P109-32 Concurrent Genomic Alterations in ALK-Rearranged Non-Small Cell Lung Cancer Patients

Background: Recent progress in genomic analysis using next-generation sequencing (NGS) has enabled the comprehensive detection of targetable alterations in non-small cell lung cancer (NSCLC) patients. As the detection of ALK gene fusions is being established by NGS, identification of concurrent alterations will lead to better characterization of the molecular landscape of ALK-rearranged patients. Conclusion: We have studied the presence of ALK fusion genes with a novel NGS panel that showed excellent correlation with standard techniques. ALK fusions can be interpreted as early strong drivers to carcinogenesis due to the low frequency of concurrent alterations. It remains to determine the clinical impact of these alterations in larger series. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1061

Authors: S. Clavé, M. Salido, J. Gibert, M. Hardy-Werbin, E. Weingartner, J. Hernandez, D. Nichol, P. Rocha, X. Riera, R. Blanco, J. Bosch-Barrera, Á. Taus, L. Pijuan, B. Bellosillo, E. Arriola

P114-47 ctDNA NGS for Guiding Crizotinib Treatment in ALK-Rearranged Advanced NSCLC Patients (Pts)

Background: FISH and IHC are commonly used and the golden standard for testing ALK rearrangement. However, they provide no information on fusion types or mutation status of other genes, which could be important prognostic factors. In addition, a tissue biopsy is not always applicable/preferred by pts. Conclusion: Information on ALK fusion types, concomitant mutations, and mutation frequencies provided by NGS could be valuable prognostic factors and deserves further investigation. ctDNA NGS could be used as an effective alternative to identify ALK+ pts, especially for elderly pts, when tissue biopsy is inapplicable or not preferred. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1198

Authors: Y. He, J. Zhao, C. Liu, R. Chen, X. Xia

Conference PaperKirk SmithOctober 1, 2019ALK, crizotinib, ctDNA

OA0206 The Sequential Therapy of Crizotinib Followed by Alectinib: Real World Data of 840 Patients with NSCLC Harboring ALK-Rearrangement (WJOG9516L)

Previous clinical trials demonstrated that alectinib (ALEC) had a longer time-to-progression than crizotinib (CRZ) in 1st-line settings. Information on long-term overall survival (OS), however, is still limited with a few studies having reported that the sequential strategy of “CRZ followed by other ALK-inhibitor” can provide extended OS. In Japan, ALEC was approved for a 1st-line setting earlier than in other countries.We reviewed the clinical data of ALK-rearranged NSCLC patients who received CRZ or ALEC between May 2012 and Dec 2016. Patients were divided into two groups according to the first-administered ALK inhibitor, the CRZ or ALEC group. In order to evaluate the efficacy of the sequential strategy of “CRZ followed by ALEC”, the combined time to treatment failure (TTF) was calculated in the CRZ group as defined by the sum of the “TTF of CRZ” plus the “TTF of ALEC” if patients were treated with ALEC followed by CRZ. In the ALEC group, the “TTF of ALEC” was calculated. The primar..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.415

Authors: S. Watanabe, T. Yamanaka, K. Ito, S. Sakata, H. Daga, T. Kijima, K. Hirano, I. Okamoto, A. Nakamura, T. Kozuki, M. Ishihara, K. Azuma, T. Seto, T. Yokoyama, Y. Oya, H. Kobayashi, K. Nishino, Y. Hattori, K. Nakagawa, N. Yamamoto

P214-38 ATAD2B-ALK, a Novel Fusion in Lung Adenocarcinoma Identified Using Next-Generation Sequencing (NGS)

Background: Anaplastic lymphoma kinase (ALK) rearrangements is an important molecular subtype of non-small cell lung cancer (NSCLC), and patients with this variant are sensitive to ALK inhibitors. Since the discovery of the EML4-ALK fusion ten years ago, several fusion partners of ALK in NSCLC have been reported, including KIF5B, KLC1, HIP1, TPR and so on. According to previous reports, different fusion partner lead to various function and activity of the fusion product. Here, we identified a novel fusion partner for ALK in a lung adenocarcinoma patient. Conclusion: The novel ALK fusion gene probably served as oncogenic driver of the patient’s tumor. This case is the first report of ATAD2B-ALK fusion in clinical tumor samples and could provide a new diagnostic and therapeutic candidate target for patients with lung cancer. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1823

