Systematic review of sequencing of ALK inhibitors in ALK-positive non-small-cell lung cancer

The objective of this study was to understand outcomes of patients treated with ALK inhibitors, especially when ALK inhibitors are followed by other ALK inhibitors. A systematic literature review was conducted in PubMed, Embase, and Cochrane through July 17, 2017. Conference abstracts (three meetings in past 2 years) also were searched. Of 504 unique publications, 80 met inclusion criteria (47 clinical trials, 33 observational studies). Observational studies have the potential to provide information for ALK inhibitors used sequentially. Ten observational studies reported median overall survival of crizotinib-led sequences ranging from 30.3 to 63.75 months from initiation of crizotinib; 49.4-89.6 months from metastatic non-small-cell lung cancer diagnosis; and 15.5-22.0 months from initiation of the second-generation ALK inhibitor after initial crizotinib. Sequencing of ALK inhibitors may benefit patients progressing on initial ALK inhibitors. READ ARTICLE

Lung Cancer: Targets and Therapy DOI:10.2147/LCTT.S179349

Authors: Barrows SM, Wright K, Copley-Merriman C, Kaye JA, Chioda M, Wiltshire R, Torgersen KM, Masters ET.

Review PaperKirk SmithFebruary 8, 2019ALK, NSCLC, carcinoma, non-small-cell lung, non-small-cell lung cancer

Comprehensive analysis of PD-L1 expression, HER2 amplification, ALK/EML4 fusion, and mismatch repair deficiency as putative predictive and prognostic factors in ovarian carcinoma

Most ovarian carcinomas (OC) are characterized by poor prognosis, particularly the most frequent type high-grade serous carcinoma. Besides PARP inhibitors, target-based therapeutic strategies are not well established. We asked the question which other therapeutic targets could be of potential value and, therefore, analyzed a large cohort of OC for several predictive factors. Two hundred eighty-eight (288) cases of OC including the major histological types were analyzed by immunohistochemistry for PD-L1HER2, ALK, and the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6. HER2 amplification and ALK/EML4 fusion were assessed by fluorescence in situ hybridization. The most frequent finding was PD-L1 expression ≥ 1% in 19.5% of the cases, which correlated with a significantly better overall survival in multivariate analysis (p < 0.001). HER2 amplification was detected in 11 cases (4%), all high-grade serous carcinomas. Amplification of HER2 did not correlate with patients’ survival...... READ ARTICLE

Virchows Archiv DOI:10.1007/s00428-019-02528-6

Authors: Elisa Schmoeckel, Sophie Hofmann, Daniel Fromberger, Miriam Rottmann, Beate Luthardt, Alexander Burges, Udo Jeschke, Thomas Kirchner, Sigurd F. Lax, Doris Mayr

Discordance between FISH, IHC, and NGS Analysis of ALK Status in Advanced Non–Small Cell Lung Cancer (NSCLC): a Brief Report of 7 Cases

BACKGROUND: Anaplastic lymphoma kinase (ALK) rearrangement represents a landmark in the targeted therapy of non–small cell lung cancer (NSCLC). Immunohistochemistry (IHC) is a sensitive and specific method to detect ALK protein expression, possibly an alternative to fluorescence in situ hybridization (FISH). In this study, the concordance of FISH and IHC to determine ALK status was evaluated, particularly focusing on discordant cases. In our discordant cases, a coexistent complex pattern (deleted, split, and amplified/polysomic) of ALK gene was observed by FISH analysis. These complex rearranged cases were not detectable by IHC, and it could be speculated that more complex biological mechanisms could modulate protein expression. These data highlight the role of IHC and underscore the complexity of the genetic pattern of ALK. It could be crucial to consider these findings in order to best select patients for anti-ALK treatment in daily clinical practice. READ ARTICLE

Translational Oncology
DOI:10.1016/j.tranon.2018.11.006

Authors: Anna Scattone, Annamaria Catino, Laura Schirosi, Lucia Caldarola, Stefania Tommasi, Rosanna Lacalamita, Elisabetta Sara Montagna, Domenico Galetta, Gabriella Serio, Francesco Alfredo Zito, Anita Mangia

Case StudyKirk SmithFebruary 1, 2019FISH, IHC, NGS, ALK Status, Advanced Non–Small Cell Lung Cancer (NSCLC)

Rapid Progression of Metastatic Panspinal Epidural Non−Small Cell Lung Cancer After Discontinuation of Alectinib

