Adverse Events of Concurrent Radiotherapy and ALK Inhibitors for Brain Metastases of ALK-Rearranged Lung Adenocarcinoma

Background: We investigated acute adverse events in patients with brain metastases (BMs) of anaplastic lymphoma kinase-rearranged (ALKr) non-small cell lung cancer (NSCLC) treated with both cranial radiotherapy and tyrosine kinase inhibitors (TKIs) of ALK. Patients and Methods: Acute AEs were retrospectively investigated in patients with BMs of ALKr-NSCLC who received both whole-brain radiotherapy (WBRT) and ALK-TKI. For comparison, they were also assessed in patients with epidermal growth factor receptor (EGFR)-mutated NSCLC and wild-type with neither ALK rearrangement nor EGFR mutation treated with WBRT. Results: Two ALKr cases were consequently eligible. Grade 3 otitis media unexpectedly occurred in both cases, while there was one case out of 11 and one case out of 18 of grade 2 otitis media among the EGFR-mutated cases and wild-type cases (p=0.013), respectively. Conclusion: Concurrent treatment with WBRT and ALK-TKI may be associated with acute severe ear toxicity in patients with BMs of ALKr-NSCLC. READ ARTICLE

In Vivo DOI:10.21873/invivo.11767

Authors: TAKAAKI NAKASHIMA, TAKESHI NONOSHITA, HIDENARI HIRATA, KOUJI INOUE, AKIRA NAGASHIMA, TADAMASA YOSHITAKE, KAORI ASAI and YOSHIYUKI SHIOYAMA

Case StudyKirk SmithJanuary 1, 2020ALK-TKI, radio therapy, adverse events, lung adenocarcinoma, brain metastases

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

Differences Between the East and the West in Managing Advanced-Stage Non-small Cell Lung Cancer

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highligh..... READ ARTICLE

Clinical Oncology DOI:10.1016/j.clon.2019.07.014

Authors: V. H. F. Lee, T. S. K. Mok, Y. Goto, V. C. C. Hsue, L. Yang, Y. Jiang, D. K. C. Leung, K. S. Lau, P. Y. Tse

Life Threatening haemoptysis in primary lung cancer-signet ring cell carcinoma

Primary signet ring cell carcinoma of the lung is a rare non-small cell carcinoma of the lung with extremely aggressive features and poor prognosis. The diagnosis mainly required tissue biopsy with immunohistochemical analysis and gene mutation studies. We describe a unique case of primary signet ring cell carcinoma of the lung presenting with life threatening haemoptysis along with literature review of prognosis and management of this rare clinical entity. READ ARTICLE

Respiratory Medicine Case Reports DOI:10.1016/j.rmcr.2020.101195

Authors: Shamsuddin Anwar, Sudeep Acharya, Dany Elsayegh, Alisa Sokoloff, Maryam Rehan

Precision Medicine in Lung Cancer Treatment

Summary: Over the past decade, tremendous progress has been made in understanding the molecular and biologic drivers of lung cancer. Testing for various biomarkers in lung cancer is improving our ability to understand the behavior of different cancers, so we can identify the optimal treatment strategy for each clinical subset of patients. This progress has helped us to deliver individualized precision therapy options for our patients with lung cancer. Ongoing clinical trials will help to improve our... READ ARTICLE

Surgical Oncology Clinics of North America DOI:Precision Medicine in Lung Cancer Treatment

Authors: Dhaval R. Shah, Gregory A. Masters

EditorialKirk SmithJanuary 1, 2020Precision Medicine, Lung Cancer

Design, synthesis and biological evaluation of 2-arylaminopyrimidine derivatives bearing 1,3,8-triazaspiro[4,5]decan-4-one or piperidine-3-carboxamide moiety as novel Type-I1/2 ALK inhibitors

Aiming to develop novel Type-I1/2 inhibitors of ALK to overcome extensive resistance mutations, especially the L1196M mutation surrounding the ATP pocket, two series of 2-arylaminopyrimidine derivatives (11a-f and 22a-t) were designed based on scaffold hopping. The extensive structural elaboration discovered compound 22o which possessed excellent IC50 values of 0.06 and 0.23 μM against ALK-positive Karpas299 and H2228 cell lines, respectively. Meanwhile, 22o displayed encouraging inhibitory potency in the ALKWT (2.5 nM) and ALKL1196M (6.5 nM) enzymatic assays. Furthermore, the AO/EB and Hoechst 33258 assays illustrated 22o could induce cell apoptosis in a dose-dependent manner. Eventually, the molecular docking of 22o with ALK clearly presented the vital interactions within the active site, which was in accordance with Type-I1/2 inhibitor binding mode. READ ARTICLE

