A pilot of Blood-First diagnostic cell free DNA (cfDNA) next generation sequencing (NGS) in patients with suspected advanced lung cancer

Introduction: The diagnostic pathway for lung cancer can be long. Availability of front-line targeted therapies for NSCLC demands access to good quality tissue for genomic sequencing and rapid reporting of results. Diagnosis of lung cancer and availability of tissue was delayed during the COVID-19 pandemic... Conclusion: Blood-first cfDNA-NGS in NSCLC patients increased the breadth and rapidity of detection of actionable variants with high tissue concordance and led to timely treatment decisions. A blood-first approach should be considered to improve the speed and accuracy of therapeutic decision-making. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2022.01.009

Authors: Wanyuan Cui, Charlotte Milner-Watts, Terri P. McVeigh, Anna Minchom, Jaishree Bholse, Michael Davidson, Nadia Yousaf, Suzanne MacMahon, Hood Mugalaasi, Ranga Gunapala, Richard Lee, Angela George, Sanjay Popat, MaryO'Brien

The Pan-Immune-Inflammation Value predicts the survival of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer treated with first-line ALK inhibitor

The Pan-Immune-Inflammation Value (PIV) has recently been demonstrated as a novel comprehensive biomarker to predict survival of patients with solid tumors. Our study aimed to evaluate the prognostic power of PIV in this group of patients. 94 patients with advanced ALK-positive NSCLC who received first-line ALK inhibitors were enrolled in this study. PIV was calculated as the product of peripheral blood neutrophil, monocyte, and platelet counts divided by lymphocyte count. The 1-year progression-free survival (PFS) was 63.5%, and the 5-year overall survival (OS) rate was 55.1%. Patients with higher PIV, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) had worse PFS in univariate analysis, but only the PIV (hazard ratio [HR] = 2.90, 95% confidence interval [CI]: 1.79–4.70, p < 0.001) was an independent prognostic factor in multivariate analysis. PIV is a comprehensive and convenient predictor of both PFS and OS in pat..... READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2021.101338

Authors: Xinru Chen, Xiangchan Hong, Gang Chen, Jinhui Xue, Jie Huang, Fan Wang, Wael Ab dullah Sultan Ali, Jing Li, Li Zhang

Safety issues with the ALK inhibitors in the treatment of NSCLC: A systematic review

Tyrosine Kinase inhibitors (TKIs) are known to have peculiar toxicity profile, hence, increasing awareness to the safety profile of ALK inhibitors is essential.
A comprehensive systematic review of literature has been conducted to include prospective trials that used the ALK inhibitors Crizotinib, Ceritinib, Alectinib, Brigatinib and Lorlatinib in patients with advanced NSCLC and have available efficacy and toxicity results.
Most of adverse effects of ALKi can be managed efficiently via dose modifications or interruptions. Timely identification of each ALKi pattern of toxicity can prevent treatment-related morbidity and mortality in this palliative setting. READ ARTICLE

Critical Reviews in Oncology/Hematology
DOI:10.1016/j.critrevonc.2018.11.004

Authors: Loay Kassem, Kyrillus S. Shohdy, Shaimaa Lasheen, Omar Abdel-Rahman, Ahmad Ali and Raafat R.Abdel-Malek

Review Paper, group2Kirk SmithNovember 29, 2021ALK inhibitors, Non-small cell lung cancer, Adverse effects

Pharmacometric analyses of alectinib to facilitate approval of the optimal dose for the first-line treatment of anaplastic lymphoma kinase–positive non-small cell lung cancer

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib-failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one-compartment models with sequential zero/first-order input and first-order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment-naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression-free survival in treatment-naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of trea..... READ ARTICLE

CPT: Pharmacometrics & Systems Pharmacology DOI:10.1002/psp4.12702

Authors: Joy C. Hsu, Felix Jaminion, Elena Guerini, Bogdana Balas, Walter Bordogna, Peter N. Morcos, Nicolas Frey

Pre-Clinical, group3Kirk SmithSeptember 21, 2021Non-small cell lung cancer, ALK, Alectinib, Pharmacometric analyses, Optimal dose

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

22 COMPARATIVE EFFICACY OF ALK-INHIBITORS IN ALK INHIBITOR-NAIVE ALK+ LUNG CANCER BRAIN METASTASES: A NETWORK META-ANALYSIS

