1199P Dose modification for the management of CNS adverse events in the phase III CROWN study of lorlatinib in non-small cell lung cancer (NSCLC)

In the ongoing phase III CROWN study (NCT03052608), lorlatinib, a 3rd-generation inhibitor of anaplastic lymphoma kinase (ALK), improved progression-free survival (PFS) and intracranial response rates vs crizotinib in patients with previously untreated ALK-positive NSCLC. Here we present data on lorlatinib dose modification for the management of CNS adverse events (AEs). CNS AEs spontaneously resolved in 53% of cases, and lorlatinib dose modification was effective in managing CNS AEs without compromising efficacy. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1804

Authors: B.J. Solomon, T.S.K. Mok, H. Hayashi, A. Bearz, K.D. Penkov, Y-L. Wu, O. Arrieta, A.M. Calella, G. Peltz, A. Polli, H. Thurm, T.M. Bauer

Conference PaperKirk SmithSeptember 1, 2021Lorlatinib, CROWN trial, crizotinib, CNS, AE

1197P First-line lorlatinib versus crizotinib in ALK-positive non-small cell lung cancer: Asian subgroup analysis of CROWN

Lorlatinib, a 3rd-generation ALK inhibitor, significantly prolonged progression-free survival (PFS) vs crizotinib in the CROWN trial in patients with untreated ALK-positive non-small cell lung cancer (NSCLC). We report data from the Asian subgroup of CROWN. In the Asian subgroup, a consistent and clinically meaningful improvement in PFS was observed for lorlatinib vs crizotinib. The efficacy and safety of lorlatinib vs crizotinib in the Asian subgroup of CROWN was consistent with the overall population. READ ARTICLE

Annals of Oncology DOI:10.1016/j.annonc.2021.08.1802

Authors: Q. Zhou, H.R. Kim, R. Soo, G-C. Chang, C-H. Chiu, H. Hayashi, S-W. Kim
S. Teraoka, Y. Goto, J. Zhou, V.H.F. Lee, B. Han, J.C.M. Ho, D-W. Kim
C-C. Lin, S. Lu, A. Polli, A.M. Calella, T.S.K. Mok, Y-L. Wu

Conference PaperKirk SmithSeptember 1, 2021Lorlatinib, CROWN trial, crizotinib

Testing for EGFR Mutations and ALK Rearrangements in Advanced Non-Small-Cell Lung Cancer: Considerations for Countries in Emerging Markets

The treatment of patients with advanced non-small-cell lung cancer (NSCLC) in recent years has been increasingly guided by biomarker testing. Testing has centered on driver genetic alterations involving the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangements. The presence of these mutations is predictive of response to targeted therapies such as EGFR tyrosine kinase inhibitors (TKIs) and ALK TKIs. However, there are substantial challenges for the implementation of biomarker testing, particularly in emerging countries. Understanding the barriers to testing in NSCLC will be key to improving molecular testing rates worldwide and patient outcomes as a result. In this article, we review EGFR mutations and ALK rearrangements as predictive biomarkers for NSCLC, discuss a selection of appropriate tests and review the literature with respect to the global uptake of EGFR and ALK testing. To help improve testing rates and unify procedures, we review our exp..... READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S313669

Authors: Mercedes L Dalurzo, Alejandro Avilés-Salas, Fernando Augusto Soares, Yingyong Hou, Yuan Li, Anna Stroganova, Büge Öz, Arif Abdillah, Hui Wan and Yoon-La Choi

ALK inhibitor-induced bradycardia: A systematic-review and meta-analysis

Anaplastic Lymphoma Kinase (ALK) inhibitors have revolutionized the treatment of advanced ALK-positive non-small cell lung cancer (NSCLC), improving progression-free survival. Bradycardia is a potential adverse effect of these agents. We aimed to determine the risk of bradycardia associated with ALK inhibitors in patients with advanced NSCLC.We find that crizotinib for the treatment of NSCLC is associated with a higher risk for bradycardia compared to standard chemotherapy. There is no evidence of a difference in bradycardia risk between crizotinib and newer ALK inhibitors. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.08.014

Authors: Filipe Cirne, Shijie Zhou, Coralea Kappel, Adam El-Kadi, Carly C. Barron, Peter M. Ellis, Stephanie Sanger, Darryl P. Leong

Successful treatment with crizotinib after alectinib-induced interstitial lung disease