Rapid progression of metastatic non−small cell lung cancer (NSCLC) after discontinuation of tyrosine kinase inhibitors or anaplastic lymphoma kinase (ALK) inhibitors has been described and is associated with a poor prognosis. We describe the first reported case of accelerated NSCLC tumor extension throughout the entire spinal epidural space
The differential diagnosis when evaluating presumed spine epidural abscess should include tumor and metastatic disease, even in cases of rapid development. Recent termination of tyrosine kinase inhibitors or ALK inhibitors may result in severe disease flares, and a history of such should raise clinical suspicion for metastatic progression. In addition to cultures, biopsy for pathologic diagnosis should be collected during decompressive surgery. READ ARTICLE

World Neurosurgery DOI:10.1016/j.wneu.2018.11.118

Authors: Carole S.L. Spake, Daniel B.C. Reid, Alan H. Daniels

$A Pilot Prospective Study of Refractory Solid Tumor Patients for NGS-Based Targeted Anticancer Therapy$

A Pilot Prospective Study of Refractory Solid Tumor Patients for NGS-Based Targeted Anticancer Therapy

With the advent of next-generation sequencing (NGS), targeted sequencing is now contributing to decision making for which chemotherapeutics to administer to cancer patients, especially in refractory and metastatic cancer. Given that most patients with refractory cancer develop resistance to chemotherapy and have few treatment options, we performed NGS test to evaluate the efficacy and clinical feasibility of NGS-based targeted anticancer therapy. We used a gene panel for capturing target regions covering 83 cancer-related genes. A total of 25 refractory metastatic solid tumor patients were enrolled in this study. Among the 25 patients, 7 had FDA-approved drug-responsive or -resistant alterations. However, the effectiveness of targeted therapy was assessed by follow-up in three patients (12%). These included crizotinib for ALK-EML4 fusion in a malignancy of undefined origin patient and everolimus for AKT3 amplification in a uterine sarcoma patient. In addition, we identified a KRAS codo..... READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2018.10.011

Authors: Young MiSeol, Chae Hwa Kwon, So Jeong Lee, Seon Jin Lee, Yuri Choi, Young Jin Choi, Hyojeong Kim, Do Youn Park

Case StudyKirk SmithFebruary 1, 2019Refractory Solid Tumor, NGS-Based Targeted Anticancer Therapy

Concurrent Presence of ALK Rearrangement and MET Mutation in Lung Adenocarcinoma

During recent years, many gene mutations have been reported in lung adenocarcinoma, and target agents against driver mutations have been explored. MNNG HOS transforming gene (MET) exon 14 mutation and ALK receptor tyrosine kinase (ALK) translocation were usually mutually exclusive. However, here, we describe a case that had intratumor heterogeneity on both genetic and pathologic characteristics. Patients whose tumors harbored MET exon 14 splice site mutations or ALK rearrangement derived meaningful clinical benefit from crizotinib.4, 5 Our findings may have profound clinical implications for potential therapeutic targeting during disease progression. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.10.149

Authors: Tian Qiu, Fanshuang Zhang, Weihua Li, Lei Guo, Jianming Ying

Case StudyKirk SmithFebruary 1, 2019ALK Rearrangement, MET Mutation, Lung Adenocarcinoma

Case report of unusual ALK gene rearrangement and review of 354 cases of ALK rearrangement study of lung non-small cell carcinoma

Background: Lung cancer is the leading cause of cancer-related death in Australia, accounting for 18.7% in 2017; and an estimated incidence of 43 cases per 100,000 persons in 2013, making it the 5th most common cancer. Many genetic abnormalities are essential in driving tumorigenesis. Anaplastic lymphoma kinase (ALK) gene rearrangement is responsible for 3–7% of all non-small cell lung cancers (NSCLC); which are responsive to tyrosine kinase inhibitors. Therefore, detection of such genetic abnormalities has become mainstay practice in the diagnostic workup for lung cancers. READ ARTICLE

Pathology DOI:10.1016/j.pathol.2018.09.044

Authors: M. Huang, A. Chou, D. Riley, Y. Kim, R. Lukeis, M. Qiu

Case StudyKirk SmithFebruary 1, 2019ALK gene rearrangement, lung non-small cell carcinoma

Variable Response to ALK Inhibitors in NSCLC with a Novel MYT1L-ALK Fusion

... We discuss the initial report of a myelin transcription factor 1 like gene (MYT1L)-ALK fusion identified in the tumor of a patient with metastatic NSCLC, and the tumor's unique response to treatment... In this case, NGS revealed a large duplication event in chromosome 2, resulting in a novel MYT1L-ALK fusion. Myelin transcription factor 1-like protein is located on the cytoplasmic surface of the Golgi membranes and the endoplasmic reticulum and is an important factor in the cell cycle (specifically, in checkpoint recovery).4 Because ALK fusion partners may be a determinant of response to treatment and its possible future resistance type,5 detection of these fusions is crucial. Fluorescence in situ hybridization testing for ALK failed to detect the fusion in either the primary lung cancer and the liver metastases. The ability of NGS to detect ALK fusions and their fusion partners may increase patients’ therapeutic options. Identifying novel events such as the MYT1L-ALK fusion may b..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.10.169

