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

HDAC inhibition synergizes with ALK inhibitors to overcome resistance in a novel ALK mutated lung adenocarcinoma model

Objectives: Somatic chromosomal rearrangements resulting in ALK fusion oncogenes are observed in 3–7 % of lung adenocarcinomas. ALK tyrosine kinase inhibitors (ALKi) induce initially response, however, various resistance mechanisms limit their efficacy. Novel therapeutic approaches are of utmost importance to tailor these targeted therapies... Conclusion: Using a patient-derived ALKi resistant lung cancer model we demonstrated the synergism of HDAC and ALK inhibition. Furthermore, our findings provide strong evidence for intratumoral heterogeneity under targeted therapy and highlight the importance of site-specific mutational analysis. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2020.04.002

Authors: Paul Stockhammer, Cassandra Su Lyn Ho, Luca Hegedus, Gabor Lotz, Eszter Molnár, Agnes Bankfalvi, Thomas Herold, Stavros Kalbourtzis, Till Ploenes, Wilfried E. E. Eberhardt, Martin Schuler, Clemens Aigner, Alexander Schramm, Balazs Hegedus

Treatment Sequencing in Patients with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer in Japan: A Real-World Observational Study

Introduction The anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) alectinib was approved in Japan in 2014 for the treatment of ALK fusion gene-positive advanced non-small cell lung cancer (NSCLC). With the approvals of crizotinib in 2012 and ceritinib in 2017, Japan became the first country with multiple ALK TKIs available for first-line or later use in patients with ALK-positive advanced NSCLC. Here, we collected and evaluated real-world data on ALK TKI clinical usage patterns and sequencing in patients with ALK-positive NSCLC in Japan. Results A total of 378 patients met the inclusion criteria and were evaluated in mutually exclusive groups of patients receiving one, two, or three ALK TKIs. The initial ALK TKI prescribed was crizotinib for 52.1% of patients and alectinib for 47.9% of patients; however, the proportion of patients receiving alectinib as the initial ALK TKI increased over time following the Japanese approval of alectinib in 2014. Of the 117 patients who ..... READ ARTICLE

Advances in Therapy DOI:10.1007/s12325-020-01392-0

Authors: Yasushi Goto, Nobuyuki Yamamoto, Elizabeth T. Masters, Hironori Kikkawa, Jack Mardekian, Robin Wiltshire, Kanae Togo and Yuichiro Ohe

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

P114-01 Are Pretreatment Inflammation-Based Prognostic Scores Useful in Predicting the Outcomes of Patients with ALK-Positive NSCLC?

To date, upfront treatment with ALK-tyrosine-kinase inhibitors (ALK-TKIs) has replaced chemotherapy in the first line setting for this subset of patients with excellent results, but reliable prognostic markers are lacking. An increased systemic inflammatory response has been shown to be associated with a poor prognosis, and some of the parameters used to characterize this response can easily be measured in clinical practice in several tumor types, but have not been analyzed extensively in ALK+ lung cancer in the era of crizotinib.We reviewed the medical records of all patients with previously treated advanced ALK-positive NSCLC who received crizotinib between January 2013 and March 2018 outside of a clinical trial. The study found that, in a cohort of patients with ALK positive NSCLC treated with crizotinib in routine practice, elevated pre-treatment SII was associated with shorter OS and PFS in univariate analysis and PNI was associated with shorter OS in multivariate analyses. Moreov..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.1152

Authors: O.F. Olmez, A. Bilici, P. Gursoy, E. Çubukçu, O. Yildiz, A. Sakin, T. Korkmaz, I. Cil, B. Cakar, S. Menekse, T. Demir, O. Acikgoz, J. Hamdard

MA1807 Identification of Neuroendocrine Transformation in Anaplastic Lymphoma Kinase Rearranged (ALK+) Tumors After Tyrosine Kinase Inhibitors

We describe results of a program utilizing routine biopsy post-progression in ALK+ patients for clinical and research purposes.Since 2014, ALK+ lung cancer patients treated at the Princess Margaret Cancer Centre have undergone routine biopsies at disease progression time points upon failure of an ALK-tyrosine kinase inhibitor (TKI) for both clinical purposes and research purposes, in particular to obtain tissue for primary derived xenograft (PDX) engraftment. The study found that routine combined clinical and research biopsy of ALK+ patients at time of TKI failure helped to identify these recent cases of neuroendocrine transformation as a possible mode of resistance and provide tissue for model development. This is the first time that ALK+ transformation to large cell neuroendocrine carcinoma is reported in the literature. (PP, AFF, SNMF, LN contributed equally). READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.08.651

Authors: P. Pal, A. Fares, D. Patel, E. Stewart, N. Perera-Low, A. Grindley, F. Allison, N. Pham, R. Shi, N. Leighl, F. Shepherd, P. Bradbury, A. Sacher, P. Rogalla, K. Yasufuku, M. Cabanero, M. Tsao, G. Liu, S. Martins-Filho, L. Nguyen

