Effectiveness of alectinib and osimertinib in a brain metastasized lung adenocarcinoma patient with concurrent EGFR mutations and DCTN1-ALK fusion

The echinoderm microtubule associated protein-like 4 gene (EML4) encodes the predominant anaplastic lymphoma kinase (ALK) fusion partner in non-small-cell lung cancer (NSCLC); however, the dynactin subunit 1 (DCTN1)-ALK rearrangement is extremely rare. The co-occurrence of primary epidermal growth factor receptor (EGFR) T790M mutation with EGFR exon 19 deletion (del) in patients with NSCLC is uncommon. Here we report a female lung adenocarcinoma patient with brain metastases and possible coexistence of primary EGFR T790M mutation/EGFR exon 19 del/DCTN1-ALK translocation. The patient received multiline treatment including chemotherapy, antivascular, and targeted therapies. To overcome developed resistance to chemotherapy or targeted therapy to prolong overall survival, the patient's circulating tumor DNA (ctDNA) was dynamically monitored. The patient responded to successive osimertinib and alectinib treatment, and alectinib achieved a nearly complete response for lung and brain lesions ..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14291

Authors: Shuyuan Wang, Bo Yan, Yanwei Zhang, Jianlin Xu, Rong Qiao, Yu Dong, Bo Zhang, Yiming Zhao, Lele Zhang, Jie Qian, Jun Lu, Ruiying Zhao, Baohui Han

Case Study, group1Kirk SmithDecember 28, 2021alectinib, osimertinib, brain metastasis, ALK, lung, EGFR, DCTN1-ALK

Identification of triple gene fusion ALK-LRRN2, LTBP1-ALK, and HIP1-ALK in advanced lung adenocarcinoma and response to alectinib: A case report

Together, we identified a rare triple ALK fusion variant, ALK-LRRN2, LTBP1-ALK and HIP1-ALK, in a patient with lung adenocarcinoma. The patient benefited from alectinib treatment, which could provide a certain reference for the patients with such gene alteration. READ ARTICLE

Medicine DOI:10.1097/MD.0000000000027999

Authors: Ning S, Shi C, Zhang H and Li J.

Case Study, group1Kirk SmithDecember 23, 2021alectinib, ALK-LRRN2, HIP1-ALK, LTBP1-ALK, lung adenocarcinoma, triple fusions

Fatal Tumour Lysis Syndrome Induced by Brigatinib in a Lung Adenocarcinoma Patient Treated With Sequential ALK Inhibitors: A Case Report

Tumour lysis syndrome (TLS) represents a group of fatal metabolic derangements resulting from the rapid breakdown of tumour cells. TLS typically occurs soon after the administration of chemotherapy in haematologic malignancies but is rarely observed in solid tumours. Here, we report a case of brigatinib-induced TLS after treatment with sequential anaplastic lymphoma kinase (ALK) inhibitors in a patient with advanced ALK-rearranged lung adenocarcinoma. The patient was treated sequentially with crizotinib, alectinib, and ensartinib. High-throughput molecular profiling after disease progression indicated that brigatinib may overcome ALK resistance mutations, so the patient was administered brigatinib as the fourth-line treatment. After 22 days of therapy, he developed oliguria, fever, and progressive dyspnoea. Clinical manifestations and laboratory findings met the diagnostic criteria for TLS. The significant decrease in the abundance of ALK mutations in plasma indicated a therapeutic res..... READ ARTICLE

Frontiers in Pharmacology DOI:10.3389/fphar.2021.809467

Authors: Wang Yadong, Wang Tiange, Xue Jianchao, Jia Ziqi, Liu Xinyu, Li Bowen, Li Ji, Li Xiaoguang, Wang Weiwei, Bing Zhongxing, Cao Lei, Cao Zhili, Liang Naixin

Case Study, group1Kirk SmithDecember 20, 2021Tumour lysis syndrome (TLS), brigatinib, ALK