Authors: Terrence C. Tsou, Kyle Gowen, Siraj M. Ali, Vincent A.Miller, Alexa B. Schrock, Christine M. Lovly, Karen L. Reckamp

EditorialKirk SmithFebruary 1, 2019ALK Inhibitors, NSCLC, MYT1L-ALK Fusion

Carcinoma of Unknown Primary with EML4‐ALK Fusion Response to ALK Inhibitors

With the advent of next‐generation sequencing (NGS) and precision medicine, investigators have determined that tumors from different tissue sources that have the same types of genetic mutations will have a positive response to the same targeted therapy. This finding has prompted us to seek potential therapeutic targets for patients with carcinoma of unknown primary (CUP) using NGS technology. Here, we reported a case of a woman with CUP resistance to chemotherapy. We detected 450 cancer‐related gene alterations using three metastatic tumor specimens and found the presence of EML4 exon13 and ALK exon20 fusion. The tumor did respond to crizotinib, a first‐generation ALK inhibitor. When her tumor progressed, circulating tumor DNA detection revealed ALK L1196 M and G1269A mutation resistance to crizotinib, but she had a response to brigatinib. This case revealed that NGS technology used to detect the genetic alterations in patients with CUP might be a reliable method to find potential ther..... READ ARTICLE

The Oncologist DOI:10.1634/theoncologist.2018-0439

Authors: Peng Zhao, Ling Peng, Wei Wu, Yi Zheng, Weiqin Jiang, Hangyu Zhang, Zhou Tong, Lulu Liu, Ruobing Ma, Liping Wang, Ming Yao, Kai Wang, Weijia Fang, Liming Wu

An overview on Vadimezan (DMXAA): The vascular disrupting agent

Vascular disrupting agents (VDAs), a group of cancer remedies, can cause a specific and irreversible destruction of established tumor vessels, and the complete halt of blood flow in the tumor. DMXAA (ASA404) or Vadimezan, a flavone-acetic acid-based drug, is the most promising VDAs that induces a rapid shutdown of blood flow in tumors but not in normal tissue. The exact mechanism of vascular disruption is unknown; however, proposed direct and indirect mechanisms of action for DMXAA comprises (i) inducing apoptosis in endothelial cells; (ii) hemorrhagic necrosis and ischemia in tumor; (iii) release of serotonin (5-HT); (vi) stimulation of innate immune system; (v) production of inflammatory cytokines, for example TNF, IL-6, GCSF, KC, IP-10, and MCP-1; (vi) activation of NFκB and p38 (MAPK); (vii) production of nitric oxide; and (viii) reducing tumor energetics and membrane turnover. Despite the remarkable results from preclinical and phase I/II, DMXAA has failed in phase III clinical tr..... READ ARTICLE

Chemical Biology and Drug Design DOI:10.1111/cbdd.13166

Authors: Amir Daei Farshchi Adli, Rana Jahanban-Esfahlan, Khaled Seidi, Sonia Samandari-Rad and Nosratollah Zarghami

Diffuse Atypical Cystic Brain Metastases in ALK+ NSCLC Treated With Whole Brain Radiation and Second-Generation ALK-Targeted Therapy

A 53-year-old African American man who had never smoked was initially diagnosed with clinical stage cT2pN3 (contralateral mediastinal node) M0, IIIB EML4-anaplastic lymphoma kinase translocation–positive (ALK+) adenocarcinoma of the right lung. He was treated with concurrent chemotherapy using pemetrexed/carboplatin and 60 Gy of radiation to the lung and mediastinum. The patient tolerated these treatments well with complete response in the chest, but he developed biopsy-proven solitary metastatic recurrence in the liver 1 year later. He underwent stereotactic radiation therapy with 30 Gy in 3 fractions, followed by crizotinib at this time. READ ARTICLE

Practical Radiation Oncology DOI:10.1016/j.prro.2018.11.002

Authors: William R. Grubb, Mitchell Machtay, Afshin Dowlati, Tithi Biswas

Case StudyKirk SmithJanuary 18, 2019

ALK inhibition in two emblematic cases of pediatric inflammatory myofibroblastic tumor: Efficacy and side effects

