Posts tagged ALK
Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001
Association of anticoagulant use with clinical outcomes from crizotinib in ALK- and ROS1-rearranged advanced non-small cell lung cancers: A retrospective analysis of PROFILE 1001

Background: ROS1- and ALK-rearranged advanced NSCLCs are associated with increased thromboembolic risk. We hypothesized that a prothrombotic phenotype offers an evolutionary advantage to subsets of these cancers. The impact of this phenotype could alter outcomes from targeted therapy.

Methods: In a retrospective analysis of ROS1- and ALK-rearranged NSCLCs treated with crizotinib in a phase 1 trial, we compared progression-free survival (PFS) and objective response rate (ORR) based on the history of anticoagulation use (a possible surrogate of thromboembolism) at baseline (within 90 days before study enrollment) or within 90 days of study treatment.

Results: Twelve out of 53 (22.6%) ROS1- and 39 out of 153 (25.5%) ALK-rearranged NSCLCs received anticoagulation before or during the trial. Most ROS1 and ALK patients on anticoagulation received low-molecular-weight heparin (75% and 64.1%, respectively). In the ROS1-rearranged group, the median PFS (95% CI) values were 5.1 (4.4-14.4) and 29.0 (16.5-48.8) months, and the ORR values were 41.7% (95% CI: 15.2 to 72.3) and 80.5% (95% CI: 65.1 to 91.2) among those with and without anticoagulation treatment, respectively. In the ALK-rearranged group, the median PFS (95% CI) was 7.1 (5.4-7.7) and 12.0 (9.4-18.3) months, and the ORR was 41% (95% CI: 25.6 to 57.9) and 74.3% (95% CI: 65.3 to 82.1) among those with and without anticoagulation, respectively.

Conclusions: Anticoagulation (as a potential surrogate of a prothrombotic subset) in ROS1- and ALK-rearranged NSCLCs may be associated with a lower PFS and ORR to crizotinib. READ ARTICLE

Cancer Medicine DOI:10.1002/cam4.4789.

Authors: Ng TL, Tsui DCC, Wang S, Usari T, Patil T, Wilner K, Camidge DR.

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Clinical TrialsKirk SmithALK, ROS1, crizotinib, lung cancer, thromboembolism
Tumor Shrinkage With Combination of Alectinib and Trastuzumab in a Patient With ALK-Rearranged Non–small Cell Lung Cancer Harboring HER2-Amplification...
Tumor Shrinkage With Combination of Alectinib and Trastuzumab in a Patient With ALK-Rearranged Non–small Cell Lung Cancer Harboring HER2-Amplification...

Clinical Practice Points:
• HER2 amplification is an acquired resistance mechanism in ALK-rearranged non–small cell lung cancer.
• FISH analysis revealed a minor subclone of HER2-amplified cells before becoming the dominant resistance mechanism.
• Combination of HER2 and ALK therapies may be an effective treatment approach for ALK-rearranged NSCLC with acquired HER2 amplification. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2021.06.012

Authors: David Chun Cheong Tsui, Dara Aisner, Hala Nijmeh, Liming Bao, Alexander Menter, D. Ross Camidge

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Case StudyKirk SmithALK, HER2, Lung cancer, Acquired resistance, Trastuzumab
ALKtALK talk with Dr Alice Shaw
ALKtALK talk with Dr Alice Shaw

Meet the Queen of Alk, Dr. Alice Shaw. Join Dr. Shaw and Gina Hollenbeck for an informal chat as they discuss Dr. Shaw's take on how treatment for the ALK Positive mutation has evolved and where it is going. Bone metastasis, pregnancies and fertility while taking tki's, and treatment dosing are just a few of the topics covered. Dr. Alice Shaw worked for over 15 years at Massachusetts General Hospital as a clinical trial investigator. She helped lung cancer evolve from a disease with few options, to one of hope with clinically proven therapies. Dr. Shaw continues to push the envelope as the Global Head of Translational Clinical Oncology at the Novartis Institutes for BioMedical Research. WATCH VIDEO

ALK Positive Inc

Authors: Dr. Alice Shaw

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VideoKirk SmithALK
A Case of ALK‐Rearranged Combined Lung Adenocarcinoma and Neuroendocrine Carcinoma with Diffuse Bone Metastasis and Partial Response to Alectinib
A Case of ALK‐Rearranged Combined Lung Adenocarcinoma and Neuroendocrine Carcinoma with Diffuse Bone Metastasis and Partial Response to Alectinib