Lung cancer has been the leading cause of cancer death for both men and women worldwide. Non-small-cell lung cancer (NSCLC) displays an array of molecular abnormalities most commonly involving ALK and EGFR pathways. NSCLC with ALK rearrangements comprises around 5% of cases. Over the years, several ALK inhibitors (ALKI) have been approved with notable activity in brain metastases. However, there have been limited comparative studies exploring their relative efficacies. This analysis was conducted to compare the relative efficacy of ALKIs against ALKI-naïve ALK+ lung cancer brain metastases.This network meta-analysis is the first to compare and rank ALKIs used in treating metastatic ALK+ lung cancer. It indicates that BRG, CER, and ALC are better therapeutic options for patients with ALK-naive ALK+ lung cancer brain metastases when compared to CRZ. READ ARTICLE

Neuro-oncology Advances DOI:10.1093/noajnl/vdaa073.012

Authors: Philip Haddad, Dalia Hammoud, Kevin Gallagher

Real-World OutcomesKirk SmithSeptember 4, 2020Non-small cell lung cancer, NSCLC, ALK, EGFR

Expression Profiling of Driver Genes in Female Never-smokers With Non-adenocarcinoma Non–small-cell Lung Cancer in China

Background: Although smoking is a primary cause of lung cancer, females are overrepresented among never-smokers with the disease. The mutational landscape of adenocarcinoma in never-smoking females has been extensively profiled; however, there is little knowledge about genomic alterations in non-adenocarcinoma non–small-cell lung cancer (NA-NSCLC). In the study, we reviewed the status of oncogenic drivers of NA-NSCLC in these populations... Conclusion: Female never-smokers with NA-NSCLC in this study had a high frequency of currently known or potentially actionable oncogenic alterations and could benefit from targeted therapy. Our study also provides evidence for the recommendation of molecular analysis in never-smoking female SQCC. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.02.005

Authors: Yiming Zhao, Yu Dong, Ruiying Zhao, Bo Zhang, Shuyuan Wang, Lele Zhang, Minjuan Hu, Qingnan He, Wei Zhang, Baohui Han

Real-World OutcomesKirk SmithSeptember 1, 2020Driver gener, Female, Genome, Never-smokers, Non-small cell lung cancer

ALK Inhibitors in ALK-positive NSCLC with Central Nervous System Metastases

In anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer, brain metastases occur in 22–33% of cases at diagnosis and could reach up to 70% after crizotinib failure. Next-generation ALK inhibitors (ngALKi) have superior intracranial activity and prolonged responses compared with crizotinib and chemotherapy, as was shown in treatment-naïve or crizotinib pre-treated patients, irrespective of prior brain irradiation. Nevertheless, central nervous system relapse is also seen with ngALKi. Tailored treatment is necessary to obtain long-term survival without detrimental effects on cognition. Possible options include profiling secondary mutations to select sequential ngALKi, stereotactic radiotherapy and/or surgery, with the aim to avoid/deter whole brain irradiation. READ ARTICLE

touchONCOLOGY DOI:10.17925/EOH.2020.16.1.18

Authors: Mihaela Aldea, Benjamin Besse, Lizza EL Hendriks

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

Detection of Nonreciprocal/Reciprocal ALK Translocation as Poor Predictive Marker in Patients With First-Line Crizotinib-Treated ALK-Rearranged NSCLC

Introduction: During nonreciprocal/reciprocal translocation process, 5′-anaplastic lymphoma kinase (ALK) sometimes gets retained in the genome and is detectable by next-generation sequencing; however, no study has investigated its clinical significance. Our study aimed to assess the impact of harboring 5′-ALK on the efficacy of crizotinib. Conclusions: Presence of nonreciprocal/reciprocal ALK translocation was predictive for worse PFS and greater likelihood of baseline brain metastases in patients with ALK-rearranged NSCLC who received first-line crizotinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.02.007

Authors: Yongchang Zhang, Liang Zeng, Chunhua Zhou, Yizhi Li, Lin Wu, Chen Xia, Wenjuan Jiang, Yijuan Hu, Dehua Liao, Lili Xiao, Li Liu, Haiyan Yang, Yi Xiong, Rui Guan, Analyn Lizaso, Aaron S. Mansfield, Nong Yang