Although alectinib is a well-tolerated and highly effective inhibitor of a second-generation anaplastic lymphoma kinase, special attention should be paid to the possibility of potentially severe and fatal adverse events such as interstitial pneumonia. We report a case of a patient with advanced non-small cell lung cancer treated with alectinib who developed immunohistochemically positive anaplastic lymphoma kinase (ALK(IHC +)) . However, due to the rapid emergence of drug-induced interstitial lung disease, alectinib treatment was halted. Once the interstitial lung disease had been successfully treated, we reluctantly chose crizotinib as a second-line treatment for ALK + NSCLC in this patient as he refused all other available treatments. Contrary to expectation, crizotinib performed well both in terms of its safety and efficacy. Our results suggest that crizotinib may provide a promising therapy option for patients with ALK + NSCLC accompanied by alectinib-induced interstitial lung dise..... READ ARTICLE

SAGE Open Medical Case Reports DOI:10.1177/2050313X211042991

Authors: Ning Zhu, Shanhong Lin, Lei He, Linfeng Wang,
Weiliang Kong, Chao Cao

Kirk SmithAugust 31, 2021

Detection of Multiple Types of Cancer Driver Mutations Using Targeted RNA Sequencing in NSCLC

Currently, DNA and RNA are used separately to capture different types of gene mutations. DNA is commonly used for the detection of SNVs, indels and CNVs; RNA is used for analysis of gene fusion and gene expression. To perform both DNA sequencing (DNA-seq) and RNA-seq, material is divided into two copies, and two different procedures are required for sequencing. Due to overconsumption of samples and experimental process complexity, it is necessary to create an experimental method capable of analyzing SNVs, indels, fusions and expression.We developed an RNA-based hybridization capture panel targeting actionable driver oncogenes in solid tumors and corresponding sample preparation and bioinformatics workflows. Analytical validation with an RNA standard reference containing 16 known fusion mutations and 6 SNV mutations demonstrated a detection specificity of 100.0% [95% CI 88.7%~100.0%] for SNVs and 100.0% [95% CI 95.4%~100.0%] for fusions. The targeted RNA panel achieved a 0.73-2.63 cop..... READ ARTICLEBioRxiv DOI:10.1101/2021.08.25.457723Authors: Sheng Ju, Zihan Cui, Yuayuan Hong, Xiaoqing Wang, Weina Mu, Zhuolin Xie, Xuexia Zeng, Lin Su, Qi Zhang, Xiaofeng Song, Songxia You, Ruixin Chen, Weizhi Chen, Xuchun, Jun Zhao

Review Paper, group3Kirk SmithAugust 26, 2021Cancer Driver Mutations, Targeted RNA Sequencing, NSCLC

Brain Metastases in EGFR- and ALK-Positive NSCLC: Outcomes of Central Nervous System-Penetrant Tyrosine Kinase Inhibitors Alone Versus in Combination With Radiation

Management of central nervous system (CNS) metastases in patients with driver-mutated NSCLC has traditionally incorporated both tyrosine kinase inhibitors (TKIs) and intracranial radiation. Whether next generation, CNS-penetrant TKIs can be used alone without upfront radiation, however, remains unknown. This multi-institutional retrospective analysis aimed to compare outcomes in patients with EGFR- or ALK-positive NSCLC who received CNS-penetrant TKI therapy alone versus in combination with radiation for new or progressing intracranial metastases. A total of 147 patients were included (EGFR n = 94, ALK n = 52, both n = 1). In patients receiving radiation, larger metastases, neurologic symptoms, and receipt of steroids were more common. There were no significant differences between TKI and CNS radiation therapy plus TKI groups for any of the study outcomes, including time to progression (8.5 versus 6.9 mo, p = 0.13 [EFGR] and 11.4 versus 13.4 mo, p = 0.98 [ALK]), time to intracranial pr..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.08.009

Authors: Nicholas J.Thomas, Nathaniel J. Myall, Fangdi Sun, Tejas Patil, Rao Mushtaq, Chandler Yu, Sumi Sinha, Erqi L. Pollom, Seema Nagpal. Ross Camidge, Chad G. Rusthoven, Steve E. Braunstein, Heather A. Wakelee and Caroline E. McCoach

68-months progression-free survival with crizotinib treatment in a patient with metastatic ALK positive lung adenocarcinoma and sarcoidosis: A case report