Case StudyKirk SmithOctober 1, 2019Neuroendocrine transformation, Anaplastic lymphoma kinase

Synthesis and structure–activity relationships of pyrazine-2-carboxamide derivatives as novel echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) inhibitors

Echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) is a valid therapeutic target for the treatment of EML4–ALK-positive non-small cell lung cancer (NSCLC). We discovered 12c as a novel and potent EML4–ALK inhibitor through structural optimization of 5a. In mice xenografted with 3T3 cells expressing EML4–ALK, oral administration of 12c demonstrated potent antitumor activity. This article describes the synthesis and biological evaluation of pyrazine-2-carboxamide derivatives along with studies of their structure–activity relationship (SAR) using computational modeling. READ ARTICLE

Bioorganic & Medicinal Chemistry DOI:10.1016/j.bmc.2019.03.018

Authors: Kazuhiko Iikubo, Kazuo Kurosawa,Takahiro Matsuya, Yutaka Kondoh, Akio Kamikawa, Ayako Moritomo, Yoshinori Iwai, Hiroshi Tomiyama, ItsuroShimada

Expression of mucins (MUC1, MUC2, MUC5AC and MUC6) in ALK-positive lung cancer: Comparison with EGFR-mutated lung cancer

ALK-positive (ALK+) lung adenocarcinoma usually shows a more advanced-staged disease with frequent nodal metastasis and highly aggressive outcomes compared with EGFR-mutated lung cancers. The aim of this study was to investigate the expression profiles of several mucins in ALK + lung cancers to gain insight into the relationship between the more aggressive biological nature of ALK + lung cancers and the role of mucins. We examined the immunohistochemical profiles of mucins MUC1, MUC2, MUC5AC, and MUC6 in 19 ALK + lung cancers compared with 42 EGFR-mutated lung cancers. ALK + cancers were found to occur in younger patients and were characterized by a solid-predominant histologic subtype with frequent signet ring cells and peritumoral muciphages. By contrast, EGFR-mutated cancers lacked ALK-specific histological patterns. Although all MUC1 and MUC5AC were expressed in both subtypes, MUC1 expression in ALK + cancers was visualized exclusively through cytoplasmic staining, whereas those in..... READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2018.12.011

Authors: Hong Kyu Lee, Mi Jung Kwon, Jinwon Seo, Jeong Won Kim, Mineui Hong, Hye-Rim Park, Soo Kee Min, Ji-Young Choe, Yong Joon Ra, Seung Hun Jang, Yong Il Hwang, Ho Young Kim, Kyueng-Whan Min

Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC)

Recently, proteolysis targeting chimera (PROTAC) technology is highlighted in drug discovery area as a new therapeutic approach. PROTAC as a heterobifunctional molecule is comprised of two ligands, which recruit target protein and E3 ligase, respectively. To degrade the anaplastic lymphoma kinase (ALK) fusion protein, such as NPM-ALK or EML4-ALK, we generated several ALK-PROTAC molecules consisted of ceritinib, one of the ALK inhibitors, and ligand of von Hippel-Lindau (VHL) E3 ligase. Among these molecules, TD-004 effectively induced ALK degradation and inhibited the growth of ALK fusion positive cell lines, SU-DHL-1 and H3122. We also confirmed that TD-004 significantly reduced the tumor growth in H3122 xenograft model. READ ARTICLE

Biochemical and Biophysical Research Communications DOI:10.1016/j.bbrc.2018.09.169

Authors: Chung Hyo Kanga, Dong Ho Lee, Chong Ock Lee, Jae Du Ha, Chi Hoon Park, Jong Yeon Hwang

A Sensitive ALK Immunohistochemistry Companion Diagnostic Test Identifies Patients Eligible for Treatment with Crizotinib

Introduction: The availability of high-quality, rigorously validated diagnostic tests that can be broadly implemented is necessary to efficiently identify patients with anaplastic lymphoma kinase (ALK)-positive NSCLC who can potentially benefit from treatment with crizotinib. Here we present data on the recently approved Ventana ALK (D5F3) CDx Assay (Ventana Medical Systems, Tucson, AZ), the only immunohistochemistry (IHC)-based assay linked to treatment outcome... Conclusions: The ALK (D5F3) CDx assay is a stand-alone companion diagnostic test for identification of patients for treatment with crizotinib. This automated assay provides an effective option to accurately and rapidly identify patients with ALK-positive NSCLC. The simple binary scoring algorithm results in high reader-to-reader precision. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2017.01.020

Authors: Trish Thorne-Nuzzo, Crystal Williams, Alice Catallini, June Clements, Shalini Singh, James Amberson, Kim Dickinson, Zoran Gatalica, Steffan N. Ho, Isabell Loftin, Abigail McElhinny, Penny Towne