Attenuated isolated 3’ signal: A highly challenging therapy relevant ALK FISH pattern in NSCLC

Objectives: ... Our aim was to examine a unique atypical ALK FISH pattern, revealed during a systematic large-scale monitoring, which carries the great risk of misinterpretation, hence may result in loss of patients eligible for targeted therapy... Conclusion: Approximately 5% of the 59 ALK positive cases exhibited atypical attenuated isolated 3′ signal pattern. The immunohistochemistry and AMP-NGS examinations helped to clarify the presence of oncoprotein and the fusion gene, respectively. Our results emphasize the importance of extensive exploration of the genetic background of any unexpected FISH finding to avoid false diagnosis. This enables clinicians to indicate the adequate therapy with higher efficiency for patients suffering from NSCLC. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.03.007

Authors: Gábor Smuk, Gábor Pajor, Károly Szuhai, Hans Morreau, Ildikó Kocsmár, Éva Kocsmár, László Pajor, Béla Kajtár, Veronika Sárosi, Gábor Lotz, Tamás Tornóczky

Complete response after ceritinib treatment in non-small cell lung cancer in an elderly patient

Introduction Ceritinib is a selective second-generation ALK inhibitor that is highly sensitive to echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) molecule. Case report In this paper, we report a 68-year-old female that was diagnosed with stage 4 ALK-positive non-small cell lung cancer (NSCLC) Management and outcome: She was treated with crizotinib first-line, cisplatin and gemcitabine as second-line. And for third-line, ceritinib was started. She had complete response over 3.5 years under ceritinib treatment. And she is still receiving ceritinib with no adverse event. Discussion Cases achieving complete response with ceritinib treatment are rare. In this paper, we aimed to emphasize the complete response in stage 4 NSCLC in an elderly patient. READ ARTICLE

Journal of Oncology Pharmacy Practice DOI:10.1177/1078155220919172

Authors: Nilay Sengul Samanci, Emir Celik, Burak Akovalı, Sait Sager, Fuat Hulusi Demirelli

Case StudyKirk SmithApril 27, 2020Non-small cell lung cancer, EML4-ALK, ceritinib

Sequential blinded treatment decisions in ALK-positive non-small cell lung cancers in the era of precision medicine

Next-generation ALK TKIs have become the new standard of care in first-line setting in advanced ALK-positive NSCLC patients. However, sequential strategies at progression are relevant, as may have an impact on patients’ outcome. In this commentary we discuss whether genomic-tailored strategies at progression would be more suitable for improving outcome of ALK-positive NSCLC patients. READ ARTICLE

Clinical and Translational Oncology. DOI: 10.1007/s12094-020-02290-1

Authors: J. Remon, F. Tabbò, B. Jimenez, A. Collazo, J. de Castro, S. Novello

Targeted therapy of oncogenic-driven advanced non-small cell lung cancer: recent advances and new perspectives

The discovery of new actionable oncogenic drivers has led to the development of effective antineoplastic targeted agents in advanced non-small cell lung cancer (NSCLC). While the role of inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) is widely acknowledged, other oncogenic drivers can be exploited as therapeutic targets. Areas covered: Our aim is to explore the therapeutic role of actionable oncogenic drivers, including well-established targets, such as EGFR, ALK, and ROS1, as well as less frequent drivers for which specific agents are at different stages of clinical development, such as MET, RET, BRAF, and NTRK. Expert opinion: Targeted agents have revolutionized the management of advanced NSCLC; in particular, novel agents and combinations targeting EGFR, ALK, ROS1, BRAF, and NTRK have become available and others are on their way. The molecularly driven approach to advanced NSCLC requires adequate tumor samples, as well as increasingly complex technologies designed to assess multiple targets on limited available tissue in an acceptable time-span. Furthermore, the role of other novel antineoplastic approaches, such as immunotherapy with immune checkpoint inhibitors, needs to be elucidated in the case of patients with oncogenic-driven NSCLC. READ ARTICLE

Expert Review of Respiratory Medicine DOI: 10.1080/17476348.2020.1714441

AUTHORS: Carlo Genova, Giovanni Rossi, Marco Tagliamento, Erika Rijavec, Federica Biello, Luigi Cerbone, Lodovica Zullo, Francesco Grossi

