Clinical Utility of Targeted Sequencing in Lung Cancer: Experience From an Autonomous Swedish Health Care Center

Objectives: Mutation analysis by massive parallel sequencing (MPS) is routinely performed in the clinical management of lung cancer in Sweden. We describe the clinical and mutational profiles of lung cancer patients subjected to the first 1.5 years of treatment predictive MPS testing in an autonomous regional health care region... Conclusion: Although the increasing importance of MPS as a predictor of response to targeted therapies is indisputable, its role in prognostics or as a predictor of clinical course in nontargetable advanced stage lung cancer requires further investigation. READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100013

Authors: Sofi Isaksson, Bassam Hazem, Mats Jönsson, Christel Reuterswärd, Anna Karlsson, Håkan Griph, Jens Engleson, Gudrun Oskarsdottir, Ronny Öhman, Karolina, Holm, Frida Rosengren, Karin Annersten, Göran Jönsson, Åke Borg, Anders Edsjö, Per Levéen, Hans Brunnström, Kajsa Ericson Lindquist, …Maria Planck

Circulating Tumor DNA Analysis for Patients with Oncogene-Addicted NSCLC With Isolated Central Nervous System Progression

Introduction: In patients with oncogene-addicted NSCLC and isolated central nervous system progression (iCNS), tissue biopsy is challenging, and the clinical utility of plasma liquid biopsy (i.e., circulating tumor DNA [ctDNA]) is unknown... Conclusions: Although tagged amplicon-based next-generation sequencing has high detection rates of GA in plasma ctDNA in patients with NSCLC with extra-CNS disease, detection rate of GAs (52%) is lower in the subset of patients with iCNS disease. Complementary tests such as cerebrospinal fluid cell-free DNA may be useful. Further evidence would be beneficial to understand the genomic landscape in patients with NSCLC and iCNS. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.024

Authors: Mihaela Aldea, Lizza Hendriks, Laura Mezquita, Cécile Jovelet, David Planchard, Edouard Auclin, Jordi Remon, Karen Howarth, Jose Carlos Benitez, Anas Gazzah, Pernelle Lavaud, Charles Naltet, Ludovic Lacroix, Frankde Kievit, Clive Morris, Emma Green, Maud Ngo-Camus, Etienne Rouleau, … , Benjamin Besse

Review PaperKirk SmithMarch 1, 2020Liquid biopsy, ctDNA, NSCLC, Brain, Leptomeningeal

Computed Tomography Imaging Features and Distribution of Metastases in ROS1-rearranged Non–Small-cell Lung Cancer

Background: ROS proto-oncogene 1 (ROS1) rearrangements are a known molecular target in non–small-cell lung cancer (NSCLC). Our goal was to determine whether ROS1-rearranged NSCLC has imaging features and patterns of metastasis, which differ from those of anaplastic lymphoma kinase (ALK)-rearranged or epidermal growth factor receptor (EGFR)-mutant NSCLC... Conclusion: Although considerable overlap exists in the imaging features of ROS1-rearranged, ALK-rearranged, and EGFR-mutant NSCLC, we found that ROS1-rearranged NSCLC has certain distinct imaging features and patterns of spread. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.10.006

Authors: Subba R. Digumarthy, Dexter P. Mendoza, Jessica J. Lin, Tianqi Chen, Marguerite M. Rooney, Emily Chin, Lecia V. Sequist, Jochen K. Lennerz, Justin F. Gainor, Alice T. Shaw

Real-World OutcomesKirk SmithMarch 1, 2020ALK, Lung cancer, Radiology, Rearrangement, ROS1

$Complete Response of Primary Refractory ALK-Positive Large B-Cell Lymphoma Treated With Single-Agent Nivolumab$

Complete Response of Primary Refractory ALK-Positive Large B-Cell Lymphoma Treated With Single-Agent Nivolumab