Lung cancer still ranks first among the most common and most lethal cancers today. The most common subtype is non-small cell lung cancer, and in this group, adenocarcinoma has the worst prognosis. EGFR, ROS1 and ALK-EML4 gene fusion mutations are common in non-small cell lung cancer.In this article, we wanted to share our experience of crizotinib in a 68-months progression-free survival in a 62-years old non-smoking female patient with metastatic lung adenocarcinoma who is also diagnosed with sarcoidosis. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220951242

Authors: Ozgur Tanriverdi, Mehmet L Tarimer, Ceren D Pak, Selcuk Uylas, Ali Alkan, Ozgur Ilhan Celik, Rabia M Kilic, Arife Zeybek

Lorlatinib in a Child with ALK-Fusion–Positive High-Grade Glioma

A child near death with an ALK-fusion–positive high-grade glioma refractory to standard treatment had a dramatic response when treatment with lorlatinib was begun. The drug was stopped once the child had an apparent complete remission, but treatment with lorlatinib resumed when relapse occurred 6 months later. At this time, the child is attending preschool and has normal neurologic function. READ ARTICLE

New England Journal of Medicine DOI:10.1056/NEJMc2101264

Authors: Aditi Bagchi, Brent A Orr, Olivia Campagne, Sandeep Dhanda, Sreenath Nair, Quynh Tran, Anthony M Christensen, Amar Gajjar, Larissa V Furtado, Aksana Vasilyeva, Frederick Boop, Clinton Stewart and Giles W Robinson

Case Study, group3Kirk SmithAugust 19, 2021ALK, glioma, loraltinib, pediatric

Case Report: Identification of Two Rare Fusions, PDK1-ALK and STRN-ALK, That Coexist in a Lung Adenocarcinoma Patient and the Response to Alectinib

Several double ALK fusions coexisting in one patient have been reported. However, few studies have reported the clinical efficacy of ALK inhibitors in rare double ALK fusions. Here, we described a rare PDK1-ALK, STRN-ALK double-fusion variant in a patient with metastatic lung adenocarcinoma. The patient responded well to alectinib (600 mg) twice daily. This case shows a promising treatment option for patients with rare ALK double-fusion variants. READ ARTICLE

Frontiers in oncology DOI:10.3389/fonc.2021.722843

Authors: Zeng H, Li Y, Wang Y, Huang M, Zhang Y, Tian P, Li W.

Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non–small-cell lung cancer: a multicenter study using targeted next-generation sequencing

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non–small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients’ clinicopathologic characteristics and treatment outcomes were analyzed. Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers. READ ARTICLE

European Journal of Cancer DOI:10.1016/j.ejca.2021.06.043

Authors: Yen-Ting Lin, Chi-Lu Chiang, Jen-Yu Hung, Mei-Hsuan Lee, Wu-Chou Su, Shang-Yin Wu, Yu-Feng Wei, Kang-Yun Lee, Yen-Han Tseng, Jian Su, Hsin-Pei Chung, Chih-Bin Lin, Wen-Hui Ku, Tsai-Shin Chiang, Chao-Hua Chiu, Jin-Yuan Shih

Cycling cancer persister cells arise from lineages with distinct programs

Non-genetic mechanisms have recently emerged as important drivers of cancer therapy failure1, where some cancer cells can enter a reversible drug-tolerant persister state in response to treatment2. Although most cancer persisters remain arrested in the presence of the drug, a rare subset can re-enter the cell cycle under constitutive drug treatment. Little is known about the non-genetic mechanisms that enable cancer persisters to maintain proliferative capacity in the presence of drugs. To study this rare, transiently resistant, proliferative persister population, we developed Watermelon, a high-complexity expressed barcode lentiviral library for simultaneous tracing of each cell’s clonal origin and proliferative and transcriptional states. Here we show that cycling and non-cycling persisters arise from different cell lineages with distinct transcriptional and metabolic programs. Upregulation of antioxidant gene programs and a metabolic shift to fatty acid oxidation are associated with..... READ ARTICLE

Nature DOI:10.1038/s41586-021-03796-6

Authors: Yaara Oren, Michael Tsabar, Michael S. Cuoco, Liat Amir-Zilberstein, Heidie F. Cabanos, Jan-Christian Hütter, Bomiao Hu, Pratiksha I. Thakore, Marcin Tabaka, Charles P. Fulco, William Colgan, Brandon M. Cuevas, Sara A. Hurvitz, Dennis J. Slamon, Amy Deik, Kerry A. Pierce, Clary Clish, Aaron N. Hata, Elma Zaganjor, Galit Lahav, Katerina Politi, Joan S. Brugge & Aviv Regev