Bioorganic Chemistry DOI:10.1016/j.bioorg.2019.103456

Authors: Xiuqi Miao, Lingyun Xing, Ming Guo, Hong Zhang, Sicong Liu, Shiliang Yin, Ping Gong, Dajun Zhang, Xin Zhai

JuLI: accurate detection of DNA fusions in clinical sequencing for precision oncology

Accurate detection of genomic fusions by high-throughput sequencing in clinical samples with inadequate tumor purity and formalin-fixed paraffin embedded (FFPE) tissue is an essential task in precise oncology. We developed the fusion detection algorithm Junction Location Identifier (JuLI) for optimization of high-depth clinical sequencing. We implemented novel filtering steps to minimize false positives and a joint calling function to increase sensitivity in clinical setting. We comprehensively validated the algorithm using high-depth sequencing data from cancer cell lines and clinical samples and whole genome sequencing data from NA12878. We showed that JuLI outperformed state-of-the-art fusion callers in cases with high-depth clinical sequencing and rescued a driver fusion from false negative in plasma cell-free DNA. JuLI is freely available via GitHub (https://github.com/sgilab/JuLI). READ ARTICLE

The Journal of Molecular Diagnostics DOI:10.1016/j.jmoldx.2019.10.015

Authors: Hyun-Tae Shin, Nayoung K. D. Kim, Jae Won Yun, Boram Lee, Sungkyu Kyung, Ki-Wook Lee, Daeun Ryu, Jinho Kim, Joon Seol Bae, Donghyun Park, Yoon-La Choi, Se-Hoon Lee, Myung-Ju Ahn, Keunchil Park, Woong-Yang Park

Pre-ClinicalKirk SmithDecember 24, 2019JuLI, DNA fusions, clinical sequencing, precision oncology

The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants

Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib. Conclusions: The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers. READ ARTICLE

Advances in Therapy DOI:10.1007/s12325-019-01198-9

Authors: Joseph Chen, Huiping Xu, Sylvester Pawlak, Leonard P. James, Gerson Peltz, Kimberly Lee, Katherine Ginman, Michelle Bergeron & Yazdi K. Pithavala

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

Cytotoxicity of curcumin derivatives in ALK positive non-small cell lung cancer

Non-small cell lung cancer with ALK rearrangements can be targeted effectively with ALK inhibitors such as crizotinib. However, cancer progression typically occurs within a year as drug resistance develops. One strategy to overcome this drug resistance is to determine if novel cytotoxic agents retain the ability to kill lung cancer cells that have developed ALK inhibitor resistance. We therefore examined curcumin, a drug with anticancer properties, and 2 s-generation curcumin derivatives (1-methyl-3,5-bis[(E)-4-pyridyl) methylidene]-4-piperidone (RL66) and 1-isopropyl-3,5-bis[(pyridine-3-yl) methylene]piperidin-4-one (RL118)) in lung cancer cell lines. The cytotoxicity of curcumin, RL66, and RL118 were tested in both ALK+ lung cancer cells (H3122), crizotinib resistant ALK+ cells (CR-H3122) and ALK- lung cancer cells (A549), both alone and in combination with crizotinib. ALK+ cells were 2-3x more sensitive to RL66 and RL118 than ALK- cells, with the drugs' eliciting IC50 values in the ..... READ ARTICLE

European Journal of Pharmacology DOI:10.1016/j.ejphar.2019.172749

Authors: Abigail R Bland, Rebekah L Bower, Mhairi Nimick, Bill C Hawkins, Rhonda J Rosengren, John C Ashton

Pre-ClinicalKirk SmithDecember 15, 2019ALK, Curcumin, Derivatives, Non-small cell lung cancer (NSCLC)

Low ALK FISH positive metastatic non-small cell lung cancer (NSCLC) patients have shorter progression-free survival after treatment with ALK inhibitors

ALK FISH assay guides clinical decision to initiate therapy with ALK inhibitors in patients with stage IV non-small cells lung cancer (NSCLC). In this single institution retrospective study, we investigated the association between the strength of ALK positivity and progression-free survival (PFS) We screened 4,829 patients tested for ALK rearrangement by FISH from 01/06/2012 to 06/30/2018 and included 66 stage IV NSCLC ALK positive patients, who were ALK inhibitor naïve, received an ALK inhibitor, and been followed at least 10 months to the study. The median PFS for cases high positive cases [≥=50% positive nuclei; n = 49] and low positive cases [16–49% positive nuclei; n = 17] is 16 months and 4 months respectively, and the hazard ratio is 2.89 [95 CI 1.34–6.2] (p = 0.0068). When cases are stratified according to cut-off ≥=30% positive nuclei, the median PFS for cases above (n = 55) and below the cut-off (n = 11) is 12 and 3 months, respectively and the hazard ratio is 9.60 [95 CI 2.6..... READ ARTICLE