Clinical Impact of Switching to Ceritinib After Severe AEs Related to Crizotinib/Alectinib in a Novel PTH2R-ALK Fusion Lung Adenocarcinoma: A Case Report

Lung cancer is still the leading cause of morbidity and mortality by cancer among men, according to the latest epidemiological data in China. Anaplastic lymphoma kinase (ALK) rearrangements act as key oncogenic drivers of non-small cell lung cancer (NSCLC) and have been identified in 5– 6% of NSCLC. Although ALK inhibitors (ALK-TKIs) were proven to be more effective than chemotherapy in ALK-positive NSCLC patients and the safety profile of these drugs was favorable, novel ALK fusions NSCLC might discontinue or switch treatment because of adverse events (AEs) have rarely previously been reported. Here, we describe a male patient with stage IV lung adenocarcinoma who carried a novel PTH2R-ALK fusion identified by next-generation sequencing (NGS). The patient first took crizotinib but switched to alectinib due to gastrointestinal AEs. Although alectinib remained effective on tumors, ceritinib (450 mg) was replaced after the AEs of hyperbilirubinemia occurred. After reducing the dose to 30..... READ ARTICLE

OncoTargets and Therapies DOI:10.2147/OTT.S340984

Authors: Shen G, Du Y, Shen J, Zhang J, Xia X, Huang M and Shen W.

Case Study, group1Kirk SmithDecember 9, 2021PTH2R-ALK, non-small cell lung cancer, ceritinib, adverse events

Coexistence of a novel NBEA-ALK, EML4-ALK double-fusion in a lung adenocarcinoma patient and response to alectinib: A case report

This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.10.015

Authors: Qi Liang, Huanhuan Xu, Yiqian Liu, Weiming Zhang, Chongqi Sun, Meng Hu, Yizhi Zhu, Shanyue Tan, Xian Xu, Sumeng Wang and Lingxiang Liu

ALK rearrangements in infantile fibrosarcoma-like spindle cell tumors of soft tissue and kidney

Recurrent alterations in receptor tyrosine kinase (RTK) and downstream effectors are described in infantile fibrosarcoma (IFS)/cellular congenital mesoblastic nephroma (cCMN) and a subset of spindle cell sarcomas, provisionally designated “NTRK-rearranged” spindle cell neoplasms. These two groups of tumors demonstrate overlapping morphologies and harbor alterations in NTRK1/2/3, RET, MET, ABL1, ROS1, RAF1, and BRAF, although their relationship is not fully elucidated. We describe herein a cohort of pediatric tumors with clinicopathologic features not typical for inflammatory myofibroblastic tumor, but rather with similarities to cCMN/IFS harboring ALK fusions.
Clinicopathologic features were assessed and partner agnostic targeted RNA sequencing on clinically validated platforms were performed. Tumors occurred in patients from 2 to 10 years (median age 2 years) with a 2:2 male to female ratio and an average size of 8.4 cm. Two tumors arose in soft tissues and 2 in the kidney. Morphologi..... READ ARTICLE

Histopathology DOI:10.1111/his.14603

Authors: Serena Y. Tan, Alyaa Al-Ibraheemi, William A. Arhens, Javier E. Oesterheld, Julie C. Fanburg-Smith, Yajuan J. Liu, Sheri L. Spunt, Erin R. Rudzinski, Cheryl Coffin, Jessica L. Davis

Dramatic response to alectinib in a lung cancer patient with a novel VKORC1L1-ALK fusion and an acquired ALK T1151K mutation

ALK-rearranged lung cancer defines a distinctive molecular cohort of patients whose
outcomes are significantly improved by the availability of ALK inhibitors. Thus, it is imperative
for clinicians to screen appropriate patients for this driver mutation with a molecular testing
platform capable of capturing all ALK fusions. Here, we report a novel VKORC1L1-ALK fusion
and an ALK T1151K resistance mutation detected in a lung cancer patient who had been on
crizotinib for over 8 years. Alectinib induced a dramatic response in this patient demonstrating
its clinical activity against T1151K. This case illustrates the importance of performing repeat
biopsy to explore mechanism(s) of resistance when patients experience disease progression
on an ALK inhibitor. The approach has a direct therapeutic impact particularly when an ALK
resistance mutation is identified. READ ARTICLE