Pre-Clinical, group3Kirk SmithAugust 11, 2021Watermelon library, lineage diversity and fate, models

Folate-Guided Protein Degradation by Immunomodulatory Imide Drug-Based Molecular Glues and Proteolysis Targeting Chimeras

Molecular glues and proteolysis targeting chimeras (PROTACs) are promising new therapeutic modalities. However, the lack of specificity for molecular glue- or PROTAC-mediated proteolysis in cancer cells versus normal cells raises potential toxicity concerns that will likely limit their clinical applications. Here, we developed a general strategy to deliver immunomodulatory imide drug (IMiD)-based molecular glues and PROTACs to folate receptor α (FOLR1)-positive cancer cells. Specifically, we designed a folate-caged pomalidomide prodrug, FA-S2-POMA, by incorporating a folate group as a caging and guiding element and validated its degradation effect on its neo-substrates in FOLR1-positive cancer cells in a FOLR1-dependent manner. We also developed a folate-caged pomalidomide-based anaplastic lymphoma kinase (ALK) PROTAC, FA-S2-MS4048, which effectively degraded ALK fusion proteins in cancer cells, again in a FOLR1-dependent manner. This novel approach provides a generalizable platform fo..... READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.1c00901

Authors: He Chen, Jing Liu, H. Ümit Kaniskan, Wenyi Wei, and Jian Jin

An unusual fusion gene EML4-ALK in a patient with congenital mesoblastic nephroma

Congenital mesoblastic nephroma (CMN), the most common renal tumor of infancy, is a mesenchymal neoplasm histologically classified into classic, cellular, or mixed types. Most cellular CMNs harbor a characteristic ETV6-NTRK3 fusion. Here, we report an unusual congenital mesoblastic nephroma presenting in a newborn boy with a novel EML4-ALK gene fusion revealed by Anchored Multiplex RNA Sequencing Assay. The EML4-ALK gene fusion expands the genetic spectrum implicated in the pathogenesis of congenital mesoblastic nephroma, with yet another example of kinase oncogenic activation through chromosomal rearrangement. The methylation profile of the tumor corresponds with infantile fibrosarcoma showing the biological similarity of these two entities. READ ARTICLE

Genes Chromosomes & Cancer DOI:10.1002/gcc.22990

Authors: Adela Misove, Ales Vicha, Michal Zapotocky, Josef Malis, Jan Balko, Tereza Nemeckova, Jana Szabova, Martin Kyncl, Daniela Novakova-Kodetova, Lucie Stolova, Pavla Jencova, Petr Broz, Lenka Krskova

Case StudyKirk SmithAugust 10, 2021EML4-ALK, congenital mesoblastic nephroma

ALK summit 2021: Keynote speaker, Tasneeem Ahmed talks about where the ALK space is today and the HOPE we have for the future with Q&A from the ALK Community.

Welcome to day 2 of ALK Summit 2021: STRONGER TOGETHER and keynote speaker, Tasneeem Ahmed talks about where the ALK space is today and the HOPE we have for the future with Q&A from the ALK Community. WATCH VIDEO

ALK Positive Inc.

Authors: Amanda Nerstad, Bill Westlake and Tasneem Ahmed

Video, group3Kirk SmithAugust 10, 2021ALK summit 2021

Research Funded by ALK Positive, updated on August 9, 2021

ALK Summit 2021: STRONGER TOGETHER: Research Funded by ALK Positive- Hear From the Researchers Mark Awad, Trever Bivona, Roberto Chiarle, Ibiayi Dagogo- Jack, Juston Gainor, John Iafrate, Christine Lovly, Raphael Nemenoff. Moderators: Colin Barton and Emily Venanzi WATCH VIDEO

ALK Positive Inc.

Authors: Mark Awad, Trever Bivona, Roberto Chiarle, Ibiayi Dagogo- Jack, Juston Gainor, John Iafrate, Christine Lovly and Raphael Nemenoff

Video, group3Kirk SmithAugust 9, 2021ALK summit 2021

ALK summit 2021: What is Next After Lorlatinib?

