A discussion of alectinib as a standard for patients with ALK-rearranged non–small cell lung cancer and mechanisms of resistance. WATCH VIDEO
OncLiveTV
Authors: Mark A. Socinski
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Lung cancer causes the highest number of cancer-related deaths worldwide. Resistance to therapy is a major clinical issue contributing to the poor prognosis of lung cancer. In recent years, targeted therapy has become a concept where subgroups of non-small cell lung cancer (NSCLC) with genetically altered receptor tyrosine kinases are targeted by tyrosine kinase inhibitors (TKIs). One such subgroup harbors a gene fusion of echinoderm microtubule-associated protein-like 4 (EML4) with anaplastic lymphoma kinase (ALK). Although most NSCLC patients with EML4-ALK fusions initially respond to ALK TKI-therapy they eventually develop resistance. While ALK kinase domain mutations contribute to ALK TKI-refractoriness, they are only present in a fraction of all ALK TKI-resistant tumors. In this study we sought to explore a possible involvement of microRNAs (miRNAs) in conferring resistance to ALK TKIs in ALK TKI-refractory NSCLC cell lines. We subjected our ALK TKI-refractory cancer cells along w..... READ ARTICLE
Biochemical and Biophysical Research Communications DOI:10.1016/j.bbrc.2019.02.016
Authors: Yi Lai, Merve Kacal, Maraam Kanony, Iga Stukan, Kenbugul Jatta, Lorand Kis, Erik Norberg, Helin Vakifahmetoglu-Norberg, Rolf Lewensohn, Per Hydbring, Simon Ekman
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase encoded by the gene ALK, which belongs to a subfamily of the insulin receptor superfamily. ALK signaling has been shown to be involved in cell proliferation, differentiation, and development, etc. Thus far, ALK aberrations are known to be involved in the oncogenesis of non-small cell lung cancer and glioblastoma. Head and neck cancer squamous cell carcinoma (HNSCC) is an aggressive cancer with genomic heterogeneity as revealed by recent whole-exome studies. READ ARTICLE
Cancer Research DOI: 10.1158/1538-7445
Authors: Lan Wang, Yuchen Liu, Wenying Piao, Peony Hiu Yan Poon, Chun Kit Yeung, Amy Bik Wan Chan, Chin Wang Lau, Yuxiong Su, Jason Ying Kuen Chan and Vivian Wai Yan Lui
Read More![Discovery of 3,6-diaryl-1H-pyrazolo[3,4-b]pyridines as potent anaplastic lymphoma kinase (ALK) inhibitors](https://images.squarespace-cdn.com/content/v1/5b6cc61596d4557796b187fe/1639062347000-15K9XASMF8EWX742HB9Q/ALK_Pre-Clinical.jpg)
A new series of 3,6-diaryl-1H-pyrazolo[3,4-b]pyridine compounds have been discovered as potent anaplastic lymphoma kinase (ALK) inhibitors. The 4-hydroxyphenyl in the 6-position of 1H-pyrazolo[3,4-b]pyridine were crucial and a fluorine atom substitution could give promising inhibitory activity. The IC50 of compound 9v against ALK was up to 1.58 nM and a binding mechanism was proposed. READ ARTICLE
Bioorganic & Medicinal Chemistry Letters DOI:10.1016/j.bmcl.2019.01.037
Authors: Changwei Chen, Peichen Pan, Ziyang Deng, Dahai Wang, Qifan Wu, Lei Xu, Tingjun Hou, Sunliang Cui
Background: Patients with anaplastic lymphoma kinase (ALK) rearrangements are particularly prone to development of brain metastases (BMs). Newer anti-ALK treatments have demonstrated far greater intracranial efficacy. Here we performed a meta-analysis with the aim of assessing the efficacy of ALK inhibitors on BMs. Conclusions: Despite the limitation from lack of published clinical data, our results showed that ALK inhibitors are effective at the brain site regardless of previous anti-ALK treatments, systemic therapy with ALK inhibitors should be considered as a preferred approach over for controlling BMs from ALK-positive NSCLC. READ ARTICLE
Journal of Thoracic Disease
DOI:10.21037/jtd.2019.03.76
Authors: Zhiguo Zhang, Hongwei Guo, Yuanli Lu, Wei Hao, Lei Han
