Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib
Association of Programmed Death-Ligand 1 Expression with Fusion Variants and Clinical Outcomes in Patients with Anaplastic Lymphoma Kinase-Positive Lung Adenocarcinoma Receiving Crizotinib

Background: Programmed death-ligand 1 (PD-L1) expression is associated with clinical outcomes of epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma (ADC) treated with tyrosine kinase inhibitors (TKIs). However, whether PD-L1 expression plays a role in anaplastic lymphoma kinase (ALK)-positive lung ADC is unknown. We aimed to evaluate the impact of PD-L1 in patients with ALK-positive lung ADC receiving crizotinib. Conclusion: Positive PD-L1 expression was associated with unfavorable clinical outcomes in patients with ALK-positive lung ADC receiving crizotinib. READ ARTICLE

The Oncologist DOI:10.1634/theoncologist.2020-0088

Authors: Yang CY, Liao WY, Ho CC, Chen KY, Tsai TH, Hsu CL, Liu YN, Su KY, Chang YL, Wu CT, Liao BC, Hsu CC, Hsu WH, Lee JH, Lin CC, Shih JY, Yang JC, Yu CJ.

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Real-World OutcomesKirk SmithAnaplastic lymphoma kinase (ALK), Crizotinib, Fusion variant, Lung cancer, Programmed death-ligand 1 (pdl-1).
Dr Nemenoff and Colin Barton post Summit interview
Dr Nemenoff and Colin Barton post Summit interview

ALK Positive awarded a $200,000 grant in 2018 to Dr Raphael Nemenoff to research new ways to better treat ALK- positive lung cancer. Dr Nemenoff is a leading researcher at the University of Colorado, working with Dr Ross Camidge, a world-leading ALK lung cancer expert and thoracic oncologist. Dr Colin Barton was diagnosed with ALK-positive lung cancer in 2016, and is Chair of the ALK Positive Medical Committee. Here, on August 14, 2020, Colin interviews Dr Nemenoff. Dr. Nemenoff discusses his research and the human immune system and specifically the complement system. WATCH VIDEO

ALK Positive Inc.

Authors: Dr. Nemenoff

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VideoKirk SmithALK summit 2020
Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing
Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing

Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes. READ ARTICLE

Cell DOI:10.1016/j.cell.2020.07.017

Authors: Ashley Maynard, Caroline E. McCoach, Julia K. Rotow, Lincoln Harris, Franziska Haderk, D. Lucas Kerr, Elizabeth A. Yu, Erin L. Schenk, Weilun Tan, Alexander Zee, Michelle Tan, Philippe Gui, Tasha Lea, Wei Wu, Anatoly Urisman, Kirk Jones, Rene Sit, Pallav K. Kolli, Eric Seeley, Yaron Gesthalter, Daniel D. Le, Kevin A. Yamauchi, David M. Naeger, Sourav Bandyopadhyay, Khyati Shah, Lauren Cech, Nicholas J. Thomas, Anshal Gupta, Mayra Gonzalez, Hien Do, Lisa Tan, Bianca Bacaltos, Rafael Gomez-Sjoberg, Matthew Gubens, Thierry Jahan, Johannes R. Kratz, David Jablons, Norma Neff, Robert C. Doebele, Jonathan Weissman, Collin M. Blakely, Spyros Darmanis, Trever G. Bivona

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Pre-ClinicalKirk Smithsingle-cell RNA, lung cancer, ALK, EGFR, Targeted therapy
Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer
Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer

Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib.Plasma concentration–time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-efects modeling (NONMEM software version 7.3).The result shows brigatinib plasma concentrations were best described by a three compartment model with a transit compartment input (number of transit compartments=2.35; mean transit time=0.9 h). The fnal model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total b..... READ ARTICLE

SpringerLink DOI:10.1007/s40262-020-00929-4

Authors: Neeraj Gupta, Xiaohui Wang, Elliot Ofman, Marita Prohn, Narayana Narasimhan, David Kerstein. Michael J. Hanley, Karthik Venkatakrishnan

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Real-World OutcomesKirk Smith
N-[18F]-Fluoroacetylcrizotinib: A potentially potent and selective PET tracer for molecular imaging of non-small cell lung cancer
N-[18F]-Fluoroacetylcrizotinib: A potentially potent and selective PET tracer for molecular imaging of non-small cell lung cancer