There is an increasing interest for anaplastic lymphoma kinase (ALK) inhibitors in pediatric oncology for specific entities such as ALK-driven inflammatory myofibroblastic tumor (IMT). IMTtreatment can be challenging due to localization of the tumor and in rare cases of metastasis.When standard surgical treatment is not feasible, ALK inhibitors may play an important role,as recently reported for the first-generation ALK inhibitors (crizotinib). However, data on thesecond-generation ALK inhibitors are limited. We report two emblematic cases of IMT in pediatric patients, treated with the second-generation ALK inhibitor ceritinib in the context of a clinical trial(NCT01742286). READ ARTICLE

Pediatric Blood & Cancer DOI: 10.1002/pbc.27645

Authors: Erica Brivio and C. Michel Zwaan

Advance of theragnosis biomarkers in lung cancer: from clinical to molecular pathology and biology

One distinct molecular subtype of non-small cell lung cancer (NSCLC) is defined by rearrangement of the anaplastic lymphoma kinase (ALK). The increasing knowledge over the last years has enabled the continuous improvement of ALK inhibitors; however, resistance in these patients remains a major concern. In this review, we summarize recent findings in ALK+-adenocarcinoma of the lung, highlighting the role of TP53 mutations in this specific cancer type and suggest new diagnostic strategies for the future, in order to improve patient’s outcome. READ ARTICLE

Journal of Thoracic Disease
DOI:10.21037/jtd.2018.12.03

Authors: Christina Alidousty, Till Baar, Carina Heydt, Svenja Wagener-Ryczek, Anna Kron, Juergen Wolf, Reinhard Buettner, Anne Maria Schultheis

Molecular findings reveal possible resistance mechanisms in a patient with ALK-rearranged lung cancer: a case report and literature review

Background: Non-small-cell lung cancer (NSCLC) is recognised as a particularly heterogeneous disease, encompassing a wide spectrum of distinct molecular subtypes. With increased understanding of disease biology and mechanisms of progression, treatment of NSCLC has made remarkable progress in the past two decades. Molecular testing is considered the hallmark for the diagnosis and treatment of NSCLC, with liquid biopsies being more and more often applied in the clinical setting during the recent years. Rearrangement of the ALK gene which results in the generation of fusion oncogenes is a common molecular event in NSCLCs. Among ALK fusion transcripts, EML4-ALK fusion is frequently observed and can be targeted with ALK tyrosine kinase inhibitors (TKI). However, acquired resistance and disease progression in many cases are inevitable. Conclusions: Based on the results, the EML4-ALK fusion initially detected in tumour tissue was preserved throughout the course of the disease. Two additional..... READ ARTICLE

ESMO Open, Cancer Horizons DOI:10.1136/esmoopen-2019-000561

Authors: Anastasia Kougioumtzi, Panagiotis Ntellas, Eirini Papadopoulou, George Nasioulas, Eleftherios Kampletsas, George Pentheroudakis

EML4-ALK TRANSLOCATION IDENTIFICATION IN RNA EXOSOMAL CARGO (EXOALK) IN NSCLC PATIENTS: A NOVEL ROLE FOR LIQUID BIOPSY

The introduction of druggable targets has significantly improved the outcomes of non-small cell lung cancer patients (NSCLC). EML4-ALK translocation represents 4–6% of the druggable alterations in NSCLC. With the approval of Crizotinib, first discovered drug for the EML4-ALK translocation, on first line treatment for patients with detected mutation meant a complete change on the treatment landscape. The current standard method for EML4-ALK identification is immunohistochemistry or FISH in a tumor biopsy. However, a big number of NSCLC patients have not tissue available for analysis and others are not suitable for biopsy due to their physical condition or the location of the tumor. Liquid biopsy seems the best alternative for identification in these patients that have no tissue available. Circulating free RNA has not been validated for the identification of this mutation. As a complementary tool, exosomes might represent a good tool for predictive biomarkers study, and due to their stab..... READ ARTICLE

Translational Cancer Research DOI:10.21037/tcr.2018.11.35

Authors: Reclusa, P. (Pablo), Laes, J.F. (Jean-François), Malapelle, U. (Umberto), Valentino, A. (Anna), Rocco, D. (Danilo), Gil-Bazo, I. (Ignacio), Rolfo, C. (Christian)

Histologic transformation of ALK-rearranged adenocarcinoma to squamous cell carcinoma after treatment with ALK inhibitor