Introduction: Anaplastic lymphoma kinase (ALK) gene rearrangements are observed in about 4% to 8% non-small cell lung cancer (NSCLC). ALK+ tumors have been associated with increased pleural and pericardial disease. Our primary objective was to determine the uncommon sites of metastasis of ALK+ NSCLC. Secondary objectives included study of coexisting mutations and factors impacting survival of ALK+ NSCLC. Conclusion: In NSCLC, ALK rearrangements may not be mutually exclusive mutations and can present with unique radiographic patterns. Patients with uncommon sites of metastasis may have worse outcomes. READ ARTICLE
American Journal of Clinical Oncology
DOI:COC.0000000000000508
Authors: Rohan Gupta, Idoroenyi Amanam, Syed Rahmanuddin, Isa Mambetsariev, Yingyu Wang, Charity Huang, Karen Reckamp, Lalit Vora, Ravi Salgia
Background: Young patients are rarely diagnosed with non-small cell lung cancer (NSCLC), and little is known about its predisposing genomic alterations and survival. Conclusions: Younger patients with NSCLC had a higher frequency of gene fusions than older patients and had a trend of worse OS. READ ARTICLE
Annals of Translational Medicine DOI:10.21037/atm.2019.03.39
Authors: Shifeng Yang, Zhengbo Song, Guoping Cheng
Background: Originally discovered in lymphomas,1 the ALK fusion oncogene with gain-of-function cytoplasmic tyrosine kinase activity has since been identified as an oncogenic driver in 3% to 10% of patients with non–small cell lung cancer (NSCLC).2,3 FDA approval of crizotinib, a small molecule ALK tyrosine kinase inhibitor (TKI), only 3 years after the discovery of the ALK fusion oncogene represents one of the most rapid bench-to-bedside translational advances in the history of targeted cancer therapy.4 Among the many fusion partners that have been reported, EML4 is the most common gene partner of ALK through a paracentric inversion of chromosome 2 inv(2) (p21;p23). We previously reported that in a cohort of 200 NSCLC specimens, the EML4-ALK–positive transcripts included 109 variant 1 (V1; 54.5%), 20 V2 (10.0%), 68 V3 (34.0%), and 3 V5a (1.5%) variants.5 Most (n=188; 94.0%) EML4-ALK–positive NSCLC tumors had adenocarcinoma histology... Conclusions: To our knowledge, this is the first..... READ ARTICLE
Journal of National Comprehensive Cancer Network DOI:10.6004/jnccn.2019.7291
Authors: Jay Gong, Jeffrey P. Gregg, Weijie Ma, Ken Yoneda, Elizabeth H. Moore, Megan E. Daly, Yanhong Zhang, Melissa J. Williams, Tianhong Li
Clinical variables describing the natural history and longitudinal therapy outcomes of stage IV anaplastic lymphoma kinase gene rearrangement positive (ALK-positive) NSCLC and their relationship with long-term overall survival (OS) have not previously been described in detail.
Patients with stage IV NSCLC treated with an ALK inhibitor at the University of Colorado Cancer Center from 2009 through November 2017 were identified retrospectively. OS curves were constructed by using Kaplan-Meier methods. Multivariate Cox proportional hazard analysis was used to determine the relationship of variables with OS.
We concluded that patients with stage IV ALK-positive NSCLC can have prolonged OS. Brain metastases at diagnosis of stage IV disease does not influence OS. Having more organs involved with tumor at stage IV presentation is associated with worse outcomes. Prolonged benefit from pemetrexed is associated with better outcomes. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.12.014
Authors: Jose M. Pacheco, Dexiang Gao, Derek Smith, Thomas Purcell, Mark Hancock, Paul Bunn, Tyler Robin, Arthur Liu, Sana Karam, Laurie Gaspar, Brian Kavanagh, Chad Rusthoven, Dara Aisner, Robert Doebele, D. Ross Camidge
Central nervous system (CNS) metastases represent a significant source of morbidity and mortality for patients with ALK tyrosine kinase gene (ALK)-positive NSCLC. Alectinib has demonstrated robust CNS activity in both crizotinib-naive and crizotinib-resistant settings. However, the CNS efficacy of alectinib has not been established in patients with untreated symptomatic, large CNS metastases.