N-[18F]fluoroacetylcrizotinib, a fluorine-18 labeled derivative of the first FDA approved tyrosine kinase inhibitor (TKI) for the treatment of Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), crizotinib, was successfully synthesized for use in positron emission tomography (PET). Sequential in vitro biological evaluation of fluoracetylcrizotinib and in vivo biodistribution studies of [18F]fluoroacetylcrizotinib demonstrated that the biological activity of the parent compound remained unchanged, with potent ALK kinase inhibition and effective tumor growth inhibition. These results show that [18F]fluoroacetylcrizotinib has the potential to be a promising PET ligand for use in NSCLC imaging. The utility of PET in this context provides a non-invasive, quantifiable method to inform on the pharmacokinetics of an ALK-inhibitor such as crizotinib prior to a clinical trial, as well as during a trial in the event of acquired drug resistance. READ ARTICLE

Bioorganic & Medicinal Chemistry Letters DOI:10.1016/j.bmcl.2020.127257

Authors: Jason R. Buck, Samir Saleh, Trey Claus, Christine Lovly, Matthew R. Hight, Michael L. Nickels, M. Noor Tantawy, H.Charles Manning

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EditorialKirk SmithCrizotinib, NSCLC, PET, Cancer, Therapy
Functional diagnostics using fresh uncultured lung tumor cells to guide personalized treatments
Functional diagnostics using fresh uncultured lung tumor cells to guide personalized treatments

Functional profiling of a cancer patient’s tumor cells holds potential to tailor personalized cancer treatment. Here we report the utility of Fresh Uncultured Tumor-derived EpCAM+ epithelial Cells (FUTC) for ex vivo drug response interrogation. Analysis of murine Kras mutant FUTCs demonstrated pharmacological and adaptive signaling profiles comparable to subtype-matched cultured cells. Applying FUTC profiling on non-small cell lung cancer patient samples, we generated robust drug response data in 18 of 19 cases, where the cells exhibited targeted drug sensitivities corresponding to their oncogenic drivers. In one of these cases, an EGFR mutant lung adenocarcinoma patient refractory to osimertinib, FUTC profiling was used to guide compassionate treatment. FUTC profiling identified selective sensitivity to disulfiram and the combination of carboplatin plus etoposide and the patient received substantial clinical benefit from the treatment with these agents. We conclude that FUTC profiling..... READ ARTICLE

BioRxiv DOI:10.1101/2020.08.12.247817

Authors: Sarang S. Talwelkar, Mikko I. Mäyränpää, Lars Søraas, Swapnil Potdar, Jie Bao, Annabrita Hemmes, Nora Linnavirta, Jon Lømo, Jari Räsänen, Aija Knuuttila, Krister Wennerberg, Emmy W. Verschuren

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Case StudyKirk SmithFunctional diagnostics, fresh uncultured lung tumor cells, personalized treatments
The deep learning model combining CT image and clinicopathological information for predicting ALK fusion status and response to ALK-TKI therapy in non-small cell lung cancer patients
The deep learning model combining CT image and clinicopathological information for predicting ALK fusion status and response to ALK-TKI therapy in non-small cell lung cancer patients

This study aimed to investigate the deep learning model (DLM) combining computed tomography (CT) images and clinicopathological information for predicting anaplastic lymphoma kinase (ALK) fusion status in non-small cell lung cancer (NSCLC) patients.Our findings showed that the DLM trained by both CT images and clinicopathological information could effectively predict the ALK fusion status and treatment responses of patients. For the small size of the ALK-target therapy cohort, larger data sets would be collected to further validate the performance of the model for predicting the response to ALK-TKI treatment. READ ARTICLE

European Journal of Nuclear Medicine and Molecular Imaging DOI:10.1007/s00259-020-04986-6

Authors: Zhengbo Song, Tianchi Liu, Lei Shi, Zongyang Yu, Qing Shen, Mengdi Xu, Zhangzhou Huang, Zhijian Cai, Wenxian Wang, Chunwei Xu, Jingjing Sun, Ming Chen

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Kirk Smith
An ALK-positive lung adenocarcinoma with gastric and skin metastasis: a case report and literature review
An ALK-positive lung adenocarcinoma with gastric and skin metastasis: a case report and literature review