Authors: H. Bai, W. Jia, X. Jin, H. Mao, D. Wu, R. Chen, X. Xia, H. Wu

Conference PaperKirk SmithOctober 1, 2019ALK, ATAD2B, ALK rearrangement, NGS, lung adenocarcinoma

OA0207 Phase 3 ALUR Study of Alectinib in Pretreated ALK+ NSCLC: Final Efficacy, Safety and Targeted Genomic Sequencing Analyses

The ALUR (NCT02604342) primary analysis (cut-off January 2017) demonstrated improved efficacy and safety with alectinib versus chemotherapy in patients with ALK+ NSCLC previously treated with chemotherapy and crizotinib. These patients can develop crizotinib resistance through ALK secondary mutations, but limited data exist regarding alectinib’s efficacy in patients with different post-crizotinib genetic profiles. We report final data from ALUR including treatment outcomes according to genetic profile. Overall, 119 patients with locally determined ALK+ NSCLC were randomised 2:1 to receive alectinib 600mg bid or chemotherapy (pemetrexed 500mg/m2 or docetaxel 75mg/m2 q3w). The primary endpoint was PFS by investigator. Targeted genomic sequencing (FoundationONE® [tissue; 315 genes] and FoundationACT® [plasma; 62 genes]) was performed retrospectively using tumour tissue (n=33) and baseline plasma (n=59). Final data from ALUR confirm the primary analysis, demonstrating improved efficacy and..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.416

Authors: J. Wolf, Å. Helland, I. Oh, M.R. Migliorino, R. Dziadziuszko, J. De Castro Carpeno, J. Mazieres, F. Griesinger, M. Chlistalla, A. Cardona, T. Ruf, K. Trunzer, V. Smoljanovic, S. Novello

Clinical TrialsKirk SmithOctober 1, 2019ALUR, alectinib, chemotherapy, ALK+ NSCLC, crizotinib

EP109-17 Spanish Lung Cancer Biomarker Testing Registry (Lungpath): Descriptive Analysis Focus in ALK Traslocation Results

Biomarker testing on pathology specimens is an essential requirement to properly treat lung cancer (LC) patients. LungPath is an on-line tool developed by the Spanish Society of Pathology (SEAP) with free and voluntary participation of differents Departments of Pathology to registry, monitor and trace biomarker results in clinical practice. After initial data reclutation step, first objective is to realize a descriptive analysis of LungPath focusing on ALK traslocation testing. Descriptive analysis of the LungPath registry. Biomarkers determinations of LC patients were collected from March 2018 to January 2019, from 38 Spanish Departments of Pathology. Development of central biomarker databases, such as Lungpath, provide an opportunity to registry clinical practice data and in the future could be an useful tool to monitor, correlate results between different centers and improve the available knowledge regarding biomarkers in LC. According the international guidelines, EGFR mutation and..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2213

Authors: J. Martin Lopez, L. Aduz Alexandre, S. Gatius Caldero, A. Navarro Gonzales, P. Saiz Lopez, C. Gomez Bellvert,, C. Camacho García, L. Melgar, E. Costa Navarro, I. Abdulkader Nallib, C.A. Vasquez Dongo, M. Saiz Camin, A. Yagüe Hernando, L. Atienza Cuevas, L. Pijuan, T. Hernández Iglesias, A. Martinez Pozo, C. Salas Anton

Conference PaperKirk SmithOctober 1, 2019ALK, Targeted therapy, Biomarker

EP101-26 Non-Small Cellular Pulmon Cancer ALK Positive in Pediatrics

This case report is from a 14-year-old adolescent patient treated in our institution with an ALK inhibitor. ALK disease is 3% to 5% of all non-cell lung cancers small adenocarcinoma type, more frequent in young people, women, nonsmokers, and with advanced disease.Male patient 14 years with respiratory symptoms productive cough. Tomography computed tomography: injury to the middle lobe and right lower lobe, biopsy: Adenocarcinoma poorly differentiated, immunohistochemistry: positive for cytokeratin 7, napsin-a, MUC-1, CK1E1 / AE3 positive and transcription factor -1 (TTF-1) and cytokeratin 20 negative, EGFR-KRAS wild type, ALK (EML-4 with clone D5F3) positive. Treatment was started with Crizotinib 250mg every 12 hours, obtaining partial response and with PFS of 36 months, gastrointestinal toxicity, hematological I grade.We report the experience of a case with excellent tolerability to an inhibitor of ALK, and its clinical benefit, (partial response and stable disease). Patients under 18..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1985