We report a rare case of stage IV pulmonary combined large-cell neuroendocrine carcinoma
(LCNEC) and adenocarcinoma (ACA), both demonstrating anaplastic lymphoma kinase (ALK)
rearrangement by IHC and FISH. This 61-year-old lifelong nonsmoking Asian woman presented with
a cough, and after diagnosis and surgical treatment, completed four cycles of adjuvant cisplatin and
etoposide chemotherapy. She subsequently developed recurrence with bony metastases of exclusively
ALK-positive LCNEC. Alectinib was started, and the patient experienced a partial response READ ARTICLE

Current Oncology DOI:10.3390/curroncol29020072

Authors: Chloe A. Lim, Norbert Banyi, Tracy Tucker, Diana N. Ionescu, Barbara Melosky

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Case StudyKirk Smithneuroendocrine, adenocarcinoma, driver mutation, ALK, LCNEC
Analyzing the morphological spectrum of epithelioid fibrous histiocytoma and the immunohistochemical performance of the ALK D5F3 and ALK1 clones
Analyzing the morphological spectrum of epithelioid fibrous histiocytoma and the immunohistochemical performance of the ALK D5F3 and ALK1 clones

Epithelioid fibrous histiocytoma (EFH) is a cutaneous neoplasm driven by translocations of the anaplastic lymphoma kinase (ALK) gene, which can be demonstrated by immunohistochemical (IHC) analysis. We analyzed the performance of two ALK clones, D5F3 and ALK1, in a cohort of EFHs and described the range of architectural variation of these lesions. TFE3 IHC was performed in ALK-negative EFHs. We identified 21 cases of EFH, 76.2% of which showed an exophytic appearance and 19% displayed flat architecture. A well-developed epidermal collarette was present in 48% of all cases with just more than a third of all the exophytic lesions presenting as dermal-based nodules. ALK D5F3 expression was identified in 76.2% (16/21) of all cases, but only 68.8% were concordantly positive with the ALK1 clone, indicative of a false-negative stain with ALK1 in 31.2% of the cases. For the subset of cases showing positivity for the ALK1 clone, a marked decrease in the percentage of immunolabelled cells was identified when compared with D5F3 (5–50% vs. 100%, respectively). Five cases (23.8%) did not demonstrate ALK expression for either clone, with 3 of those cases showing nuclear positivity for TFE3 IHC and the remaining 2 cases being double negative (ALK-/TFE3-). In summary, we identified that the prototypically described exophytic appearance with epidermal collarette is present in only less than half of the cases. We also demonstrated that the ALK1 antibody is suboptimal in EFH and should not be utilized in this setting. A subset of ALK-negative cases express TFE3, but double-negative cases occur. READ ARTICLE

Human Pathology DOI:10.1016/j.humpath.2021.12.004

Authors: Leila Moayed-Alaei, Ana Cristina Vargas, Dariush Adybeik, Fiona Maclean, Denis Moir

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Case StudyKirk SmithEpithelioid fibrous histiocytoma, ALK, D5F3, ALK1, Clone
Safety and activity of WX-0593 (Iruplinalkib) in patients with ALK- or ROS1-rearranged advanced non-small cell lung cancer: a phase 1 dose-escalation and dose-expansion trial
Safety and activity of WX-0593 (Iruplinalkib) in patients with ALK- or ROS1-rearranged advanced non-small cell lung cancer: a phase 1 dose-escalation and dose-expansion trial

WX-0593 (Iruplinalkib) is a novel, highly selective oral ALK and ROS1 tyrosine kinase inhibitor (TKI). In this study, the safety, antitumor activity, and pharmacokinetics of WX-0593 were evaluated in advanced non-small cell lung cancer (NSCLC) patients with ALK or ROS1 rearrangement. In the dose-escalation phase and dose-expansion phase, patients were treated with WX-0593 until disease progression, unacceptable toxicity, or subject withdrawal. In the dose-escalation phase, the primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and safety assessed by investigators. In the dose-expansion phase, the primary endpoint was objective response rate (ORR) assessed by investigators. Between September 25, 2017 and October 15, 2018, a total of 153 patients received WX-0593 treatment. Two dose-limiting toxicities (DLTs) including one grade 3 QT interval prolonged and one grade 2 chronic heart failure were reported at the dose of 300 mg in one patient. MTD was not rea..... READ ARTICLE

Signal Transduction and Targeted Therapy DOI:10.1038/s41392-021-00841-8

Authors: Shi, Y., Fang, J., Hao, X. et al.