Primary lung cancer with gastric metastasis is rare to see in the world, little is known about its characteristics. Here, we describe the first case of primary lung adenocarcinoma with gastric and skin metastases along with a review of literature to help clinical decision making. A 49-year-old woman admitted to our department for abdominal distension. The immunohistochemistry staining for the biopsy in the gastric fundus, back and lung showed positive for CK5/6, TTF-1, Napsin A and CK7, but negative for CK20, which strongly indicated all of them were homologous and might originate from lung adenocarcinoma. Chromosome mutation analysis presented an EML4-ALK fusion gene. Brain metastases occurred after 6 months with crizotinib treatment. More than two months later, intracranial lesions became more and larger as she persisted in taking crizotinib plus whole-brain radiotherapy (WBRT). Hence, alectinib was performed due to the continuous growth of brain lesions. When reexamined three months..... READ ARTICLE

National Library of Medicine DOI:10.21037/apm-20-1025

Authors: Xueqin Duan, Xinhan Zhao, Shuhong Wang

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Case StudyKirk SmithXueqin Duan, Xinhan Zhao, Shuhong Wang
Anaplastic lymphoma kinase rearrangement may increase the incidence of venous thromboembolism by increasing tissue factor expression in advanced lung adenocarcinoma
Anaplastic lymphoma kinase rearrangement may increase the incidence of venous thromboembolism by increasing tissue factor expression in advanced lung adenocarcinoma

Background Patients with lung cancer are at an increased risk for venous thromboembolism (VTE). Approximately 8–15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE throughout the course of the disease. However, the incidence of VTE in different NSCLC molecular subtypes is rarely reported, although there are significant differences in clinical feature and prognosis. Tissue factor (TF) expressed in many solid tumors could trigger the downstream coagulation cascade and lead to thrombin generation and clot formation. Results: At a median follow up of 2.5 years, 5.85% (n=30/513) patients with advanced lung adenocarcinoma experienced VTE. Compared to patients with EGFR mutation (n=11/218, 5.05%) or both negative (n=13/266, 4.89%), patients with ALK-rearrangement were more likely to develop VTE (n=6/29, 20.69%; P=0.006, P=0.004; respectively). In ALK-rearrangement-positive tissues, 41.67% (n=10/24) had a high TF protein expression; the incidence was significantly..... READ ARTICLE

Annals of Translational Medicine DOI:10.21037/atm-20-6619

Authors: Yang S, Yang L, Wu Y, Zhang C, Wang S, Ma N, Wang L, Wang

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Real-World OutcomesKirk SmithNon-small cell lung cancer (NSCLC), venous thromboembolism, anaplastic lymphoma kinase (ALK), tissue factor
Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer
Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.
We concluded that high TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations. READ ARTICLE

Journal for ImmunoTherapy of Cancer DOI:10.1136/jitc-2021-002891

Authors: Marcelo V Negrao, Ferdinandos Skoulidis, Meagan Montesion, Katja Schulze, Ilze Bara, Vincent Shen, Hao Xu, Sylvia Hu, Dawen Sui, Yasir Y Elamin, Xiuning Le, Michael E Goldberg, Karthikeyan Murugesan, Chang-Jiun Wu, Jianhua Zhang, David S Barreto, Jacqulyne P Robichaux, Alexandre Reuben, Tina Cascone, Carl M Gay, Kyle G Mitchell, Lingzhi Hong, Waree Rinsurongkawong, Jack A Roth, Stephen G Swisher, Jack Lee, Anne Tsao, Vassiliki Papadimitrakopoulou, Don L Gibbons, Bonnie S Glisson, Gaurav Singal, Vincent A Miller, Brian Alexander, Garrett Frampton, Lee A Albacker, David Shames, Jianjun Zhang, and John V Heymach

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Real-World OutcomesKirk Smithimmunotherapy, lung neoplasms, tumor biomarker
Intracranial disease control for EGFR-mutant and ALK-rearranged lung cancer with large volume or symptomatic brain metastases
Intracranial disease control for EGFR-mutant and ALK-rearranged lung cancer with large volume or symptomatic brain metastases