... Here we report a case of relapsed/refractory (R/R) ALK-positive LBCL with a prolonged complete response to single-agent nivolumab... Case Report: Here we report a case of relapsed/refractory (R/R) ALK-positive LBCL with a prolonged complete response to single-agent nivolumab... Conclusion: This is to our knowledge the first report of a complete response in a patient with primary refractory ALK-positive LBCL after treatment with nivolumab. Although recent reports showing low single-agent activity of checkpoint inhibitors in R/R DLBCL have been disappointing, patients with disease exhibiting exceptional response to immunotherapy are still seen and need to be further characterized. New cellular therapies may prove to be effective in these uncommon and aggressive lymphomas... READ ARTICLE

Clinical Lymphoma Myeloma and Leukemia DOI:10.1016/j.clml.2019.08.015

Authors: Jose D. Sandoval-Sus, Amanda Brahim, Alina Khan, Yehuda Deutsch, Barbara Raphael, Ali Ansari-Lari, Hugo F. Fernandez, Luis E. Raez

Case StudyKirk SmithMarch 1, 2020ALK-Positive, Large B-Cell Lymphoma, Nivolumab

Targeted Therapy and Checkpoint Immunotherapy in Lung Cancer

Lung cancer is the leading cause of cancer
mortality. It is classified into different histologic subtypes, including adenocarcinoma, squamous carcinoma, and large cell carcinoma (commonly referred as non–small cell lung cancer) and small cell lung cancer. Comprehensive molecular characterization of lung cancer has expanded our understanding of the cellular origins and molecular pathways affected in each of these subtypes. Many of these genetic alterations represent potential therapeutic targets for which drugs are constantly under development. This article discusses the molecular characteristics of the main lung cancer subtypes and discusses the current guidelines and novel targeted therapies, including checkpoint immunotherapy. READ ARTICLE

Surgical Pathology Clinics DOI:10.1016/j.path.2019.11.002

Authors: Roberto Ruiz-Cordero, Walter Patrick Devine

Catalog of 5’ Fusion Partners in ALK-positive NSCLC Circa 2020

Since the discovery of anaplastic lymphoma kinase fusion-positive (ALK+) NSCLC in 2007, the methods to detect ALK+ NSCLC have evolved and expanded from fluorescence in situ hybridization and immunohistochemistry to next-generation DNA sequencing, targeted RNA sequencing, and whole transcriptome sequencing. As such, the deep sequencing methods have resulted in the expansion of distinct fusion partners identified in ALK+ NSCLC to 90 (one variant PLEKHM2-ALK is found in small cell lung cancer but included in this catalog) by the end of January 2020; about 65 of them (since 2018) and most of the recent novel fusion partners were reported from China. Thirty-four of the distinct fusion partners are located on the short arm of chromosome 2; 28 of these 34 fusion partners are located on 2p21-25, in which ALK is located on 2p23.2-p23.1. Many of these new ALK+ NSCLC fusion variants have responded to ALK tyrosine kinase inhibitors (TKIs). Several of these novel ALK fusion variants were identified..... READ ARTICLE

Journal of Thoracic Oncology, Clinical and research reports DOI:10.1016/j.jtocrr.2020.100015

Authors: Sai-Hong IgnatiusOu, Viola W. Zhu and Misako Nagasaka

First-Line Therapy Using Brigatinib vs Crizotinib in Patients With Advanced Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Results From a Phase 3 Trial