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Clinical TrialsKirk SmithWX-0593 (Iruplinalkib), ALK, ROS1, tyrosine kinase inhibitor (TKI), maximum tolerated dose (MTD), dose-limiting toxicity (DLT)
Multiplex fluorescence in situ hybridization testing for anaplastic lymphoma kinase and c-ros oncogene 1 gene rearrangements on cytology smears in lung adenocarcinomas:..
Multiplex fluorescence in situ hybridization testing for anaplastic lymphoma kinase and c-ros oncogene 1 gene rearrangements on cytology smears in lung adenocarcinomas:..

Introduction: Multiplex anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) fluorescence in situ hybridization (FISH) probes conserve tissue by analyzing both ALK and ROS1 gene rearrangements (ALK-R/ROS1-R) in a single test. The positivity cutoffs have been validated on formalin-fixed, paraffin-embedded (FFPE) tissue sections and not tested on non–cell block (CB) cytology preparations. We sought to validate non-CB cytology preparations for the detection of ALK-R/ROS1-R using multiplex ALK/ROS1 FISH probes by comparing the results with matched FFPE results... Conclusions: Non-CB cytology smears are highly suitable for multiplex FISH analysis with 100% concordance with FFPE FISH and/or ALK D5F3 companion diagnostics assay results. READ ARTICLE

Journal of the American Society of Cytopathology DOI:10.1016/j.jasc.2022.01.001

Authors: Aruna Nambirajan, Deeksha Rana, Komal Samant, Aswini Prabakaran, Prabhat Malik, Deepali Jain

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Review PaperKirk SmithALK, ROS1, Multiplex FISH, Cytology smear, Lung adenocarcinoma
Effectiveness of alectinib and osimertinib in a brain metastasized lung adenocarcinoma patient with concurrent EGFR mutations and DCTN1-ALK fusion
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

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Case Study, group1Kirk Smithalectinib, osimertinib, brain metastasis, ALK, lung, EGFR, DCTN1-ALK
Deciphering the Mechanism of Gilteritinib Overcoming Lorlatinib Resistance to the Double Mutant I1171N/F1174I in Anaplastic Lymphoma Kinase

Anaplastic lymphoma kinase (ALK) is validated as a therapeutic molecular target in multiple malignancies, such as non-small cell lung cancer (NSCLC). However, the feasibility of targeted therapies exerted by ALK inhibitors is inevitably hindered owing to drug resistance. The emergence of clinically acquired drug mutations has become a major challenge to targeted therapies and personalized medicines. Thus, elucidating the mechanism of resistance to ALK inhibitors is helpful for providing new therapeutic strategies for the design of next-generation drug. Here, we used molecular docking and multiple molecular dynamics simulations combined with correlated and energetical analyses to explore the mechanism of how gilteritinib overcomes lorlatinib resistance to the double mutant ALK I1171N/F1174I. We found that the conformational dynamics of the ALK kinase domain was reduced by the double mutations I1171N/F1174I. Moreover, energetical and structural analyses implied that the double mutations ..... READ ARTICLE

Frontiers of Cell and Developmental Biology DOI:10.3389/fcell.2021.808864

Authors: Liang Shuai, Wang Qing, Qi Xuesen, Liu Yudi, Li Guozhen, Lu Shaoyong, Mou Linkai, Chen Xiangyu

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Pre-Clinical, group1Kirk SmithGilteritinib, Lorlatinib, Resistance, ALK
Fatal Tumour Lysis Syndrome Induced by Brigatinib in a Lung Adenocarcinoma Patient Treated With Sequential ALK Inhibitors: A Case Report
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

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Case Study, group1Kirk SmithTumour lysis syndrome (TLS), brigatinib, ALK
Analysis of methods in the Prospective Central Lung Cancer Biomarker Registry (LungPath) from the Spanish Society of Pathology (SEAP)
Analysis of methods in the Prospective Central Lung Cancer Biomarker Registry (LungPath) from the Spanish Society of Pathology (SEAP)

Aims The aim of this study is to extend the analysis of the Lung Cancer Biomarker Testing Registry (LungPath), by analysing the techniques used in the determination of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ros oncogene 1 (ROS1) and programmed death ligand-1 (PD-L1) for the diagnostic of patients with advanced non-small-cell lung cancer (NSCLC). Methods Information of the technique used for the determination of EGFR, ALK, ROS1 and PD-L1 was recorded from March 2018 to January 2019 from 44 centres, but only 34 centres matched with the 38 centres previously analysed, allowing to analyse the techniques used in 8970 matched determinations of EGFR, ALK, ROS1 and PD-L1. Therefore, a by-centre analysis studied the level of implementation of the techniques in the 44 centres, while a by-determination analysis made it possible to assess the overall frequency of the techniques used on the 9134 matched samples. Results By-centre analysis showed that only 46.5%..... READ ARTICLE