Lung Cancer: Targets and Therapy
DOI:10.2147/LCTT.S186804

Authors: Viola W Zhu, Alexa B Schrock, Thangavijayan Bosemani, Bryan S Benn, Siraj M Ali, and Sai-Hong Ignatius Ou

Case Study, group2Kirk SmithNovember 29, 2021VKORC1L1, T1151, fusion, resistance, crizotinib, lorlatinib

Identification of a High-Level MET Amplification in CTCs and cfTNA of an ALK-Positive NSCLC Patient Developing Evasive Resistance to Crizotinib

We report the case of a 47-year-old female patient with stage IV NSCLC harboring an echinoderm microtubule associated protein like 4 (EML4)-ALK E20;A20 fusion who was initially treated with four cycles of platinum/pemetrexed until progressive disease. Thereafter, she was treated with crizotinib for 9 months until development of evasive resistance. Subsequently, the patient was primarily resistant to alectinib and ceritinib.
We obtained low-pass copy number profiles of single isolated CTCs after the patient had experienced development of evasive resistance to crizotinib and shown primary resistance to alectinib. Furthermore, we generated additional copy number profiles of CTCs upon development of primary resistance to ceritinib. These analyses revealed the presence of an approximately eightfold MNNG HOS Transforming gene (MET) amplification in all evaluable CTCs at both time points. MET amplification (∼sevenfold) could also be detected in the cfTNA at comparable time points.
This study ..... READ ARTICLE

Journal of Thoracic Oncology
DOI:10.1016/j.jtho.2018.08.2025

Authors: Lars-Arne Berger, Melanie Janning, Janna-Lisa Velthaus, Isabel Ben-Batalla, Stefanie Schatz, Markus Falk, Peter Iglauer, Ronald Simon, Ru Cao, Claudio Forcato, Nicolò Manaresi, Kelli Bramlett, Genny Buson, Annkathrin Hanssen, Markus Tiemann, Guido Sauter, Carsten Bokemeyer, Sabine Riethdorf, Martin Reck, Klaus Pantel, Harriet Wikman, and Sonja Loges

Case Study, group2Kirk SmithNovember 29, 2021Crizotinib, Resistance, MET amplification

Epithelioid inflammatory myofibroblastic sarcoma with VCL-ALK fusion of central nervous system: case report and brief review of the literature

Epithelioid inflammatory myofibroblastic sarcomas are an aggressive variant of inflammatory myofibroblastic tumor described primarily in the abdomen and less commonly in pulmonary location. The anaplastic lymphoma kinase (ALK) fusion partners described in this tumor include RANB2, RRBP1 and EML4. While rare examples of inflammatory myofibroblastic tumors have been described in the central nervous system, the epithelioid variant has never been described. The ALK-VCL fusion has been described in renal cell carcinoma, high-grade glioma and epithelioid fibrous histiocytoma but has not been described in epithelioid inflammatory myofibroblastic sarcoma or even inflammatory myofibroblastic tumor. Herein, we report the first case of epithelioid inflammatory myofibroblastic sarcoma in the central nervous system as well as the first case with VCL as the fusion partner for ALK. READ ARTICLE

Brain Tumor Pathology DOI:10.1007/s10014-021-00416-z

Authors: Shefali Chopra, Nolan Maloney & Wei Lien Wang

A Case of Small Cell Lung Carcinoma Harboring an EML4–ALK Fusion with Partial Response to Crizotinib

