Short communication: The activity of brigatinib in patients with disease progression after next generation anaplastic lymphoma tyrosine kinase inhibitors...

Highlights:
- Brigatinib demonstrated activity in patients with disease progression after next-generation anaplastic lymphoma (ALK) tyrosine kinase inhibitors (TKI’s).
- The objective response was similar in patients who received next generation ALK inhibitors as first-line or second line therapy, and patients with and without brain metastases at baseline.
- Circulating tumor DNA testing (ctDNA) for ALK resistance mutations is feasible; however, a number of patients did not have detectable ctDNA or an ALK resistance mutations. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.12.019

Authors: Thomas E. Stinchcombe, Xiaofei Wang, Robert C. Doebele, Leylah M. Drusbosky, David E. Gerber, Leora Horn, Erin M. Bertino, Geoff Liu, Liza C. Villaruz, D. Ross Camidge

Clinical TrialsKirk SmithJanuary 3, 2022Targeted therapy, biomarker, ctDNA, liquid biopsy

New Advances in Liquid Biopsy Technologies for Anaplastic Lymphoma Kinase (ALK)—Positive Cancer

A new methodology of cancer testing, called “liquid biopsy”, has been under investigation in the past few years. It is based on blood tests that can be analyzed by novel genetics and bioinformatics tools, in order to detect cancer, predict or follow the response to therapies and understand the mechanisms of relapse. This technology is still experimental, yet it has sparked much interest within the scientific community because it promises a new era of cancer management. We here review its application in a subset of tumors characterized by the presence of the ALK oncogene: patients affected by these tumors can benefit from targeted therapy, but show frequent relapses, which call for improved methods of disease detection.
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Cancers DOI:10.3390/cancers13205149

Authors: Villa, Matteo, Geeta G. Sharma, Chiara Manfroni, Diego Cortinovis, and Luca Mologni

Review Paper, group2Kirk SmithOctober 14, 2021ALK, lung cancer, liquid biopsy

Lung Cancer Stem Cells—Origin, Diagnostic Techniques and Perspective for Therapies

Lung cancer is still a serious oncological problem worldwide. Thus, the biology of this cancer is of interest. Cancer stem cells (CSCs) are involved in tumor initiation and progression. Spontaneously occurring mutations accumulate in stem cells or/and progenitor cells throughout a person’s lifetime resulting in the formation of CSCs. In this review, we discuss the CSC hypothesis with an emphasis on age-associated changes that govern carcinogenesis. The evidence from the scientific literature, as well as our own results and observations, has been presented. READ ARTICLE

Cancers DOI: 10.3390/cancers13122996

Authors: Agata Raniszewska, Iwona Kwiecie, Elzbieta Rutkowska, Piotr Rzepecki and Joanna Domagała-Kulawik

Review Paper, group5Kirk SmithJune 15, 2021NSCLC, cancer stem cells, liquid biopsy, immunotherapy, aging, biopsy

Earlier extracranial progression and shorter survival in ALK-rearranged lung cancer with positive liquid rebiopsies

Background: Liquid rebiopsies can detect resistance mutations to guide therapy of anaplastic lymphoma kinase-rearranged (ALK+) non-small-cell lung cancer (NSCLC) failing tyrosine kinase inhibitors (TKI). Here, we analyze how their results relate to the anatomical pattern of disease progression and patient outcome. Conclusions: Positive blood-based liquid rebiopsies in ALK+ NSCLC characterize biologically more aggressive disease and are common with extracranial, but rare with CNS-only progression or benign radiologic changes. These results reconcile the increased detection of ALK resistance mutations with other features of the high-risk EML4-ALK V3-associated phenotype. Conversely, most oligoprogressive patients with negative liquid biopsies have a more indolent course without need for early change of systemic treatment. READ ARTICLE

Transl Lung Cancer Research DOI:10.21037/tlcr-21-32

Authors: Petros Christopoulos, Steffen Dietz, Arlou K. Angeles, Stephan Rheinheimer, Daniel Kazdal, Anna-Lena Volckmar, Florian Janke, Volker Endris, Michael Meister, Mark Kriegsmann, Thomasz Zemojtel, Martin Reck, Albrecht Stenzinger, Michael Thomas, Holger Sültmann

Clinical Relevance of an Amplicon-Based Liquid Biopsy for Detecting ALK and ROS1 Fusion and Resistance Mutations in Patients With Non–Small-Cell Lung Cancer