ALK Summit 2021: STRONGER TOGETHER. What is Next After Lorlatinib? 4th Generation TKI’s and Beyond Speakers: dr. Ross Camidge, MD, PHD University of Colorado Cancer Center, Dr. Christine Lovly, MD PhD, BA Vanderbilt- Ingram Cancer Center. Moderator(s): Colin Barton, Emily Vennzi. Dr. Ross Camidge and Dr. Christine Lovly speak about the many treatment options that are available NOW if a patient experiences progression on Lorlatinib. Even more exciting, they speak about what's already visible on the horizon for new treatments that could transform our future. WATCH VIDEO

ALK Positive Inc.

Authors: Dr. Ross Camidge and Dr. Christine Lovly

Video, group3Kirk SmithAugust 9, 2021ALK summit 2021

ALK summit 2021: Benefits of a Multi Disciplinary Team

ALK summit 2021: Benefits of a Multi-Disciplinary Team: Stronger Together Dr. Ross Camidge, MD, PhD University of Colorado Cancer Center, Dr. Vicent Lam, MDAssistant Professor of Oncology, Johns Hopkins University, Dr. Drew Maghanaki, MD, MPH, UCLA Department of Radiation Oncology, Dr. Brendon Stiles, MD, Professor and Chief of Thoracic Surgery Oncology Montefiore Health System, Dr. Laura Petrilo, MD, Palliative Care at Massachusetts General Hospital Moderator: Amanda Nerstad, ALK Summit Chair. WATCH VIDEO

ALK Positive Inc.

Authors: Dr. Ross Camidge, Dr. Vicent Lam, Dr. Drew Maghanaki, Dr. Brendon Stiles, Dr. Laura Petrilo and Amanda Nerstad

Video, group3Kirk SmithAugust 9, 2021ALK summit 2021

ALK Gene Rearrangements in Lung Adenocarcinomas: Concordance of Immunohistochemistry, Fluorescence In Situ Hybridization, RNA In Situ Hybridization, and RNA Next-Generation Sequencing Testing

The 2018 updated molecular testing guidelines for patients with advanced lung cancer incorporated ALK immunohistochemistry (IHC) analysis as an equivalent to fluorescence in situ hybridization (FISH) method recommended in 2013. Nevertheless, no specific recommendation for alternative methods was proposed owing to insufficient data. The aim of this study was to compare the results of ALK IHC, FISH, RNA next-generation sequencing (NGS), and RNA in situ hybridization (ISH) with available clinical data. Our results reveal high concordance among IHC, RNA NGS, and RNA ISH. In cases of discordance with available RNA NGS, FISH result was positive whereas IHC and ISH results were negative. On the basis of our data, multimodality testing is recommended to identify discrepant results and patients (un)likely to respond to tyrosine kinase inhibitors. READ ARTICLE

JTO Clinical and Research Reports DOI:0.1016/j.jtocrr.2021.100223

Authors: Carleigh R. Canterbury, Helen Fernandes, John P. Crapanzano, Vundavalli V. Murty, Mahesh M.Mansukhani, Catherine A. Shu, Matthias Szabolcs, Anjali Saqi

Comparison of solid tissue sequencing and liquid biopsy accuracy in identification of clinically relevant gene mutations and rearrangements in lung adenocarcinomas

Screening for therapeutic targets is standard of care in the management of advanced non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. “Liquid biopsies” are plasma-based next generation sequencing (NGS) assays that use circulating tumor DNA to identify relevant targets. To compare the sensitivity, specificity, and accuracy of a plasma-based NGS assay to solid-tumor-based NGS we retrospectively analyzed sequencing results of 100 sequential patients with lung adenocarcinoma at our institution who had received concurrent testing with both a solid-tissue-based NGS assay and a commercially available plasma-based NGS assay. Patients represented both new diagnoses (79%) and disease progression on treatment (21%); the majority (83%) had stage IV disease. Tissue-NGS identified 74 clinically relevant mutations, including 52 therapeutic targets, a sensitivity of 94.8%, while plasma-NGS identified 41 clinically relevant mutations, a ..... READ ARTICLE

Modern Pathology DOI:10.1038/s41379-021-00880-0

Authors: Lawrence Hsu Lin, Douglas H. R. Allison, Yang Feng, George Jour, Kyung Park, Fang Zhou, Andre L. Moreira, Guomiao Shen, Xiaojun Feng, Joshua Sabari, Vamsidhar Velcheti, Matija Snuderl, Paolo Cotzia