In this retrospective study, patients were eligible if they had advanced ALK-positive NSCLC with large (defined as ≥1 cm) or symptomatic CNS metastases and received alectinib. Medical records and radiographic imaging were reviewed to determine treatment outcomes. CNS efficacy was assessed per the modified Response Evaluation Criteria in Solid Tumors version 1.1.
Alectinib demonstrated meaningful CNS efficacy in patients with ALK-positive NSCLC with untreated symptomatic or large brain metastases. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.12.002
Authors: Jessica J Lin, Ginger Y Jiang, Nencyben Joshipura, Jennifer Ackil, Subba R Digumarthy, Sandra P Rincon, Beow Y Yeap, Justin F Gainor, Alice T Shaw
This study aims to determine whether advanced ROS1 gene-rearranged NSCLC (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate.
The risk of peridiagnostic TEEs is significantly elevated in patients with advanced ROS+ NSCLC compared to EGFR+ and KRAS+ cases. TEE risk may be similarly elevated in ALK+ NSCLC. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.12.001
Authors: Terry L Ng, Derek E Smith, Rao Mushtaq, Tejas Patil, Anastasios Dimou, Shuo Yang, Qian Liu, Xuefei Li, Caicun Zhou, Robert T Jones, Megan M Tu, Flora Yan, I Alex Bowman, Stephen V Liu, Siera Newkirk, Joshua Bauml, Robert C Doebele, Dara L Aisner, Dexiang Gao, Shengxiang Ren, D Ross Camidge
... Here, we report a case of adenocarcinoma harboring a novel S1 RNA binding domain 1 (SRBD1)–ALK fusion gene identified accidentally during routine molecular profiling by next-generation sequencing... Without any other oncogenic mutation detected, we speculate that the novel SRBD1-ALK fusion served as a driver mutation of the patient’s disease. And ALK TKIs might be effective in the treatment of tumors with this new fusion gene. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.11.027
Authors: Xue Hou, Huamin Xu, Likun Chen
Background: Pts with anaplastic lymphoma kinase (ALK)-rearranged NSCLC have benefited from ALK tyrosine kinase inhibitors (TKIs); however, most pts eventually acquire resistance. Identification of resistance mutations informs subsequent therapy but has typically required invasive repeat biopsies. Here, we assessed the utility of ctDNA analysis and the ability to monitor response longitudinally and detect resistance mutations during therapy with ensartinib, a potent second-generation ALK TKI. Conclusions: Overall, the data suggest that plasma ctDNA analysis can potentially identify a subgroup of pts with ALK+ NSCLC who may derive clinical benefit from ensartinib. Furthermore, serial assessments of ctDNA during therapy offer a convenient method to track tumor response and identify the mutational landscape of acquired resistance. READ ARTICLE
Annals of Oncology DOI:10.1093/annonc/mdz063.010
Authors: L. Horn, J. G. Whisenant, H. Wakelee, K. L. Reckamp, H. Qiao, L. Du, J. Hernandez, V. Huang, S. N. Waqar, S. Patel, R. E. Sanborn, T. Shaffer, K. Garg, A. Holzhausen, K. Harrow, C. Liang, L. P. Lim, M. Li, C. M. Lovly
The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib, in a real-world clinical setting.
We concluded that crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.11.022
Authors: Akihiko Gemma, Masahiko Kusumoto, Yasuyuki Kurihara, Noriyuki Masuda, Shigeo Banno, Yutaka Endo, Hiroyuki Houzawa, Naomi Ueno, Emiko Ohki, Akinobu Yoshimura
Objective: We investigated the prevalence of ALK rearrangements in a Chinese NSCLC population, and correlated clinical outcomes of crizotinib with different ALK partners/variants. Conclusions: This study illustrates the patterns of ALK fusion variants present in Chinese NSCLC patients and might help explain heterogeneous clinical outcomes to crizotinib treatment according to different ALK fusion variants. READ ARTICLE
Targeted Oncology DOI:10.1007/s11523-019-00631-x
Authors: Yudong Su, Xiang Long, Yang Song, Peng Chen, Shanqing Li, Huaxia Yang, Pancheng Wu, Yanyu Wang, Zhongxing Bing, Zhili Cao, Lei Cao, Yijun Wu, Zhe Zhang, Jing Liu, Bing Li, Jianxing Xiang, Ke Ma, Tengfei Zhang, Lu Zhang, Xinru Mao, Hao Liu, Puyuan Xing, Naixin Liang
Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that ALK resistance mutations may represent a biomarker of response in previously treated patients.
Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non–small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK mutation–focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to ALK mutation status.
We concluded that in patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with ALK mutations compared with patients without ALK mutations. Tumor genotyping for ALK mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib. READ ARTICLE
Journal of Clinical Oncology DOI:10.1200/JCO.18.02236
Authors: Alice T. Shaw, Benjamin J. Solomon, Benjamin Besse, Todd M. Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou, Jill S. Clancy, Sherry Li, Antonello Abbattista, Holger Thurm, Miyako Satouchi, D. Ross Camidge, Steven Kao, Rita Chiari, Shirish M. Gadgeel, Enriqueta Felip, Jean-François Martini
Anaplastic lymphoma kinase inhibitors (ALKi) like ceritinib are considered standard for front-line treatment of non-small cell lung cancers (NSCLC) harboring a translocation of the anaplastic lymphoma kinase (ALK) gene. We report herein a case of interstitial lung disease (ILD) that developed following a 7-month ceritinib treatment without recurrence under either crizotinib or brigatinib, two others ALKi. READ ARTICLE
Annuals of Translational Medicine DOI:10.21037/atm.2019.01.24
Authors: Laura Bender, Guillaume Meyer, Elisabeth Quoix and Bertrand Mennecier
Introduction: In an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted. Conclusion: Ceritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.03.002
Authors: Byoung Chul Cho, Radka Obermannova, Alessandra Bearz, Mark McKeage, Dong-Wang Kim, Ullas Batra, Gloria Borra, Sergey Orlov, Sang-We Kim, Sarayut L. Geater, Pieter E. Postmus, Scott A. Laurie, Keunchil Park, Cheng-Ta Yang, Andrea Ardizzoni, Anna C. Bettini, Gilberto de Castro Jr., Flavia Kiertsman, Zhe Chen, Yvonne Y. Lau, Kalyanee Viraswami-Appanna, Vanessa Q. Passos, Rafal Dziadziuszko
Introduction: This study was aimed at clarifying the failure pattern after definitive chemoradiotherapy in patients with stage III non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and/or anaplastic lymphoma kinase (ALK) translocation. Conclusions: Although the ALK-positive group showed no characteristic failure pattern, the EGFR-mutant group showed a lower rate of in-field failure and higher rate of out-of-field failure. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2019.02.021
Authors: Masaki Nakamura, Shun-ichiro Kageyama, Seiji Niho, Masayuki Okumura, Hidehiro Hojo, Atsushi Motegi, Naoki Nakamura, Sadamoto Zenda, Kiyotaka Yoh, Koichi Goto, Tetsuo Akimoto
The treatment approach to advanced anaplastic lymphoma kinase fusion-positive (ALK-positive) non-small cell lung cancer (NSCLC) serves as a paradigm for precision oncology. To date, five ALK-tyrosine kinase inhibitors (TKIs)—crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib—have been approved by the US Food and Drug Administration [1,2]. Although each TKI has significant efficacy in ALK-positive NSCLC, the duration of benefit is invariably limited by the development of acquired resistance... Finally, although not addressed in this study, ALK-independent mechanisms of resistance such as bypass signaling or lineage changes remain a major therapeutic hurdle in ALK-positive NSCLC. In an analysis of 20 lorlatinib-resistant tumour biopsies, 65% did not harbour compound ALK resistance mutations [8], implicating ALK-independent resistance. The prevalence of ALK-independent resistance mechanisms will likely rise as strategies to overcome ALK mutations continue to improve. Thus, eff..... READ ARTICLE
eBioMedicine
DOI:10.1016/j.ebiom.2019.01.059
Authors: Jessica J. Lin and Alice T. Shaw