Clinical Practice Points: •A patient with metastatic small cell lung cancer (SCLC) had an echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) fusion.
•He had a partial response to crizotinib in the primary lesions.
•ALK tyrosine kinase inhibitors should be considered in SCLC patients with EML4–ALK fusions.
•Gene testing should be performed in young SCLC patients with a limited smoking history. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2021.03.012

Authors: Qian Shen, Farhin Shaheed Kalyani, Jingjing Qu, Zhen Chen, Jing Zhang, Jianying Zhou

Case StudyKirk SmithNovember 1, 2021SCLC, EML4-ALK, Crizotinib, Partial response, Gene testing

Novel treatment of endobronchial inflammatory myofibroblastic tumor in a child

Isolated endobronchial inflammatory myofibroblatic tumors (IMT) are rare, accounting for about 1% of primary endobronchial tumors in children. The mainstay of treatment for this tumor has been surgical resection. Recently, the identification of anaplastic lymphoma kinase (ALK) gene mutations in half of the IMTs and promising results of treatment with ALK inhibitors in other ALK-positive tumors have opened the possibility of alternative approaches. We present a 4-year-old child with an ALK-positive endobronchial IMT, treated with endoscopic resection and neoadjuvant therapy with Crizotinib, without evidence of tumor recurrence 2 years after the initial resection. READ ARTICLE

Pediatric Pulmonology DOI:10.1097/CAD.0000000000001224

Authors: Jessica Reyes-Angel, Louis B. Rapkin, Jeffrey P. Simons and Hiren Muzumdar

Targeted Therapy in a Young Adult With a Novel Epithelioid Tumor Driven by a PRRC2B-ALK Fusion

This case report describes an 18-year-old woman with an unusual epithelioid tumor of the omentum with a novel PRRC2B-ALK fusion. Although the atypical pathologic features raised significant diagnostic challenges, expression of CD30 on tumor cells and detection of an ALK rearrangement provided critical information for selecting targeted therapy in a patient not suitable for surgical resection. Despite an initially promising therapeutic response, the patient died. The efficacy of treatment was confirmed by the lack of viable tumor cells at autopsy. This case highlights the role of timely targeted therapy in patients with rare tumors and novel actionable molecular targets. READ ARTICLE

Journal of the National Comprehensive Cancer Network DOI:10.6004/jnccn.2021.7056

Authors: Ajay Gupta, Huifei Liu, Kathleen M. Schieffer, Selene C. Koo, Catherine E. Cottrell PhD, Elaine R. Mardis, Ryan D. Roberts and Nicholas D. Yeager MD

Case Study, group2Kirk SmithOctober 15, 2021PRRC2B-ALK, abdominal mass

Brigatinib treated ALK positive lung squamous cell carcinoma after failed chemotherapy: A case report

The definitive efficacy of anaplastic lymphoma kinase (ALK) inhibitors in ALK positive lung squamous cell carcinoma (sqCC) patients remain unclear. Here, we report a case in which brigatinib had a therapeutic effect on ALK-positive lung squamous cell carcinoma. The patient in this report was diagnosed with ALK-positive lung squamous cell carcinoma with brain metastases, and received brigatinib after failure of first-line chemotherapy. Response duration was approximately 11 months, with tolerable side effects. In conclusion, a good clinical effect was achieved in a patient with ALK positive lung squamous cell carcinoma who received treatment with an ALK inhibitor. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14133

Authors: Shuluan Li, Pei Zhang, Tianyu Wang, Jie Wang, Jianchun Duan,

Case Study, group2Kirk SmithOctober 13, 2021ALK, brigatinib, chemotherapy lung squamous cell carcinoma

A Novel ME1-ALK Fusion Identified in an Invasive Lung Adenocarcinoma Patient with Micropapillary and Solid Patterns: Case Report