Methods: This open-label, multicenter study enrolled patients with advanced ALK+ NSCLC who had ≤ 1 prior systemic therapy; asymptomatic CNS metastases were allowed. Patients were randomized 1 : 1 to brigatinib 180 mg QD with 7-day lead-in at 90 mg or crizotinib 250 mg BID. Primary endpoint: blinded independent review committee (BIRC)-assessed PFS (RECIST v1.1). Secondary efficacy endpoints included BIRC-assessed ORR, intracranial (i) ORR (iORR), and PFS (iPFS). Interim analyses were planned at 50% and 75% of 198 expected PFS events. Results: 275 patients were randomized (brigatinib/crizotinib, n = 137/138); median age: 58/60 y. 26%/27% received prior chemotherapy for advanced disease; 29%/30% had baseline brain metastases. At data cutoff (19 Feb 2018) for the first interim analysis, median follow-up of brigatinib/crizotinib was 11.0/9.25 mo. With 99 PFS events, brigatinib met the prespecified threshold for statistical superiority vs. crizotinib in the primary endpoint, BIRC-assessed P..... READ ARTICLE

Pneumologie DOI:10.1055/s-0039-3403360

Authors: MJ Hochmair , DR Camidge , HR Kim , MJ Ahn , JCH Yang , J Youn Han , KH Lee , A Delmonte , MR Garcia Campelo , DW Kim , F Griesinger , E Felip , R Califano , A Spira , S Gettinger , M Tiseo , Q Ni , P Zhang , S Popat

Clinical TrialsKirk SmithFebruary 28, 2020ALK, Brigatinib, Crizotinib

Efficacy of Crizotinib, Ceritinib, and Alectinib in ALK-Positive Non-Small Cell Lung Cancer Treatment: A Meta-Analysis of Clinical Trials

This study aimed to evaluate the efficacy of anaplastic lymphoma kinase (ALK)-inhibitors in the treatment of ALK-positive non-small cell lung cancer (NSCLC) by using a meta-analysis of clinical trials. We searched PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov by using keywords related to the topic in August 2018. The pooled effect sizes were calculated based on a random-effects model. We also performed subgroup meta-analysis by types of ALK inhibitors (crizotinib, ceritinib, and alectinib). A total of 20 clinical trials with 10 single-arm trials and 10 double-arm trials were included in the final meta-analysis. The median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), 1 year survival rate, and 2 year survival rate were 19.14 months, 8.47 months, 62%, 78%, 74%, and 62%, respectively. ALK inhibitors showed a significantly superior efficacy compared with chemotherapy (hazard ratio (HR) for OS, 0.83; HR for PFS, 0..... READ ARTICLE

Cancers DOI:10.3390/cancers12030526

Authors: Hoang, T.; Myung, S.-K.; Pham, T.T.; Park, B.

ALK Rearrangement Adenocarcinoma with Histological Transformation to Squamous Cell Carcinoma Resistant to Alectinib and Ceritinib

Specific tyrosine-kinase inhibitors (TKIs) are widely used for the treatment of non-small-cell lung cancers with anaplastic lymphoma kinase (ALK) translocations. However, most treated patients eventually develop resistance to the TKIs. The histological transformation into small cell carcinoma is well known to be the underlying mechanism for acquired resistance; however, transformation to squamous cell carcinoma is extremely rare. We, herein, report a case of ALK rearrangement-positive adenocarcinoma that transformed to squamous cell carcinoma after administration of alectinib, and was found to be resistant to ceritinib. READ ARTICLE

OncoTargets and therapy DOI:10.2147/OTT.S236706

Authors: Kaiho T, Nakajima T, Iwasawa S, Yonemori Y, Yoshino I.

Brain Penetration of Lorlatinib: Cumulative Incidences of CNS and Non-CNS Progression with Lorlatinib in Patients with Previously Treated ALK-Positive Non-Small-Cell Lung Cancer

Lorlatinib is a potent, brain-penetrant, third-generation ALK/ROS1 TKI. We performed an analysis of CNS and non-CNS progression in patients with pretreated ALK+ NSCLC. Our results indicate that lorlatinib is active in the treatment and prevention of CNS metastases in patients with ALK+ NSCLC, including those who had progressed on crizotinib or second-generation TKIs. READ ARTICLE

Targeted Oncology Volume DOI:10.1007/s11523-020-00702-4

Authors: Bauer, T.M., Shaw, A.T., Johnson, M.L. et al.