Tyrosine kinase inhibitors (TKIs) are commonly employed for patients with brain metastases from lung
cancer and specific driver mutations. We sought to identify the correlation between intracranial tumor
burden and outcomes in patients with brain metastases treated with TKIs.... Most patients receiving TKIs
as part of their initial therapy achieve an early and durable volumetric intracranial response, irrespective of
presenting disease burden or neurologic symptoms. READ ARTICLE

Journal of Neuro-Oncology volume DOI:10.1007/s11060-020-03615-4

Authors: Sunil W. Dutta, Marie L. Mack, Eric Aliotta, Kristin A. Ward, Donald A. Muller, James M. Larner, Camilo E. Fadul, Richard D. Hall, Ryan D. Gentzler, Jason P. Sheehan

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Real-World OutcomesKirk SmithTKI, Radiation, Brain metastases, NSCLC
Acquired Exon 14 MET Mutation Associated With Resistance to Alectinib in a Patient With ALK–Rearranged NSCLC

As far as we are aware, this present clinical case is the first to report an acquired exon14 MET mutation
mediated resistance to alectinib in a patient with ALK rearrangement NSCLC. We had chosen to treat
our patient at the time of progression under alectinib with crizotinib with a short time efficacy, three and a
half months. READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100082

Authors: Catherine Daniel, Celine Callens, Samia Melaabi, Ivan Bieche, Nicolas Girard,

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Case StudyKirk Smithexon 14, MET, mutation–mediated, resistance, alectinib, ALK, NSCLC.
Abstract CT025: Impact of the EML4-ALK fusion variant on the efficacy of lorlatinib in patients (pts) with ALK-positive advanced non-small cell lung cancer (NSCLC)
Abstract CT025: Impact of the EML4-ALK fusion variant on the efficacy of lorlatinib in patients (pts) with ALK-positive advanced non-small cell lung cancer (NSCLC)

In this heavily pretreated group of ALK+ NSCLC pts, the presence of an ALK resistance mutation might enrich for EML4-ALK variants 1 and 3. Lorlatinib exhibited antitumor activity irrespective of EML4-ALK variant and across a variety of ALK resistance mutations. READ ARTICLE

AACR abstract. DOI: 10.1158/1538-7445.AM2020-CT025

Authors: Todd M. Bauer, Jean-François Martini, Benjamin Besse, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou, Francesca Toffalorio, Antonello Abbattista, Holger Thurm, D. Ross Camidge, Steven Kao, Rita Chiari, Shirish Gadgeel, Enriqueta Felip, Alice T. Shaw, Benjamin J. Solomon

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Real-World OutcomesKirk Smithlorlatinib, ALK variants
Lung adenocarcinoma with a novel SRBD1-ALK Fusion responding to crizotinib
Lung adenocarcinoma with a novel SRBD1-ALK Fusion responding to crizotinib

Objectives: ... Here, we reported a case of lung adenocarcinoma harboring a novel S1 RNA binding domain 1 (SRBD1)–ALK fusion which the breakpoints was (S6,A20). To our knowledge, this case is the first report showed clinical evidence of SRBD1-ALK fusion responding to crizotinib. Conclusion: To our knowledge, our case is the first case of SRBD1-ALK fusion with excellent response to crizotinib. This case merits further follow-up and provides valuable information on the response to crizotinib of NSCLC patients with SRBD1-ALK fusion. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.04.031

Authors: Yao, Chen, Xiaochen Zhang, Qi Jiang, Bo Wang, Yina Wang, Yan Junrong

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Case StudyKirk SmithNSCLC, SRBD1-ALK, crizotinib, NGS
NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer
NTRK and ALK rearrangements in malignant pleural mesothelioma, pulmonary neuroendocrine tumours and non-small cell lung cancer

Objectives: Gene rearrangements involving NTRK1, NTRK2, NTRK3, ROS1 and ALK have been identified in many types of cancer, including non-small cell lung cancer (NSCLC). Data in malignant pleural mesothelioma (MPM), lung neuroendocrine tumors (NETs) and small-cell lung cancer (SCLC) are lacking. Given the activity of NTRK, ROS-1 and ALK inhibitors in tumors harboring gene fusions, we sought to explore such rearrangements in these less common tumors in addition to NSCLC. Conclusions: To our knowledge, we report for the first time NTRK and ALK rearrangements in a small subset of MPM. An ALK rearrangement was also detected in lung intermediate-grade NET (or atypical carcinoid). Our data suggest that IHC could be a useful screening test in such patients to ensure that all therapeutic strategies including targeted therapy are utilized. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.05.019