Authors: L. Ramirez, A. Guerrero Villota, J. Herrera Parga. M. Velasco, J. Lòpez

Case StudyKirk SmithOctober 1, 2019ALK, pediatric, gastrointestinal, toxicity, tolerability, Colombia

EP108-07 Correlation Between Genetic Profiling and Response in Danish ALK-Positive NSCLC Patients Treated with Crizotinib

In 2011 Crizotinib received FDA approval for the treatment of ALK-positive NSCLC. Due to large diversity in clinical course of these patients, baseline genomic profiling at diagnostic biopsy was performed to find possible correlations with clinical features. We performed a retrospective analysis of 28 consecutive patients receiving Crizotinib for metastatic, immunohistochemistry (IHC)- and fluorescens in-situ hybridization (FISH)-determined ALK-positive NSCLC, between September 2011 and DATE. Clinical data were collected by chart review. DNA/RNA genomic profile were performed using the patients’ biopsy at the time of diagnosis or at initiation of therapy using targeted next-generation sequencing (NGS) Oncomine™ Focus (ThermoFisher Scientific) and Archer® Solid Tumor (ArcherDx) assays. Baseline clinical features and genetic information were correlated with overall survival and progression free survival. Although this small cohort does not allow to draw unambiguous conclusions, it does i..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.2196

Authors: L. Melchior, E. Santoni Rugiu, J. Sørensen, J. Bjerregaard, E. Urbanska

Kirk SmithOctober 1, 2019ALK positive NSCLC, DNA-NGS, RNA-NGS

Dr. Shaw: ALK-positive Lung Cancer Presentation

Keynote speaker Dr. Shaw at the 2019 ALK Positive Summit in Atlanta Georgia. She is the top ALK-positive expert. WATCH VIDEO

ALK Positive Inc.

Authors: Dr. Alice Shaw

VideoKirk SmithSeptember 29, 2019

Straight from the Doctors: ALK-positive Community Research Panel.

Our ALK-positive experts speak on this panel at the 2019 ALK Positive Summit. From left to right: Board member Colin Barton, Dr. Amy Moore, Dr. Upal Basu Roy, Dr. Vincent Lam, Dr. Christine Lovely WATCH VIDEO

ALK Positive Inc.

Authors: Colin Barton, Dr. Amy Moore, Dr. Upal Basu Roy, Dr. Vincent Lam, Dr. Christine Lovely

VideoKirk SmithSeptember 27, 2019ALK summit 2019

The Impact of Clinical Factors, ALK Fusion Variants, and BIM Polymorphism on Crizotinib-Treated Advanced EML4–ALK Rearranged Non-small Cell Lung Cancer

Patients' clinical factors and genetics factors such as anaplastic lymphoma kinase (ALK) fusion variants and BIM (Bcl-2-like 11) polymorphism were reported to be associated with clinical outcome in crizotinib-treated advanced non-small cell lung cancer (NSCLC). However, the results were still controversial. We analyzed outcome of 54 patients with known ALK fusion variants who received crizotinib for advanced NSCLC. Thirty of them had successful BIM polymorphism analysis and 6 (20%) had a BIM deletion. Multivariate Cox regression analysis found that previous anticancer therapy [adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI), 1.04–1.76 for each additional line of therapy, p = 0.025] and Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (aHR 8.35, 95% CI, 1.52–45.94, p = 0.015) were independent factors for progression-free survival (PFS). Only ECOG performance status ≥2 (aHR 7.20, 95% CI, 1.27–40.79, p = 0.026) was an independent factor for overall survival (..... READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2019.00880

Authors: Yen-Ting Lin, Yi-Nan Liu, Jin-Yuan Shih

Case StudyKirk SmithSeptember 23, 2019Non-small cell lung cancer, ALK, ALK variant, BIM, crizotinib

Prospective detection of mutations in cerebrospinal fluid, pleural effusion, and ascites of advanced cancer patients to guide treatment decisions

