Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study)

Brigatinib is a next-generation ALK inhibitor initially developed in ALK-positive NSCLC pretreated with crizotinib.This retrospective multicentric study analyzed ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS).Real-world results confirm that the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-positive advanced NSCLC. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.08.010

Authors: Renaud Descourt, Maurice Perol, Gaëlle Rousseau-Bussac, David Planchard, Bertrand Mennecier, Marie Wislez Alexis Cortot, Florian Guisier, Loïck Galland, Pascal Dô, Roland Schott, Eric Dansin, Jennifer Arrondeau, Jean-Bernard Auliac, Christos Chouaid

Monitoring therapeutic response and resistance: analysis of circulating tumor DNA in patients with ALK+ lung cancer

Clinical utility of ctDNA was shown, both at pre-treatment by identifying a potential subgroup of ALK+ NSCLC patients who may derive more benefit from ensartinib and longitudinally by tracking resistance. Prospective application of this technology may translate to improved outcomes for NSCLC patients treated with ALK TKIs. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/j.jtho.2019.08.003

Authors: Leora Horn MD, Jennifer G. Whisenant PhD, Heather Wakelee MD, Karen L. Reckamp MD, Huan Qiao, MD PhD, Ticiana A. Leal MD, Liping Du PhD, Jennifer Hernandez BS, Vincent Huang BS, George R. Blumenschein MD, Saiama N. Waqar MD, Sandip P. Patel MD, Jorge Nieva MD, Geoffrey R. Oxnard MD, Rachel E. Sanborn MD, Tristan Shaffer, Kavita Garg, Allison Holzhausen MS, Kimberly Harrow MBA, Chris Liang PhD, Lee P. Lim PhD, Mark Li, Christine M. Lovly MD, PhD

Pre-ClinicalKirk SmithAugust 22, 2019ctDNA, ALK, next-generation sequencing (NGS), liquid biopsy

An exploration of solvent-front region high affinity moiety leading to novel potent ALK & ROS1 dual inhibitors with mutant-combating effects

The pyrimidine-2,4-diamine analogs exerted excellent activities in down-regulation of ALK phosphorylation. However, the prevalent drug-resistant site-mutation has gradually prevented the agents from being widely used. Herein, we conducted an exploration of high affinity moiety that bound to the solvent-front region (G1202R located) within the ATP binding site of ALK leading to the synthesis of thirty-five pyrimidine-2,4-diamine derivatives. Among these compounds, urea group was extensively derivatized which finally resulted in the identification of the ‘semi-free urea’ compound 39. All compounds were assayed cytotoxicity and enzymatic activities and 39 turned out to be the most potent one with IC50 values of 2.1, 0.91, 4.3 and 0.73 nM towards ALKwt, ALKL1196M, ALKG1202R and ROS1, respectively. The performances of 39 on ALK- & ROS1-dependent cell lines were in good accordance with enzymatic activities with IC50 values below 0.06 µM. Besides, 39 induced cell apoptosis in a dose-dependent..... READ ARTICLE

Bioorganic & Medicinal Chemistry DOI:10.1016/j.bmc.2019.115051

Authors: Hongrui Lei, Fang Jia, Meng Cao, Jie Wang, Ming Guo, Minglin Zhu, Daiying Zuo, Xin Zhai

Drug Discovery Targeting Anaplastic Lymphoma Kinase (ALK)

As a receptor tyrosine kinase of insulin receptor (IR) subfamily, anaplastic lymphoma kinase (ALK) has been validated to play important roles in various cancers, especially anaplastic large cell lymphoma (ALCL), nonsmall cell lung cancer (NSCLC), and neuroblastomas. Currently, five small-molecule inhibitors of ALK, including Crizotinib, Ceritinib, Alectinib, Brigatinib, and Lorlatinib, have been approved by the U.S. Food and Drug Administration (FDA) against ALK-positive NSCLCs. Novel type-I1/2 and type-II ALK inhibitors with improved kinase selectivity and enhanced capability to combat drug resistance have also been reported. Moreover, the "proteolysis targeting chimera" (PROTAC) technique has been successfully applied in developing ALK degraders, which opened a new avenue for targeted ALK therapies. This review provides an overview of the physiological and biological functions of ALK, the discovery and development of drugs targeting ALK by focusing on their chemotypes, activity, selectivity, and resistance as well as potential therapeutic strategies to overcome drug resistance. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.9b00446

Authors: Kong X, Pan P, Sun H, Xia H, Wang X, Li Y, Hou T.

Pre-ClinicalKirk SmithAugust 16, 2019Drug resistance, Peptides and proteins, Genetics, Inhibitors

Malignant Pleural Effusion and Its Current Management: A Review

Malignant pleural effusion (MPE) is an exudative effusion with malignant cells. MPE is a common symptom and accompanying manifestation of metastatic disease. It affects up to 15% of all patients with cancer and is the most common in lung, breast cancer, lymphoma, gynecological malignancies and malignant mesothelioma. In the last year, many studies were performed focusing on the pathophysiological mechanisms of MPE. With the advancement in molecular techniques, the importance of tumor-host cell interactions is becoming more apparent. Additionally, the process of pathogenesis is greatly affected by activating mutations of EGFR, KRAS, PIK3CA, BRAF, MET, EML4/ALK and RET, which correlate with an increased incidence of MPE. Considering all these changes, the authors aim to present a literature review of the newest findings, review of the guidelines and pathophysiological novelties in this field. Review of the just recently, after seven years published, practice guidelines, as well as analys..... READ ARTICLE