Background: Anaplastic Lymphoma Kinase (ALK) re arrangement is observed in about 3% to
7% lung Adenocarcinoma (ADC). With the development of Next-Generation Sequencing (NGS)
technology, more novel ALK fusions have been discovered, which can provide patients more
opportunities to receive target therapies and achieve clinical effects.
Case Report: A case of an invasive lung ADC patient with micropapillary and solid patterns
harboring a novel ALK fusion (ME1-ALK) was reported. Then, thoracoscopic resection of right upper
lung and cautery division of pleural adhesions were performed with general anesthesia. Considering
that solid and micropapillary components accounted for 50%, nedaplatin plus pemetrexed were
administrated for 4 cycles after operation with the patient's consent. The patient had no recurrence
and the Disease Free Survival (DFS) was 10 months by May 17th, 2021.
Conclusion: This case highlights that NGS profiling can identify more novel fusions and help solid/
micropapillary-lung ADC patients find more opportunities to receive target therapies if the patient
recurrence. READ ARTICLE

Annuals of Clinical Case Report DOI:ISSN: 2474-1655

Authors: Wang X, Zhang C, Shang Z, Yang D, Li M, Luo N, Wu Y

Efficacy of Targeted Inhibitors in Metastatic Lung Squamous Cell Carcinoma With EGFR or ALK Alterations

The efficacy of targeted therapies in oncogene-driven lung adenocarcinomas (LUADs) has been well established; however, the benefit for EGFR-mutant or ALK-rearranged lung squamous cell carcinomas (LUSCs) is less known, partially owing to the rarity of the incidence. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtocrr.2021.100237

Authors: Whitney E. Lewis, Lingzhi Hong, Frank E. Mott, George Simon, Carol C. Wu, Waree Rinsurongkawong, J. Jack Lee, Vincent K. Lam, John V. Heymach, Jianjun Zhang, Xiuning Le

Successful treatment with lorlatinib in a patient with meningeal carcinomatosis of ALK-positive non-small cell lung cancer resistant to alectinib and brigatinib

Although anaplastic lymphoma kinase (ALK) inhibitors are effective treatment options for ALK-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis, achieving long-term survival in patients with NSCLC with meningeal carcinomatosis resistant to ALK inhibitors is difficult. Lorlatinib, a third-generation ALK inhibitor, was designed for selective CNS penetration, and exerts potent antitumor activity against tumors resistant to first- and/or second-generation ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis. Here, we report a case of ALK-positive lung adenocarcinoma with meningeal carcinomatosis in which lorlatinib was used after resistance to alectinib and brigatinib.We find lorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors. Therefore, lorlatinib should be considered in such cases, even when patients exhibit serious symptoms associated with meningeal carcinomatosis. READ ARTICLE

Medicine DOI:10.1097/MD.0000000000027385

Authors: Nakashima, Koki MD, Demura, Yoshiki MD, PhD, Kurokawa, Kosuke MD, Takeda, Toshihiro MD, Jikuya, Norihiro MD, Oi, Masahiro MD, Tada, Toshihiko MD, Akai, Masaya MD, PhD, Ishizuka, Tamotsu MD, PhD

Identification of a Novel SLC8A1-ALK Fusion and Non-Canonical Expression Significantly Responding to ALK-TKIs in Lung Adenocarcinoma: A Case Report

Approximately 2–7% of patients with non-small cell lung cancer harbor anaplastic lymphoma kinase (ALK) rearrangement events. Of note, typical ALK actionable rearrangements are sensitive to treatment with tyrosine kinase inhibitors (TKIs). However, different types of ALK fusion influence the clinical outcomes of this therapeutic approach. Approximately 10–40% of patients with ALK-fusion positive non-small cell lung cancer do not response to ALK-TKI therapy. Therefore, it is important to accurately identify the types of ALK rearrangement for appropriate selection of clinical treatment. We find a strategy combining DNA-targeted next-generation sequencing with RNA reverse transcriptase-polymerase chain reaction and sequencing, besides fluorescence in situ hybridization and immunohistochemistry, may provide an effective and practical solution for correct identification of partner genes and fusion structures in the diagnosis of ALK rearrangements, particularly for non-canonical expression patterns of ALK fusion events. The combined approach may lead to more benefits for patients. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S319845