Many advanced cases of cancer show central nervous system, pleural, or peritoneal involvement. In this study, we prospectively analyzed if cerebrospinal fluid (CSF), pleural effusion (PE), and/or ascites (ASC) can be used to detect driver mutations and guide treatment decisions. We collected 42 CSF, PE, and ASC samples from advanced non-small-cell lung cancer and melanoma patients. Cell-free DNA (cfDNA) was purified and driver mutations analyzed and quantified by PNA-Q-PCR or next-generation sequencing. All 42 fluid samples were evaluable; clinically relevant mutations were detected in 41 (97.6%). Twenty-three fluids had paired blood samples, 22 were mutation positive in fluid but only 14 in blood, and the abundance of the mutant alleles was significantly higher in fluids. Of the 34 fluids obtained at progression to different therapies, EGFR resistance mutations were detected in nine and ALK acquired mutations in two. The results of testing of CSF, PE, and ASC were used to guide treatm..... READ ARTICLE

Molecular Oncology DOI:10.1002/1878-0261.12574

Authors: Sergio Villatoro, Clara Mayo-de-las-Casas, Núria Jordana-Ariza, Santiago Viteri-Ramírez, Mónica Garzón-Ibañez, Irene Moya-Horno, Beatriz García-Peláez, María González-Cao, Umberto Malapelle, Ariadna Balada-Bel, Alejandro Martínez-Bueno, Raquel Campos, Noemí Reguart, Margarita Majem, Remei Blanco, Ana Blasco, María J. Catalán, Xavier González, Giancarlo Troncone, Niki Karachaliou, Rafael Rosell, Miguel A. Molina-Vila

Serial liquid biopsies for detection of treatment failure and profiling of resistance mechanisms in KLC1–ALK-rearranged lung cancer

Genetic rearrangements involving the anaplastic lymphoma kinase (ALK) gene confer sensitivity to ALK tyrosine kinase inhibitors (TKIs) and superior outcome in non-small-cell lung cancer (NSCLC). However, clinical courses vary widely, and recent studies suggest that molecular profiling of ALK+ NSCLC can provide additional predictors of therapy response that could assist further individualization of patient management. In summary, our findings illustrate the utility of noninvasive longitudinal molecular profiling for assessing remission status, exploring mechanisms of treatment failure, predicting subsequent clinical course, and dissecting dynamics of drug-resistant clones in ALK+ lung cancer. READ ARTICLE

Cold Spring Harbor Molecular Case Studies DOI:10.1101/mcs.a004630

Authors: Steffen Dietz, Petros Christopoulos, Lisa Gu, Anna-Lena Volckmar, Volker Endris, Zhao Yuan, Simon J. Ogrodnik, Tomasz Zemojtel, Claus-Peter Heussel, Marc A. Schneider, Michael Meister, Thomas Muley, Martin Reck, Matthias Schlesner, Michael Thomas, Albrecht Stenzinger, Holger Sültmann

Case StudyKirk SmithSeptember 4, 2019Lung adenocarcinoma

Available Therapies for ALK-Rearranged NSCLC

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

VideoKirk SmithSeptember 4, 2019

Next-generation Sequencing Identified a Novel WDPCP-ALK Fusion Sensitive to Crizotinib in Lung Adenocarcinoma

Anaplastic lymphoma kinase (ALK) fusion has been identified in 3% to 7% of patients with non–small-cell lung cancer (NSCLC), and such patients benefit greatly from ALK tyrosine kinase inhibitors (ALK-TKIs). The most common ALK fusion is echinoderm microtubule-associated protein-like 4 (EML4)-ALK, and several variants that are generally sensitive to crizotinib exist.1 In recent years, other fusion types sensitive to crizotinib, such as DYSF&ITGAV-ALK, BCL11A-ALK, and BIRC6-ALK, have been discovered by next-generation sequencing (NGS).2, 3, 4, 5, 6 However, a WD (Trp-Asp) planar cell polarity (PCP) effector gene (WDPCP)-ALK fusion has not been previously published. Here, we report this novel WDPCP-ALK fusion, which is sensitive to crizotinib, in a patient with lung adenocarcinoma. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.06.001

Authors: Zhen He, Xuan Wu, Shuxiang Ma, Cuicui Zhang, Zhe Zhang, Shuai Wang, Sheng Yu, Qiming Wang

Case StudyKirk SmithSeptember 1, 2019C1156Y, Crizotinib, Next-generation sequencing, Sensitivity, WDPCP-ALK

Response to Crizotinib Re-administration After Progression on Lorlatinib in a Patient With ALK-rearranged Non–small-cell Lung Cancer