Clinical TrialsKirk SmithFebruary 14, 2020Lorlatinib, ALK, TKI, progression, CNS metastases

Life-threatening hypertriglyceridemia-induced pancreatitis related to alectinib successfully treated by plasmapheresis: A review of the literature on metabolic toxicities...

Case report A 52-year-old male presented with a right hilar lung mass, and workup revealed a stage IIIA adenocarcinoma. He underwent treatment with concurrent chemoradiation; however, disease recurred one year later with a right hilar mass and contralateral mediastinal lymphadenopathy, biopsy of which resulted positive for adenocarcinoma. Molecular analysis showed anaplastic lymphoma kinase rearrangement and alectinib was started. Six months into therapy, he presented with hematochezia, nausea, and epigastric pain and was diagnosed with acute pancreatitis. Triglyceride level resulted above the measurable level at >5680mg/dL, thought to be the inciting event of pancreatitis. Management and outcome: Despite treatment with intravenous hydration, insulin infusion, and antibiotics, he decompensated with development of respiratory failure, shock requiring intensive care. Therapeutic plasmapheresis was initiated due to persistently elevated triglyceride. Following the third plasmapheresis, t..... READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220904141

Authors: Rao A, Reddy A, Dinunno C, Elali I.

Case StudyKirk SmithFebruary 13, 2020Alectinib, anaplastic lymphoma kinase mutation, pancreatitis, plasmapheresis

Emerging Roles of ALK in Immunity and Insights for Immunotherapy

Anaplastic lymphoma kinase (ALK) is mostly known for its oncogenic role in several human cancers. Recent evidences clearly indicate new roles of ALK and its genetic aberrations (e.g. gene rearrangements and mutations) in immune evasion, innate and cell-mediated immunity. New ALK-related immunotherapy approaches are demonstrating both preclinical and clinical promises. Here, we provide a timely review on the most updated laboratory and patient-related findings on ALK and immunity, which would grant us important insights for the development of novel ALK immunotherapies for ALK-altered cancers. READ ARTICLE

Cancers DOI: 10.3390%2Fcancers12020426

Authors: Lan Wang and Vivian Wai Yan Lui

Review PaperKirk SmithFebruary 12, 2020ALK and aberrations in immunity, immunotherapies

Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1

Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has sufficient clinical efficacy and satisfactory safety in ALK-positive non-small cell lung cancer (NSCLC) patients with or without brain metastasis. Alectinib has now become an important drug in the first-line treatment of advanced ALK-positive NSCLC; however, resistance is almost inevitable. The increased expression of hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been shown to be linked to acquired resistance to various tyrosine kinase inhibitors (TKIs), and this phenomenon has been observed in some ALK-positive NSCLC tumour tissues. In this study, we found that HGF levels in the culture supernatant of an ALK-positive cell line tended to increase with time and could be further increased by alectinib in a time-dependent manner. Exogenous or endogenous HGF did not cause resistance to the ALK/MET double-targeted small molecule inhibitor crizotinib, but it was an im..... READ ARTICLE

Cell Death & Disease DOI:10.1038/s41419-020-2307-5

Authors: Chen, H., Lin, C., Peng, T. et al.

Pre-ClinicalKirk SmithFebruary 10, 2020Metformin, HGF-induced resistance, alectinib, Gab1

Discovery of a putative blood-based protein signature associated with response to ALK tyrosine kinase inhibition