Authors: Xingyu Zhu, Yuqi He, Yin Wang,Yan Lei, Xiaoxing Su, Yifan Liu, Shuangxiu Wu, Zhengfu He

Mixed responses to first-line alectinib in non-small cell lung cancer patients with rare ALK gene fusions: A case series and literature review

Anaplastic lymphoma kinase (ALK) fusion is a well-defined biomarker for ALK tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC). Alectinib, a second-generation ALK-TKI, has been shown to have significantly longer progression-free survival (PFS) than first-generation ALK inhibitors in untreated ALK-rearranged NSCLC patients. However, its clinical efficacy on rare ALK fusions remains unclear. Herein, two advanced NSCLC patients received first-line alectinib treatment, given their positive ALK fusion status as determined by immunohistochemistry (IHC) testing results. Patients showed limited clinical response (PFS: 4 months) and primary resistance to alectinib respectively. Molecular profiling using next-generation sequencing (NGS) further revealed a striatin (STRN)-ALK fusion in the first patient accompanied by MET amplification, and a LIM domain only protein 7 (LMO7)-ALK fusion in another patient without any other known oncogenic alterations. Both patients d..... READ ARTICLE

Wiley DOI:10.1111/jcmm.16897

Authors: Mengnan Li, Zhou An, Qiusu Tang, Yutong Ma, Junrong Yan, Songan Chen, Yina Wang

Case StudyKirk SmithSeptember 19, 2021ALK, alectinib, NGS, molecular profiling

STRN-ALK Fusion in a Case of Malignant Peritoneal Mesothelioma: Mixed Response to Crizotinib, Mode of Resistance, and Brigatinib Sequential Therapy

To our knowledge, this is the first description of an STRN-ALK fusion(+) MPM sequentially treated with two different ALK inhibitors. This case underlines the benefit of molecular testing in MPM. Furthermore, it suggests the generalizability of the lessons learned from lung cancer to another entity, which can offer some guidance in the treatment of this rare disease. READ ARTICLE

Journal of Clinical Oncology: Precision Oncology DOI:10.1200/PO.21.00184

Authors: Valeria Gerthofer, Alexander Scheiter, Florian Lüke, Felix Keil, Kirsten Utpatel, Laura-Maria-Giovanna
Pöhmerer, Johannes Seitz, Christoph Niessen, Atanas Ignatov, Wolfgang Dietmaier, Diego F. Calvisi, Matthias Evert, Olaf Ortmann, and Stephan Seitz

High Tumor Mutation Burden and DNA Repair Gene Mutations are Associated with Primary Resistance to Crizotinib in ALK-Rearranged Lung Cancer

About 20% of patients with ALK-rearranged non-small cell lung cancer (NSCLC) develop acquired resistance to tyrosine kinase inhibitor (TKI) during the first 6 months. This study aimed to examine the molecular mechanisms of early TKI resistance and prognosis in ALK-rearranged NSCLC.Ten patients with ALK-rearranged NSCLC were included: five who developed rapid resistance to crizotinib (progression-free survival (PFS) ≤3 months) and five who exhibited a good response to crizotinib (PFS ≥36 months). The study finds a higher mutation burden and mutations in DNA repair gene, including TP53, were potentially associated with primary resistance to crizotinib in ALK-rearranged NSCLC. An immune-checkpoint inhibition strategy could be examined, which might overcome primary resistance to crizotinib in ALK-rearranged NSCLC. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S325443

Authors: Dakai Xiao, Qiuhua Deng, Dongyun He, Ying Huang, Wenchi Liang, Fengnan Wang, Haihong Yang

Case StudyKirk SmithSeptember 15, 2021ALK, non-small cell lung cancer, TKI, resistance, prognosis