Cancer Genetics DOI:10.1016/j.cancergen.2019.12.003

Authors: Gokce A. Toruner, Zhenya Tang, Guilin Tang, L. Jeffrey Medeiros, Shimin Hu

Case StudyKirk SmithDecember 12, 2019ALK, FISH, PFS, Lung cancer

Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer

Anaplastic lymphoma kinase (ALK) rearrangement, a key oncogenic driver in a small subset of non-small cell lung cancers, confers sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a first generation ALK-TKI, has superiority to standard chemotherapy with longer progression-free survival and higher objective response rate. However, clinical benefit is limited by development of resistance, typically within a year of therapy. In this study the combined effect of crizotinib and the MEK inhibitor selumetinib was investigated in both crizotinib naïve (H3122) and crizotinib resistant (CR-H3122) ALK-positive lung cancer cells. Results showed that combination treatment potently inhibited the growth of both H3122 and CR-H3122 cells, resulting from increased apoptosis and decreased cell proliferation as a consequence of suppressed downstream RAS/MAPK signalling. The drug combination also elicited a greater than 3-fold increase in Bim, a mediator of apoptosis, and p27, a cyclin depen..... READ ARTICLE

Scientific Reports DOI:10.1038/s41598-019-55376-4

Authors: N. Shrestha, M. Nimick, P. Dass, R. J. Rosengren, J. C. Ashton

Pre-ClinicalKirk SmithDecember 11, 2019ALK, MEK, Crizotinib

Brain metastases from non-small cell lung cancer with EGFR or ALK mutations: A systematic review and meta-analysis of multidisciplinary approaches

Background and purpose: To analyze outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases harboring EGFR or ALK mutations and examine for differences between tyrosine kinase inhibitors (TKIs) alone, radiotherapy (RT) alone (either whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS)), or combined TKIs and RT. Conclusion: NSCLC patients with brain metastases harboring EGFR or ALK mutations have superior OS compared to wild-type patients. No PFS or OS benefit was found with the addition of TKIs to RT. READ ARTICLE

Radiotherapy and Oncology. DOI: 10.1016/j.radonc.2019.11.010

Authors: Raj Singh, Eric J. Lehrer, Stephen Ko, Jennifer Peterson, Yanyan Lou, Alyx B. Porter, Rupesh Kotecha, Paul D. Brown, Nicholas G. Zaorsky, Daniel M. Trifiletti

Review PaperKirk SmithDecember 6, 2019Radiosurgery, ALK, EGFR, Mutated, Brain metastases

Brigatinib: New-generation ALK inhibitor for nonsmall cell lung cancer

Lung cancer, specifically nonsmall cell lung cancer (NSCLC) is the leading cause of death around the world. First-line therapies for metastatic NSCLC such as crizotinib, a tyrosine kinase inhibitor (TKI), have developed resistance due to a rearrangement of the anaplastic lymphoma kinase (ALK) gene. Brigatinib, approved in May 2016, is an ALK inhibitor specifically indicated for ALK-positive metastatic NSCLC in patients who have progressed on or resistant to crizotinib therapy. In several clinical trials, brigatinib has exhibited significant improvement in progression-free survival in patients that have experienced resistance to crizotinib therapy. The optimal dose of brigatinib was found to be 180 mg once daily and demonstrated greater efficacy as compared to its 90 mg once daily dose. Brigatinib was also found to be well tolerated. Although more studies are needed, the current data from these studies indicate brigatinib may be the most favorable therapeutic approach to treat NSCLC ALK..... READ ARTICLE

Current Problems in Cancer
DOI:10.1016/j.currproblcancer.2019.03.005

Authors: Stewart Umbela, Shahinaz Ghacha, Revika Matuknauth, Stacey Gause, Shrijana Joshee, Rahul R. Deshmukh

Review PaperKirk SmithDecember 1, 2019Brigatinib, Crizotinib-resistance, NSCLC, ALK, TKI

Abstract A125: Predication of lorlatinib resistance mechanisms and therapeutic strategies to overcome the resistance in ALK rearranged non-small cell lung cancer

Introduction: ALK fusion gene is found in 3-5% of NSCLC patients. As the resultant ALK fusion protein constitutively activates ALK tyrosine kinase that causes tumorigenesis, ALK tyrosine kinase inhibitors have been developed for the treatment of ALK rearranged cancer and currently five ALK-TKIs have been clinically applied. Now, alectinib is widely used in first-line therapy. However, most of the patients experience the emergence of alectinib resistance due to the secondary mutation in ALK kinase domain such as I1171N or G1202R. Lorlatinib, third generation ALK-TKI, has shown to be able to overcome any of the earlier generation ALK-TKI resistant single point mutants including G1202R and I1171N. Conclusion: Our results imply that the clinical sequences after lorlatinib resistance using biopsy or liquid-biopsy might provide important information to choose the effective sequential ALK-TKI therapy. Further studies are still needed to uncover the unidentified lorlatinib resistance mechanisms. READ ARTICLE