Introduction: Chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene are detected in approximately 5% of non–small-cell lung cancers (NSCLCs) and function as oncogenic driver genes.1 First- and second-generation ALK-tyrosine kinase inhibitors (TKIs) were developed and showed clinical response for ALK-rearranged NSCLC.2, 3, 4 However, resistance to those ALK-TKIs almost develops, resulting in clinical relapse.5, 6 Lorlatinib is a third-generation ALK-TKI and has demonstrated significant antitumor activity against ALK-rearranged NSCLC with previous ALK-TKI resistance.7, 8 Although lorlatinib response was observed, relapse on lorlatinib ultimately developed.9, 10, 11 Mechanisms of lorlatinib resistance were reported,9, 10, 11 but remained unknown. Moreover, post-lorlatinib treatment has not been determined. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.06.021

Authors: Jun Sakakibara-Konishi, Hidenori Kitai, Yasuyuki Ikezawa, Yutaka Hatanaka, Takaaki Sasaki, Ryohei Yoshida, Shinichi Chiba, Shingo Matsumoto, Koichi Goto, Hidenori Mizugaki, Naofumi Shinagawa

Case StudyKirk SmithSeptember 1, 2019ALK-TKI, MET, Mutation, NGS, Sequential treatment

Management of CNS disease in ALK-positive non-small cell lung cancer: Is whole brain radiotherapy still needed?

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and ..... READ ARTICLE

Cancer/Radiothérapie DOI:10.1016/j.canrad.2019.03.009

Authors: A. Wrona

Inflammatory myofibroblastic tumor of bone harboring an ALK gene amplification

Inflammatory myofibroblastic tumor (IMT) is a neoplastic proliferation of myofibroblastic/fibroblastic cells with a variable admixture of inflammatory cells. It primarily affects soft tissue and viscera of children and young adults. IMT occurring in bone is extremely rare. Approximately 50% of IMTs carry a clonal rearrangement of the anaplastic lymphoma kinase (ALK) gene, while other receptor tyrosine kinase gene rearrangements have been seen in a small subset of IMT. Herein, we report the first case of IMT which harbors an ALK gene amplification rather than a rearrangement thus resulting in overexpression of the protein, arising from the femur of a 24-year-old man. Our case provides a novel pathogenesis for IMT. An overview of cytogenetic abnormalities of IMT is also integrated into this report. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2019.152535

Authors: Kai Wang, Rongjun Guo, Gene P. Siegal, Shi Wei

Clinical significance of ROS1 5’ deletions in non-small cell lung cancer

Objectives: Patients harboring rearrangements of the ROS1 gene are eligible for first-line therapy with Crizotinib, which represents the best available treatment option. Diagnostic criteria, based on break-apart fluorescence in situ hybridization, were mirrored from ALK by analogy and include tumors with 5' deletions. However, the probability of response to Crizotinib in patients with 5' deletion in ROS1 is unknown given the rarity of this condition. Conclusion: 5' ROS1 deletions detected by FISH are associated with a high chance of response to Crizotinib in NSCLC, similarly to canonical ROS1 split-apart FISH rearrangements. However, the confirmation of the ROS1 gene fusion with at least another method, such as NGS, seems beneficial in order to define the ROS1 fusion partner and to avoid possible false positive results. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.07.017

Authors: Elisa Capizzi, Filippo Gustavo, Dall’Olio, Elisa Gruppioni, Francesca Sperandi, Annalisa Altimari, Francesca Giunchi, Michelangelo Fiorentino, Andrea Ardizzoni

Case StudyKirk SmithSeptember 1, 2019Non-small cell lung cancer, ROS1 fusions, ROS1 deletions, FISH, NGS, Crizotinib

A Novel Intergenic Region between CENPA and DPYSL5-ALK Exon 20 Fusion Variant Responding to Crizotinib Treatment in a Patient with Lung Adenocarcinoma

Herein, we report a novel intergenic region between centromere protein A gene (CENPA) and dihydropyridiminase like 5 (DPYSL5)-ALK fusion in a patient with lung adenocarcinoma... To our knowledge, the shortcoming of traditional FISH and IHC was that the precise ALK fusion variants could not be identified, and the application of next-generation sequencing might be used as an optional and supplementary method. Because this patient received a remarkable tumor response after crizotinib therapy, our case report has expanded the spectrum of ALK fusion and provided useful information for precise ALK inhibitor administration in the future. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.04.012

Authors: Xiaodong Fei, Liqun Zhu, Hongxuan Zhou, Chuang Qi, Chun Wang