Authors: Jose Luis Leal, Geoffrey Peters, Marcin Szaumkessel, Trishe Leong, Khashayar Asadi, Gareth Rivalland, Hongdo Do, Clare Senko, Paul L.Mitchell, Chai Zi Quing, Alexander Dobrovic, Bibhusal Thapa, Thomas John

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Case StudyKirk SmithMesothelioma, NTRK, ALK, Lung neuroendocrine tumors, Non-small cell lung cancer
Abstract 4900: An ALK fusion gene regulates different signaling pathways in mortal versus immortalized normal human cells for cellular senescence and transformation
Abstract 4900: An ALK fusion gene regulates different signaling pathways in mortal versus immortalized normal human cells for cellular senescence and transformation

Accumulating results of clinical trials lead targeted therapies to be the first choice for unresectable or recurrent lung cancer with driver mutations. Echinoderm Microtubule Associated Protein Like 4 (EML4) - Anaplastic lymphoma kinase (ALK) fusion is known as such a driver mutation. It presents in 3-6% of non-small cell lung carcinoma (NSCLC). EML4-ALK fusion protein generate the constitutive ALK kinase activity in NSCLC. The basic understanding of EML4-ALK remains insufficient due to the lack of functional studies using normal human cells. We investigated the role of EML4-ALK in mortal and immortalized normal human cells. The expression of EML4-ALK in normal, mortal human fibroblasts caused accumulated DNA damage, telomere shortening and the early induction of cellular senescence with senescence-associated beta-galactosidase activity and upregulation of p16INK4A and p21WAF1. In contrast, when EML4-ALK was expressed in telomerase reverse transcriptase (hTERT)-immortalized normal huma..... READ ARTICLE

Cancer Research DOI:10.1158/1538-7445.AM2020-4900

Authors: Masaru Matsumoto, Akihiko Miyanaga, Jessica Beck, Izumi Horikawa, Mohammed Khan, Delphine Lissa, Masahiro Seike, Akihiko Gemma, Hiroyuki Mano and Curtis Harris

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Conference PaperKirk SmithEML4-ALK, non-small cell lung cancer, NSCLC
Analysis of multigene detection in patients with advanced lung adenocarcinoma using cytological specimens
Analysis of multigene detection in patients with advanced lung adenocarcinoma using cytological specimens

Objective: To investigate the mutation status and clinical characteristics of multigene detection in advanced lung adenocarcinoma using cytological specimens... Conclusions: In the study, cytological specimens and biopsy samples have a very high coincidence rate of gene detection. EGFR, ALK and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma. We speculate that EGFR and ALK are more prone to concomitant mutations respectively and the treatment of advanced lung adenocarcinoma patients with concomitant mutations deserves further study. The rate of KRAS, NRAS, BRAF, PIK3CA, RET and MET exon14 skipping mutation were low but may had a significant impact on the targeted therapy of patients with advanced lung adenocarcinoma. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2020.153036

Authors: Yang Ma, Yun Du, Rui Wang, Xiaokun Ji, Juan Wu, Ying Liu, Xiao Guo, Yan Zhang

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Review PaperKirk SmithLung adenocarcinoma, Cytological, Specimen, ARMS, Driver mutations
Novel PNPT1-ALK fusion variant exerted significant benefit to crizotinib in NSCLC
Novel PNPT1-ALK fusion variant exerted significant benefit to crizotinib in NSCLC

The frequency of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) is approximately 3%–5% [ [1] ], and the administration of ALK tyrosine kinase inhibitors has achieved impressive outcomes. Apart from EML4–ALK, various ALK fusion partner genes have recently been identified [ [2] ]. In this case, we report a novel PNPT1 (polyribonucleotide nucleotidyl transferase 1)–ALK fusion responding to crizotinib in a patient with lung adenocarcinoma. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.05.014

Authors: Linling Jin, Yanli Wang, Si Li, Dongsheng Chen, Xin Zhao

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Case StudyKirk SmithPNPT1-ALK, fusion variant, crizotinib, NSCLC