Molecular Targets and Cancer Therapeutics DOI:10.1158/1535-7163.TARG-19-A125

Authors: Koutaroh Okada, Mitsugu Araki, Tomoko Oh-hara, Makoto Nishio, Yasushi Okuno, Naoya Fujita and Ryohei Katayama

ALK-rearranged renal cell carcinomas in Polish population

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, the activation of which is considered an important event in the pathogenesis of several neoplasms and a predictive factor for the targeted therapy with ALK inhibitors. Thus far, ALK rearrangements have been identified in 22 renal cell carcinomas in both pediatric and adult patients. We evaluated the incidence of ALK rearrangement-associated RCC in adult Central European population. An immunohistochemical evaluation of 1019 kidney tumors was performed with use of three different clones of anti-ALK antibodies. None of the tested samples showed positive staining, which suggests that the incidence of ALK rearrangement-associated renal cell carcinomas is significantly lower in the Polish population, and indicates a potential association between ethnicity and occurrence of these rare neoplasms. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2019.152669

Authors: Adam Gorczynski, Piotr Czapiewski, Aleksandra Korwat, Lukasz Budynko, Monika Prelowska, Krzysztof Okon, Wojciech Biernat

The Dandelion Dilemma Revisited for Oligoprogression: Treat the Whole Lawn or Weed Selectively?

When early-stage metastases appear, what is the evidence comparing the utility of systemic drug treatment versus focused radiation? "Oligoprogressive disease is a relatively new clinical concept describing progression at only a few sites of metastasis in patients with otherwise controlled widespread disease. Local ablative therapy for oligoprogressive disease may allow the continuation of systemic treatments by overcoming the few sub-clones that have developed resistance." READ ARTICLE

Clinical Oncology; DOI: 10.1016/j.clon.2019.05.015;

Authors: P.H. Patel, D. Palma, F. McDonald, A.C. Tree

Coexistence of a Novel PRKCB-ALK, EML4-ALK Double-Fusion in a Lung Adenocarcinoma Patient and Response to Crizotinib

ALK receptor tyrosine kinase (ALK) rearrangement is a common driver mutation for patients with NSCLC. More than 20 other fusion partners for ALK in NSCLC have been reported.1 However, one patient with double ALK fusions simultaneously is still rare, and the double ALK fusions changing after treatment is also rarely reported. Here, a lung adenocarcinoma patient with EMAP like 4 (EML4)-ALK and protein kinase C beta (PRKCB)–ALK double fusion variant was presented who responded to crizotinib and showed the changes of two ALK fusions before and after treatment... In summary, this study is the first to describe a novel EML4-ALK, PRKCB-ALK double-ALK fusion lung adenocarcinoma patient who is sensitive to crizotinib. This is also the first study to describe a novel PRKCB-ALK fusion that may have promising efficacy by crizotinib treatment. In addition, the case also shows that liquid biopsy can provide more information of mutation to guide treatment and multiple liquid biopsy procedures can a..... READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.07.021

Authors: Jing Luo, Dejian Gu, Huasong Lu, Si Liu, Jinliang Kong

Case StudyKirk SmithDecember 1, 2019PRKCB-ALK, EML4-ALK Double-Fusion, Lung Adenocarcinoma, Crizotinib

Clinical observation of crizotinib in the treatment of ALK-positive advanced non-small cell lung cancer

Background: ALK is a prognostic and predictive tumor marker in non-small cell lung carcinoma (NSCLC), and is more often found in lung adenocarcinomas. Conclusions:The efficacy of crizotinib in patients with advanced NSCLC is related to the number of metastatic organs, age and timing of treatment. The use of crizotinib is prone to intracranial progression, and progression of simple brain metastases is not an indication that crizotinib is discontinued. Patients will continue to benefit from combination of local radiotherapy. READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2019.152695

Authors: Huiyan Deng, Bin Li, Lina Li, Jingcui Peng, Tongshuai Lv, Yueping Liu, CuiminDing

Stratégies thérapeutiques dans le cancer bronchique non à petites cellules ALK positif de stade IV Therapeutic strategies in advanced ALK positive non-small cell lung cancer

Stratégies thérapeutiques dans le cancer bronchique non à petites cellules ALK positif de stade IVTherapeutic strategies in advanced ALK positive non-small cell lung cancer. READ ARTICLE

Revue des Maladies Respiratoires DOI:Therapeutic strategies in advanced ALK positive non-small cell lung cancer

Authors: A. Tiotiu, Y. Billon, P. Vaillant, O. Menard, P. Hofman, C. Mascaux

Review PaperKirk SmithDecember 1, 2019ALK TKI, Therapeutic strategy, Rebiopsy, Resistance