Background ALK tyrosine kinase inhibition has become a mainstay in the clinical management of ALK fusion positive NSCLC patients. Although ALK mutations can reliably predict the likelihood of response to ALK tyrosine kinase inhibitors (TKIs) such as crizotinib, they cannot reliably predict response duration or intrinsic/extrinsic therapeutic resistance. To further refine the application of personalized medicine in this indication, this study aimed to identify prognostic proteomic biomarkers in ALK fusion positive NSCLC patients to crizotinib. Results Patients were categorized by duration of response: long-term responders [PFS ≥ 24 months (n = 7)], normal responders [3 < PFS < 24 months (n = 10)] and poor responders [PFS ≤ 3 months (n = 5)]. Several proteins were identified as differentially expressed between long-term responders and poor responders, including DPP4, KIT and LUM. Next, using machine learning algorithms, we evaluated the classification potential of 40 proteins. Finally, b..... READ ARTICLE

Clinical Proteomics DOI:10.1186/s12014-020-9269-6

Authors: Couëtoux du Tertre, M., Marques, M., McNamara, S. et al.

Clinical TrialsKirk SmithFebruary 7, 2020Protein signature, Crizotinib, Liquid biopsy, NSCLC, Prediction of response

B07 Mechanisms of Alectinib Resistance in a Leptomeningeal Carcinomatosis of EML4-ALK Lung Cancer and Its Circumvention by EGR-TKIs

... This study aimed to clarify the mechanism of resistance to alectinib in LMC and seek a novel therapeutic strategy... Our findings may provide rationale for clinical trials to investigate the effects of novel therapies dual-targeting ALK and EGFR in ALK-rearranged NSCLC with alectinib-resistant LMC. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.12.076

Authors: S. Yano, S. Arai, K. Fukuda, S. Takeuchi

Case StudyKirk SmithFebruary 1, 2020Alectinib, Leptomeningeal Carcinomatosis, EML4-ALK, Lung Cancer, EGR-TKIs

Tumor-educated platelet as liquid biopsy in lung cancer patients

Lung cancer is the most frequent cancer for males and third most frequent cancer for females. Targeted therapy drugs based on molecular alterations, such as angiogenesis inhibitors, epidermal growth factor receptor (EGFR) inhibitors, and anaplastic lymphoma kinase (ALK) inhibitors are important part of treatment of NSCLC. However, the quality of the available tumor biopsy and/or cytology material is sometimes not adequate to perform the necessary molecular testing, which has prompted the search for alternatives. This review examines the use of tumor-educated platelet (TEP) as a liquid biopsy in lung cancer patients. The development of sensitive and accurate techniques have made it possible to detect the specific genetic alterations for which targeted therapies are already available. Liquid biopsy offers opportunities to detect resistance mechanisms at an early stage. To conclude, tumor-educated platelet has the potential to be used as liquid biopsy for a variety of clinical and investigational applications. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI:10.1016/j.critrevonc.2020.102863

Authors: Lian Liua, Fang Lin, Xiaoting Ma, Zhaoxin Chen, Jing Yu

EditorialKirk SmithFebruary 1, 2020Tumor educated platelets, Liquid biopsy, Lung cancer, Methodologies

Drug resistance to targeted therapeutic strategies in non-small cell lung cancer

Rapidly developing molecular biology techniques have been employed to identify cancer driver genes in specimens from patients with non-small cell lung cancer (NSCLC). Inhibitors and antibodies that specifically target driver gene-mediated signaling pathways to suppress tumor growth and progression are expected to extend the survival time and further improve the quality of life of patients. However, the health of patients with advanced and metastatic NSCLC presents significant challenges due to treatment resistance, mediated by cancer driver gene alteration, epigenetic alteration, and tumor heterogeneity. In this review, we discuss two different resistance mechanisms in NSCLC targeted therapies, namely changes in the targeted oncogenes (on-target resistance) and changes in other related signaling pathways (off-target resistance) in tumor cells. We highlight the conventional mechanisms of drug resistance elicited by the complex heterogeneous microenvironment of NSCLC during targeted ther..... READ ARTICLE

Pharmacology & Therapeutics DOI:10.1016/j.pharmthera.2019.107438

Authors: Wen-juan Liu, Yue Du, Ru Wen, Ming Yang, JianXu

Multiplex fluorescence in situ hybridisation to detect anaplastic lymphoma kinase and ROS proto-oncogene 1 receptor tyrosine kinase rearrangements in lung cancer cytological samples