PURPOSE Liquid biopsy specimen genomic profiling is integrated in non–small-cell lung cancer (NSCLC) guidelines; however, data on the clinical relevance for ALK/ROS1 alterations are scarce. We evaluated the clinical utility of a targeted amplicon-based assay in a large prospective cohort of patients with ALK/ROS1-positive NSCLC and its impact on outcomes. CONCLUSION Next-generation, targeted, amplicon-based sequencing for liquid biopsy specimen profiling provides clinically relevant detection of ALK/ROS1 fusions in TKI-naïve patients and allows for the identification of resistance mutations in patients treated with TKIs. Liquid biopsy specimens from patients treated with TKIs may affect clinical outcomes and capture heterogeneity of TKI resistance, supporting their role in selecting sequential therapy. READ ARTICLE

JCO Precision Oncology DOI:10.1200/PO.19.00281

Authors: Laura Mezquita, Aurélie Swalduz, Cécile Jovelet, Sandra Ortiz-Cuaran, Karen Howarth, David Planchard, Virginie Avrillon, Gonzalo Recondo, Solène Marteau, Jose Carlos Benitez, Frank De Kievit, Vincent Plagnol, Ludovic Lacroix, Luc Odier, Etienne Rouleau, Pierre Fournel, Caroline Caramella, Claire Tissot, Julien Adam, Samuel Woodhouse, Claudio Nicotra, Edouard Auclin, Jordi Remon, Clive Morris, Emma Green, Christophe Massard, Maurice Pérol, Luc Friboulet, Benjamin Besse, and Pierre Saintigny

Real-World OutcomesKirk SmithApril 2, 2021Next-generation sequencing, liquid biopsy, ALK, ROS1, resistance

Detecting Resistance to Therapeutic ALK Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a Clinical Routine Practice

The survival of most patients with advanced stage non-small cell lung cancer is prolonged by several months when they are treated with first- and next-generation inhibitors targeting ALK rearrangements, but resistance inevitably emerges. Some of the mechanisms of resistance are sensitive to novel ALK inhibitors but after an initial tumor response, more or less long-term resistance sets in. Therefore, to adapt treatment it is necessary to repeat biological sampling over time to look for different mechanisms of resistance. To this aim it is essential to obtain liquid and/or tissue biopsies to detect therapeutic targets, in particular for the analysis of different genomic alterations. This review discusses the mechanisms of resistance to therapeutics targeting genomic alterations in ALK as well as the advantages and the limitations of liquid biopsies for their identification. READ ARTICLE

Cells DOI:10.3390/cells10010168

Authors: Paul Hofman

Review PaperKirk SmithJanuary 15, 2021liquid biopsy, lung cancer, ALK, resistance, targeted therapy

The role of plasma genotyping in ALK- and ROS1-rearranged lung cancer

Review discusses technical aspects of plasma genotyping strategies and summarize findings from studies exploring plasma genotyping (including ctDNA analysis and profiling of nucleic acids contained in other plasma components) in two rearrangement-driven NSCLC subsets (ALK-rearranged and ROS1-rearranged). READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-2019-cnsclc-09

Authors: Dagogo-Jack I, Ritterhouse LL.

Review PaperKirk SmithDecember 9, 2020ctDNA, next-generation sequencing, NGS, ALK, liquid biopsy

Humanistic burden of living with anaplastic lymphoma kinase-positive non-small-cell lung cancer: findings from the ALKConnect patient insight network and research platform

ALKConnect demonstrated that disease progression, HRQoL, fatigue/sleep, ALK TKIs and employment matter in ALK+ NSCLC. READ ARTICLE

Lung Cancer Management DOI: 10.2217/lmt-2020-0018

Authors: Lin HM, Pan X, Biller A, J Covey K, Huang H, Sugarman R, Scipione F, West H.

Case StudyKirk SmithNovember 20, 2020ctDNA, ALK, liquid biopsy, next-generation sequencing (NGS)

Next-generation sequencing to dynamically detect mechanisms of resistance to ALK inhibitors in ALK-positive NSCLC patients: a case report

Tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase gene (ALK) have significantly improved the quality of life and survival of non-small cell lung cancer (NSCLC) patients whose tumors harbor an ALK translocation. However, most of these patients relapse within 2 to 3 years as the tumor acquires resistance mutations. Unlike beaming and digital PCR (dPCR), which only allow a few mutations to be analyzed, next-generation sequencing (NGS) approaches enable the simultaneous screening of multiple genetic alterations even when the frequencies of the variants are very low. We present the case of a 52-year-old man who was diagnosed with an ALK-positive NSCLC and was treated with crizotinib and, subsequently, ceritinib. The analysis of serial liquid biopsies by NGS detected two asynchronous mutations arising in the ALK locus during disease progression, namely p.Gly1269Ala (c.3806G>C) and p.Gly1202Arg (c.3604G>A), that conferred resistance to crizotinib and ceritinib, respectively...... READ ARTICLE

Translational Lung Cancer Research DOI:10.21037/tlcr.2020.02.07

Authors: Sánchez-Herrero E, Blanco Clemente M, Calvo V, Provencio M, Romero A.

