Authors: HuiWen Qian, Juan Li, LiRong Zou, Cheng Ji, Hayen Li, YuShuang Zheng, LingChuan Guo, WeiDong Zhu, Yi Zhang
Anaplastic lymphoma kinase (ALK) inhibitors are important treatment options
for non-small-cell lung cancer (NSCLC), associated with ALK gene rearrangement. Patients
with ALK gene rearrangement show sensitivity to and benefit clinically from treatment with
ALK tyrosine kinase inhibitors (ALK-TKIs). To date, crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, and entrectinib have received approval from the US Food and Drug
Administration and/or the European Medicines Agency for use during the treatment of ALKgene-rearrangement forms of NSCLC. Although the oral route of administration is convenient and results in good compliance among patients, oral administration can be affected by
many factors, such as food, intragastric pH, cytochrome P450 enzymes, transporters, and
p-glycoprotein. These factors can result in increased risks for serious adverse events or can
lead to reduced therapeutic effects of ALK-TKIs. This review characterizes and summarizes
the pharmacokinetic parameters and drug–-drug interactions associated with ALK-TKIs to
provide specific recommendations for oncologists and clinical pharmacists when prescribing
ALK-TKIs READ ARTICLE
Drug Design, Development and Therapy DOI:10.2147/DDDT.S249098
Authors: Dehua Zhao, Jing Chen, Mingming Chu, Xiaoqing Long, Jisheng Wang
Objectives: Transforming anaplastic lymphoma kinase (ALK) gene rearrangements are well known as a unique subset of non-small cell lung cancer (NSCLC) with mutations other than EGFR. Currently, crizotinib is the standard first-line treatment for ALK-positive NSCLC. Conclusion: Considering this rare SOS1-ALK fusion and remarkable response to an ALK-inhibitor, it is important to be aware of the presence of SOS1-ALK fusions in patients with advanced NSCLC to better guide targeted therapy. Precision methods, such as NGS for oncogenic alteration detection, should also be encouraged in clinical practice. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.02.012
Authors: Hua-fei Chen, Wen-xian Wang, Chun-wei Xu, Li-chao Huang, Xiao-feng Li, Gang Lan, Zhan-qiang Zhai, You-cai Zhu, Kai-qi Du, Lei Lei, Mei-yu Fang
Objectives: Treatment options for malignant pleural mesothelioma (MPM) are limited but some studies on immune checkpoint inhibitors (ICIs) in MPM have reported antitumor activity. Very little is known about immune-related predictive factors. Conclusions: Our findings indicate that the use of immunotherapy in MPM warrants further investigation. Furthermore, the impressive clinical response obtained by our patient suggests that immune checkpoint inhibitors could help in the management of the disease after the failure of other treatments. READ ARTICLE
Lung Cancer DOI:10.1016/j.lungcan.2020.02.006
Authors: Giuseppe Bronte, Angelo Delmonte, Marco Angelo Burgio, Alberto Verlicchi, Maurizio Puccetti, Sara Bravaccini, Paola Cravero, Maria MaddalenaTumedei, Danila Diano, Giulio Rossi, Paola Ulivi, Giovanni Martinelli, Lucio Crinòa
Lung cancer remains the most common cancer and the leading cause of cancer death worldwide. Despite effective chemotherapy and molecular-based therapies, the median and overall survival remains poor. Immune checkpoint inhibitors have changed the treatment landscape for patients with non-small cell lung cancer (NSCLC) by inhibiting negative T cell regulators, including programmed death 1 (PD-1, CD279) and programmed death ligand 1 (PD-L1, also known as B-H1, CD274) inhibitors. Nonetheless, most patients do not respond to these inhibitors. Recently, PD-L1 expression has been demonstrated to influence the anti-tumor efficacy of immune checkpoint inhibitors. However, the mechanisms of PD-L1 regulation are not clearly understood. This review thus aims to summarize the current knowledge and recent developments in the regulatory mechanisms of PD-L1 expression levels and attempts to clarify its latent function in anti-tumor activity, with the goal of guiding better designs for future NSCLC immunotherapies. READ ARTICLE
Pathology - Research and Practice DOI:10.1016/j.prp.2020.152852
Authors: Lingling Zhu, Jiewei Liu, Li Wang, Danli Yan, Jie Zhou, Wen Li, Dan Pu, Lei Peng, Qinghua Zhou