Review PaperKirk SmithJanuary 17, 2020Non-small cell lung cancer, targeted therapy, oncogenic drivers

Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes

Purpose: This study aimed to determine the molecular features and clinical outcomes of young patients with non-small cell lung cancer (NSCLC) harboring ALK fusion genes. Conclusion: Unique genetic characteristics were found in ALK-rearranged NSCLC patients with early disease onset, and these patients responded better to crizotinib and had longer PFS compared to patients with later disease onset. However, patients with concomitant TP53 mutations may not have a significant response to treatment. READ ARTICLE

Journal of Cancer Research and Clinical Oncology. DOI: 10.1007/s00432-019-03116-6

Authors: Panwen Tian, Yujie Liu, Hao Zeng, Yuan Tang, Analyn Lizaso, Junyi Ye, Lin Shao & Yalun Li

Association of ALK rearrangement and risk of venous thromboembolism in patients with non-small cell lung cancer: A prospective cohort study

Background: Isolated reports are inconsistent regarding the risk of venous thromboembolism (VTE) in patients with anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer (NSCLC). This study examined whether ALK rearrangement could have an influence on VTE in a prospective cohort. Conclusions: The presence of ALK rearrangement is associated with increased risk of VTE in patients with NSCLC. READ ARTICLE

Thrombosis Research DOI:10.1016/j.thromres.2019.12.009

Authors: Feifei Dou, Yuan Zhang, Jiawen Yi, Min Zhu, Shu Zhang, Di Zhang, Yuhui Zhang

The Impact of Clinical Factors, ALK Fusion Variants, and BIM Polymorphism on Crizotinib-Treated Advanced EML4–ALK Rearranged Non-small Cell Lung Cancer

Patients' clinical factors and genetics factors such as anaplastic lymphoma kinase (ALK) fusion variants and BIM (Bcl-2-like 11) polymorphism were reported to be associated with clinical outcome in crizotinib-treated advanced non-small cell lung cancer (NSCLC). However, the results were still controversial. We analyzed outcome of 54 patients with known ALK fusion variants who received crizotinib for advanced NSCLC. Thirty of them had successful BIM polymorphism analysis and 6 (20%) had a BIM deletion. Multivariate Cox regression analysis found that previous anticancer therapy [adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI), 1.04–1.76 for each additional line of therapy, p = 0.025] and Eastern Cooperative Oncology Group (ECOG) performance status ≥2 (aHR 8.35, 95% CI, 1.52–45.94, p = 0.015) were independent factors for progression-free survival (PFS). Only ECOG performance status ≥2 (aHR 7.20, 95% CI, 1.27–40.79, p = 0.026) was an independent factor for overall survival (..... READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2019.00880

Authors: Yen-Ting Lin, Yi-Nan Liu, Jin-Yuan Shih

Case StudyKirk SmithSeptember 23, 2019Non-small cell lung cancer, ALK, ALK variant, BIM, crizotinib

Clinical significance of ROS1 5’ deletions in non-small cell lung cancer

Objectives: Patients harboring rearrangements of the ROS1 gene are eligible for first-line therapy with Crizotinib, which represents the best available treatment option. Diagnostic criteria, based on break-apart fluorescence in situ hybridization, were mirrored from ALK by analogy and include tumors with 5' deletions. However, the probability of response to Crizotinib in patients with 5' deletion in ROS1 is unknown given the rarity of this condition. Conclusion: 5' ROS1 deletions detected by FISH are associated with a high chance of response to Crizotinib in NSCLC, similarly to canonical ROS1 split-apart FISH rearrangements. However, the confirmation of the ROS1 gene fusion with at least another method, such as NGS, seems beneficial in order to define the ROS1 fusion partner and to avoid possible false positive results. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.07.017

Authors: Elisa Capizzi, Filippo Gustavo, Dall’Olio, Elisa Gruppioni, Francesca Sperandi, Annalisa Altimari, Francesca Giunchi, Michelangelo Fiorentino, Andrea Ardizzoni

Case StudyKirk SmithSeptember 1, 2019Non-small cell lung cancer, ROS1 fusions, ROS1 deletions, FISH, NGS, Crizotinib