P103-15 Non-Invasive Detection of Secondary Resistance Mutations in ALK-Positive NSCLC Patients by Next-Generation Sequencing

Remarkably different mutations can confer different sensitivities to different ALK inhibitors. However, 2nd and 3rd line treatment is often prescribe empirically without knowing the molecular mechanism underlying treatment failure.21 samples from ALK-positive NSCLC patients were collected at disease progression. Circulating Nucleic Acids were isolated from platelets, exosomes and plasma. Libraries were prepared using 20ng of template and Oncomine™ Pan-Cancer Cell-Free Assay. Samples were sequenced on an Ion GeneStudio S5 Plus System. Sequencing data was first analyzed using Torrent Suite software. Subsequently variant calling, annotation and filtering was performed on the Ion Reporter (v5.10) platform using the Oncomine TagSeq Pan-Cancer Liquid Biopsy w2.1 workflow. The results show that secondary ALK-TKI resistance mutations could be detected using liquid biopsies in a high proportion of patients. Non-invasive molecular profiling of samples collected at disease progression is feasible being useful for further treatment selection in ALK-positive NSCLC patients.
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Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.867

Authors: E. Sánchez Herrero, M. Barquin, V. Calvo De Juan, M. Auglyte, R. Garcia Campelo, J.M. Sánchez, M. Domine, B. Massuti, E. Jantus, C. Camps, N. Reguart, M. Provencio, A. Romero

Conference PaperKirk SmithOctober 1, 2019ctDNA, liquid biopsy, ALK

P114-07 Genomic Profiling of Liquid Biopsies During 2nd/3rd Generation ALK Inhibitor Therapy to Identify Novel Mechanisms of Resistance

Second- and third-generation ALK inhibitors each have diverse mechanisms of resistance. Only a fraction of resistance is due to secondary mutations of the ALK gene. Altered bypass tracts are likely the case in some other instances. Genomic alterations of other genes and pathways may be a third mechanism of resistance. Repeat liquid biopsies during the course of patients’ treatments can provide a minimally invasive method for sampling cancer-specific genomic information that leads to improved treatment selection. In the Lung Cancer Clinic of the Princess Margaret Cancer Centre, serial plasma samples were collected from six lung cancer patients with ALK rearrangement at multiple serial clinic visits pre- and post- progression on next-generation ALK inhibitors. We focused on next generation agents, as there has been previous focus on crizotinib resistance mechanisms already.The study found that broad panel-based NGS of plasma cfDNA enabled noninvasive detection of systemic (but not CNS-pr..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1158

Authors: E. Stewart, A. Wang, J. Huang, H. Bao, X. Wu, D. Patel, Z. Chen, J. Law, P. Bradbury, F. Shepherd, A. Sacher, M. Tsao, S. Bratman, N. Leighl, T. Pugh, G. Liu

Conference PaperKirk SmithOctober 1, 2019NGS, plasma, cfDNA, ALK, resistance, Genomic alterations, liquid biopsy

Monitoring therapeutic response and resistance: analysis of circulating tumor DNA in patients with ALK+ lung cancer

Clinical utility of ctDNA was shown, both at pre-treatment by identifying a potential subgroup of ALK+ NSCLC patients who may derive more benefit from ensartinib and longitudinally by tracking resistance. Prospective application of this technology may translate to improved outcomes for NSCLC patients treated with ALK TKIs. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2019.08.003

Authors: Leora Horn MD, Jennifer G. Whisenant PhD, Heather Wakelee MD, Karen L. Reckamp MD, Huan Qiao, MD PhD, Ticiana A. Leal MD, Liping Du PhD, Jennifer Hernandez BS, Vincent Huang BS, George R. Blumenschein MD, Saiama N. Waqar MD, Sandip P. Patel MD, Jorge Nieva MD, Geoffrey R. Oxnard MD, Rachel E. Sanborn MD, Tristan Shaffer, Kavita Garg, Allison Holzhausen MS, Kimberly Harrow MBA, Chris Liang PhD, Lee P. Lim PhD, Mark Li, Christine M. Lovly MD, PhD

Pre-ClinicalKirk SmithAugust 22, 2019ctDNA, ALK, next-generation sequencing (NGS), liquid biopsy