Journal of Clinical Pathology DOI:10.1136/jclinpath-2021-208034

Authors: Martín-López J, Rojo F, Martínez-Pozo A,Hernández-Iglesias T, Carcedo D, Ruiz de Alda L, García JF, Salas C

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Real-World Outcomes, group1Kirk SmithNSCLC, ALK, EGFR, ROS, Biomarker Testing
Outcomes of Gamma Knife Radiosurgery for Brain Metastases From Anaplastic Lymphoma Kinase Rearrangement-Positive and EGFR Mutation-Positive Non-Small Cell Lung Cancer
Outcomes of Gamma Knife Radiosurgery for Brain Metastases From Anaplastic Lymphoma Kinase Rearrangement-Positive and EGFR Mutation-Positive Non-Small Cell Lung Cancer

The outcomes after gamma knife radiosurgery (GKRS) were retrospectively analysed in patients with brain metastases from anaplastic lymphoma kinase (ALK) rearrangement-positive and epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) to evaluate the efficacy, safety and difference for overall survival and local tumor control. ALK rearrangement-positive NSCLC patients tended to have significantly longer survival, but had higher incidence of new intracranial metastases due to long-term survival after GKRS, compared with EGFR mutation-negative and driver gene mutation-negative NSCLC patients. GKRS induced significantly satisfactory local tumor control in driver gene mutation-positive tumors but GKRS-related complication frequency was higher, especially in ALK-positive NSCLC patients. Therefore, more careful imaging follow-up is necessary after GKRS for patients with driver gene mutation-positive NSCLC. READ ARTICLE

Cureus DOI:10.7759/cureus.20398

Authors: Matsunaga S and Shuto T

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Real-World Outcomes, group1Kirk SmithGamma Knife Radiosurgery (GKRS), Brain Metastases, ALK, EGFR, NSCLC
Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials
Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials

Background
Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC.

Methods
We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases.


Results
A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg an..... READ ARTICLE

BMC Cancer DOI:10.1186/s12885-021-08977-0

Authors: Ma HC, Liu YH, Ding KL, Liu YF, Zhao WJ, Zhu YJ, Chang XS, Chen YD, Xiao ZZ, Yu YY, Zhou R, Zhang HB.

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Review Paper, group2Kirk SmithALK, NSCLC, First-line treatment, clinical trial meta-analysis
Genetic landscape of patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study
Genetic landscape of patients with ALK-rearranged non-small-cell lung cancer (NSCLC) and response to ceritinib in ASCEND-1 study

Objectives: To better understand genetic determinants of response to ceritinib, an exploratory analysis was conducted using tumor biopsies from anaplastic lymphoma kinase (ALK)-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients treated with ceritinib at doses of ≥ 300 mg in the ASCEND-1 study. Conclusions: This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.11.007

Authors: D S-W Tan, M Thomas, D-W Kim, S Szpakowski, P Urban, R Mehra, L Q M Chow, S Sharma, B J Solomon, E Felip, D R Camidge, J Vansteenkiste, L Petruzzelli, S Pantano, A T Shaw

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Clinical TrialsKirk SmithALK, Anaplastic lymphoma kinase (ALK), Ceritinib, Gene expression profiling, Molecular cytogenetics, NSCLC, ASCEND-1
P8-133: Clinical course of the patients who survived more than five-years in patients with EGFR mutated OR ALK rearranged advanced non-small cell lung cancer (NSCLC)
P8-133: Clinical course of the patients who survived more than five-years in patients with EGFR mutated OR ALK rearranged advanced non-small cell lung cancer (NSCLC)

Background and Aims: The discovery of driver oncogenes like EGFR mutation and ALK fusion gene, and the development of their specific inhibitors have improved prognosis of NSCLC patients. Because the patients had been followed up to about 5 years in most of the clinical trials, the long-term clinical course especially after 5 years has been undefined. The object is to know clinical course after 5 years from the first chemotherapy, and to investigate factors that lead to long-term survival.
Methods: One hundred seventy-seven patients with EGFR mutated or ALK rearranged advanced NSCLC who received the first chemotherapy between December 2008 and September 2015 were included. Kaplan Meier curves were drawn for the total cohort and for the subgroups of characteristics and metastases.
Results: Median OS in the total cohort was 40.6 months, the 1-year survival rate was 89 %, the 3-year survival rate was 54 %, and the 5-year survival rate was 28 %. “Long tail” in OS curve existed, but most of ..... READ ARTICLE