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) treated with ALK tyrosine kinase inhibitor (TKI) eventually acquires resistance to the treatment. However, our current knowledge regarding the resistance mechanisms is based on non-synonymous mutation and amplification in ALK, with the reasons still unknown for nearly half of all such cases. Other than genomic alteration as a resistance mechanism, up to 10% of NSCLC with activating epithelial growth factor receptor (EGFR) mutation showed resistance to EGFR TKI through histologic transformation. Although limited in number, there are cases showing transformed samples retaining the initial genomic alteration, which support lineage transition as a novel resistance mechanism. In this report, we described the first case of squamous cell carcinoma (SCC) transformation from adenocarcinoma (ADC) in NSCLC with ALK rearrangement after treatment with ALK TKI. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2018.11.027

Authors: Sehhoon Park, Joungho Han, Jong-Mu Sun

ALK positive lung cancer identification and targeted drugs evaluation using microscopic hyperspectral imaging technique

It is important to distinguish ALK positive lung cancer from ALK negative lung cancer and to monitor the efficacy of targeted drugs. This paper applies a microscopic hyperspectral imaging technique to identify ALK positive lung cancer cells and evaluate the therapeutic effect. The hyperspectral images of five groups of lung tissues are captured by the home-made microscopic hyperspectral imaging system. A preprocessing algorithm is proposed to reduce obvious banding noise and noise particles from original data. Then a segmentation algorithm, which assembles Supported Vector Machine (SVM) and Majority analysis together with the Clumping processing, is presented. The ALK positive and negative lung cancers can be distinguished by both the fluctuation of spectral curves and the relative proportion between cytoplasm and cell nucleus. In addition, the treatment efficacy can be surveyed in the same way. The experimental results show that the relative proportion of cytoplasm in Group ALK-neg is..... READ ARTICLE

Infrared Physics & Technology DOI:10.1016/j.infrared.2018.12.001

Authors: Jing Song, Menghan Hu, Jiansheng Wang, Mei Zhou, Li Sun, Song Qiu. Qingli Li, Zhen Sun, Yiting Wang

Concomitant resistance mechanisms to multiple tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer

ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next generation TKIs, have demonstrated beneficial clinical outcomes in ALK-positive non-small cell lung cancer (NSCLC). However, resistance mechanisms following multiple TKI treatments in ALK-positive NSCLC are not fully elucidated.
Mutation profiles of 422 cancer-relevant genes in 52 patients with post-TKI biopsy samples were analyzed using next-generation sequencing (NGS), and compared between patients receiving crizotinib alone (n = 35) and multi-TKIs (n = 17).
Concurrent ALK activating mutations and/or upregulated bypass signaling are more enriched in patients undergoing multiple ALK TKI treatments compared to crizotinib alone. Concomitant TP53 mutation correlated to unfavorable survival when receiving a single TKI crizotinib. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2018.11.024

Authors: Yongfeng Yu, Qiuxiang Ou, Xue Wu, Hairong Bao,
Yan Ding, Yang W. Shao, Shun Lu

Activity of Brigatinib in the Setting of Alectinib Resistance Mediated by ALK I1171S in ALK-Rearranged Lung Cancer

Multiple ALK receptor tyrosine kinase (ALK) inhibitors have upended the evidence-based management of advanced NSCLC over the last half decade.1 Crizotinib was the first ALK inhibitor to reach regulatory approval in the first-line management of ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC, and the next-generation ALK inhibitors ceritinib, alectinib, and brigatinib are highly active after intracranial or systemic progression during crizotinib therapy.1 More recently, alectinib improved outcomes in the treatment-naive setting in comparison with crizotinib, and ceritinib was shown to be superior to cytotoxic therapies in the same setting.1 The management of ALK-rearranged tumors that become biologically resistant to next-generation ALK inhibitors continues to be undefined, but knowledge of the mechanism of resistance may allow for sequencing of approved or in-development ALK inhibitors.2, 3, 4, 5 Here, we present what, to the best of our knowledge, is the first reported case..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.06.020

Authors: Kartik Sehgal, Mary Linton B. Peters, Paul A. VanderLaan, Deepa Rangachari, Susumu S. Kobayashi, Daniel B. Costa

Pre-ClinicalKirk SmithJanuary 1, 2019ALK, Brigatinib, Alectinib, ALK I1171S

A Novel CAMKMT Exon3-ALK Exon20 Fusion Variant was Identified in a Primary Pulmonary Mucinous Adenocarcinoma

... Here, we reported a novel calmodulin-lysine N-methyltransferase (CAMKMT)–ALK fusion in a patient with PPMA... This first report of a CAMKMT-ALK fusion expands the spectrum of ALK fusion variants and supports comprehensive genomic profiling in PPMA to optimize therapeutic options. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.09.020

Authors: Xueting Hu, Qiang Cui, Minghui Wang