Aims: Several predictive biomarkers of response to specific inhibitors have become mandatory for the therapeutic choice in non-small-cell lung cancer (NSCLC). In most lung cancer patients, the biological materials available to morphological and molecular diagnosis are exclusively cytological samples and minimum tumour wastage is necessary. Multiplex fluorescence in situ hybridisation (mFISH) to detect simultaneously ALK-rearrangement and ROS1-rearrangement on a single slide could be useful in clinical practice to save cytological samples for further molecular analysis. In this study, we aim to validate diagnostic performance of multiplex ALK/ROS1 fluorescence in situ hybridisation (FISH) approach in lung adenocarcinoma cytological series compared with classic single break apart probes. Conclusion: Multiplex ALK/ROS1 FISH probe test is a useful tool to detect simultaneously ALK-rearrangement and ROS1-rearrangement on a single slide in cytological specimens with a small amount of biomaterial. READ ARTICLE

Clinical Pathology DOI:10.1136/jclinpath-2019-206152

Authors: Federica Zito Marino, Giulio Rossi, Immacolata Cozzolino, Marco Montella, Mariacarolina Micheli, Giuseppe Bogina, Enrico Munari, Matteo Brunelli, Renato Franco

Keratinocytes apoptosis contributes to crizotinib induced-erythroderma

Crizotinib is a multi-target receptor tyrosine kinase inhibitor which is of great importance for the management of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Serious erythroderma and toxic epidermal necrolysis have been reported associated with crizotinib treatment. The underlying mechanisms have not been examined. In this study, we tested the toxicity of crizotinib on immortal human keratinocytes (HaCaT) and human primary keratinocytes. We found that crizotinib directly cause cytotoxic on these two cells, which could be the explanation of the clinical characteristic of pathology. Apoptosis was observed and Z-VAD-FMK, a pan-caspase inhibitor can almost totally reverse the apoptosis induction effect of crizotinib. However, mitochondrial dysfunction and DNA damage were not involved in crizotinib-induced apoptosis, indicating the intrinsic apoptosis pathway have no connection with this cutaneous toxicity. Further studies showed that crizotinib significantly increased clea..... READ ARTICLE

Toxicology Letters DOI:10.1016/j.toxlet.2019.11.007

Authors: Yuhuai Hu, Xiaochen Zhang, Ziying Zhao, Xueqin Chen, Ziye Zhou, Xiaochun Yang, Bo Yang, Qiaojun He, Peihua Luo

Review PaperKirk SmithFebruary 1, 2020Crizotinib, Cutaneous, toxicity, Erythroderma, Apoptosis, Cleaved-caspase-8

B01 Active YAP as a Functional Marker of Drug-Tolerant Persister Cells in EGFR-Mutant and ALK Fusion-Positive NSCLC

... Using RNA sequencing, we show a clear evolutionary path from drug-sensitive parental cells to drug-tolerant persisters and long-term derived drug-acquired resistant cells. We are currently profiling vulnerabilities of drug-tolerant EGFR-mutant and EML4-ALK fusion persisters using genetic and pharmacologic approaches. In conclusion, YAP activation is a functional marker of EGFR-mutant and EML4-ALK fusion persisters derived under high-dose drug treatment with third-generation TKIs. Targeting YAP activation either on the level of upstream signaling input, its relocalization between cytoplasm and nucleus, or its action as transcriptional coactivator may represent a promising combinatorial treatment approach to limit resistance development and improve patient survival in lung adenocarcinoma. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.12.070

Authors: F. Haderk, C. Fernández-Méndez, K. N. Shah, W. Wu, J. Guan, J. Rotow, D. Allegakoen, V. Olivas, S. Bandyopadhyay, C. Kuo, T. Bivona