Respirology DOI:10.1111/resp.14150_645

Authors: Shoko Shimamura, Takehito Shukuya, Tetsuhiko Asao, Daisuke Hayakawa, Kana Kurokawa, Shiting Xu, Yoichiro Mitsuishi, Ken Tajima, Rina Shibayama, Naoko Shimada, Fumiyuki Takahashi, Kazuhisa Takahashi

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Conference PaperKirk SmithEGFR, ALK, 5 years+
P8-170: A patient with ALK translocation-positive lung adenocarcinoma in whom an EGFR mutation developed during the treatment with ALK inhibitors
P8-170: A patient with ALK translocation-positive lung adenocarcinoma in whom an EGFR mutation developed during the treatment with ALK inhibitors

Background: Generally, ALK gene translocation and EGFR gene mutation are mutually exclusive in non-small cell lung cancer (NSCLC). We present a patient with ALK translocation-positive lung adenocarcinoma in whom an EGFR mutation developed during the treatment with an ALK inhibitors.

Case Presentation: A 70-year-old man was diagnosed with Stage IVb (cT2N3M1c) adenocarcinoma of the lung in July 20XX-8. Initial chemotherapy with CDDP+PEM was started in August, and 6 courses were performed with best response of PR. Maintenance therapy was performed for 26 courses. In May 20XX-5, multiple bone metastases emerged and 5 courses of DTX was given as the 2nd-line chemotherapy from July 20XX-5 to May 20XX-4 with the best response of SD until bone metastases developed. A trans-bronchial re-biopsy of the primary tumor in the upper lobe of the right lung revealed the translocation of ALK gene. Crizotinib was started in June as the 3rd-line chemotherapy. In August 20XX-3, multiple brain metastases de..... READ ARTICLE

Respirology DOI:10.1111/resp.14150_682

Authors: Misaki Morishita, Yoshiki Negi, Taiichiro Otsuki, Koji Mikami, Eisuke Shibata, Daisuke Horio, Maiko Niki, Akio Tada, Mayuko Tokuda, Jotaro Kiyota, Toshiyuki Minami, Ryo Takahashi, Takashi Yokoi, Kozo Kuribayashi, Takashi Kijima

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Conference PaperKirk SmithALK and EGFR co-mutation, ALK, EGFR, Co-mutation
Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis
Efficacy and Safety of First-Line Treatment Strategies for Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis

Background: Targeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance.
Conclusions: Lorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.754768

Authors: Ling Peng, Dafeng Lu2, Yang Xia, Shaodong Hong, Giovanni Selvaggi, Justin Stebbing, Yilan Sun, Fei Liang

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Real-World OutcomesKirk Smithnon-small cell lung cancer, ALK, tyrosine kinase inhibitor, network meta-analysis, first-line
New Advances in Liquid Biopsy Technologies for Anaplastic Lymphoma Kinase (ALK)—Positive Cancer
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

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Review Paper, group2Kirk SmithALK, lung cancer, liquid biopsy
Brigatinib treated ALK positive lung squamous cell carcinoma after failed chemotherapy: A case report
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,

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Case Study, group2Kirk SmithALK, brigatinib, chemotherapy lung squamous cell carcinoma
Structural basis of cytokine-mediated activation of ALK family receptors
Structural basis of cytokine-mediated activation of ALK family receptors

Anaplastic lymphoma kinase (ALK)1 and the related leukocyte tyrosine kinase (LTK)2 are recently deorphanized receptor tyrosine kinases3. Together with their activating cytokines, ALKAL1 and ALKAL24,5,6 (also called FAM150A and FAM150B or AUGβ and AUGα, respectively), they are involved in neural development7, cancer7,8,9 and autoimmune diseases10. Furthermore, mammalian ALK recently emerged as a key regulator of energy expenditure and weight gain11, consistent with a metabolic role for Drosophila ALK12. Despite such functional pleiotropy and growing therapeutic relevance13,14, structural insights into ALK and LTK and their complexes with cognate cytokines have remained scarce. Here we show that the cytokine-binding segments of human ALK and LTK comprise a novel architectural chimera of a permuted TNF-like module that braces a glycine-rich subdomain featuring a hexagonal lattice of long polyglycine type II helices. The cognate cytokines ALKAL1 and ALKAL2 are monomeric three-helix bundles..... READ ARTICLE

Nature DOI:10.1038/s41586-021-03959-5

Authors: Steven De Munck, Mathias Provost, Michiko Kurikawa, Ikuko Omori, Junko Mukohyama, Jan Felix, Yehudi Bloch, Omar Abdel-Wahab, J. Fernando Bazan, Akihide Yoshimi & Savvas N. Savvides

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Pre-Clinical, group2Kirk Smithcancer, metabolism, X-ray crystallography, ALK