Medicina (Kaunas) DOI:10.3390/medicina55080490

Authors: Kristijan Skok, Gaja Hladnik, Anja Grm, Anton Crnjac

Definition of Synchronous Oligometastatic Non–Small Cell Lung Cancer—A Consensus Report

Introduction: Improved outcome has been shown in patients with synchronous oligometastatic (sOM) NSCLC when treated with radical intent. As a uniform definition of sOM NSCLC is lacking, we developed a definition and diagnostic criteria by a consensus process. Conclusion: A multidisciplinary consensus statement on the definition and staging of sOM NSCLC has been formulated. This statement will help to standardize inclusion criteria in future clinical trials. READ ARTICLE

Journal of Thoracic Oncology. DOI: 10.1016/j.jtho.2019.07.025

Authors: Anne-Marie C. Dingemans, Lizza E.L. Hendriks, Thierry Berghmans, Antonin Levy, Baktiar Hasan, Corinne Faivre-Finn, Matteo Giaj-Levra, Niccolò Giaj-Levra, Nicolas Girard, Laurent Greillier, Sylvie Lantuéjoul, John Edwards, Mary O’Brien, Martin Reck, Egbert F. Smit, Paul Van Schil, Pieter E. Postmus, Sara Ramella, Yolande Lievens, Mina Gaga, Nir Peled, Giorgio V. Scagliotti, Suresh Senan, Luiz Paz-Ares, Matthias Guckenberger, Fiona McDonald, Simon Ekman, Tanja Cufer, Hester Gietema, Maurizio Infante, Rafal Dziadziuszko, Solange Peters, Ramon Rami Porta, Johan Vansteenkiste, Christophe Dooms, Dirk de Ruysscher, Benjamin Besse, Silvia Novello

When Should we Irradiate the Primary in Metastatic Lung Cancer?

Metastatic lung cancer encompasses a heterogenous group of patients in terms of burdens of disease, ranging from patients with extensive metastases to those with a limited number of metastatic lesions (oligometastatic disease). Histopathological heterogeneity also exists within two broad categories, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), portraying different patterns and evolution of disease. Local consolidative therapy to the primary tumour and metastatic sites, including surgery and/or radical dose radiotherapy, is increasingly being used to improve survival outcomes, particularly in the context of oligometastatic disease, with or without the use of molecular targeted therapy and immunotherapy. Recently, randomised studies in oligometastatic NSCLC have shown that local consolidative therapy may confer a survival advantage. This review explores whether treating just the primary tumour with radiotherapy may similarly produce improved clinical outcomes. Su..... READ ARTICLE

Clinical Oncology DOI:10.1016/j.clon.2019.07.012

Authors: A. M. Shiarli, F. McDonald, D. R. Gomez

Chapter 8 - Approach to Anaplastic Lymphoma Kinase (ALK) Gene Rearranged Non–Small Cell Lung Cancer (NSCLC)

Anaplastic lymphoma kinase (ALK) gene rearrangement occurs in 2%–4% of all non–small cell lung cancer (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses in these patients. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superior clinical benefit compared with chemotherapy. Eventually, all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site. Several next-generation ALK inhibitors were evaluated in crizotinib-treated patients and found to be effective. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Clinical efficacy observed with these agents, particularly in the CNS prompted evaluating these agents as front-line therapy. Recently, in two separate phase III trials, alectinib has demonstrated superior clinical efficacy as front-l..... READ ARTICLE

Pulmonary Adenocarcinoma: Approaches to Treatment DOI:10.1016/B978-0-323-55433-6.00008-0

Authors: Shirish Gadgeel Editor: Leora Horn

Kirk SmithAugust 1, 2019Alectinib, ALK, Brigatinib, CNS metastases, Lorlatinib, NSCLC

The clinical impact of family history of cancer in female never-smoker lung adenocarcinoma

Accumulating evidence reveals the association between the risk of never-smoker lung cancer and family history of cancer. However, the clinicogenomic effect of family history of cancer in never-smoker lung cancer remains unknown.We screened 3,241 lung cancer patients who (a) underwent curative resection at National Cancer Center (Goyang, Korea) between 2001–2014, and (b) completed a pre-designed interview about family/smoking history at the time of diagnosis and identified 604 female never smoker lung adenocarcinoma. A positive family history of cancer [categorized as pulmonary cancer (FH-PC) or non-pulmonary cancer (FH-NPC)] was defined as a self-reported history of cancer in first-degree relatives. Survival data were followed up until January 2017. Multiplexed targeted next-generation sequencing was performed for genetic profiling.The study found that the type of family history of cancer was associated with distinct clinocogenomic subtypes and prognosis of never-smoker lung adenocarcinoma. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.07.031

Authors: Youngjoo Lee, Jae Hyun Jeon, Sung-Ho Goh, Hanseong Roh, Ji-Young Yun, Nak-Jung Kwon, Jin Ho Choi, Hee Chul Yang, Moon Soo Kim, Jong Mog Lee, Geon Kook Lee, Ji-Youn Han

Case StudyKirk SmithJuly 31, 2019Never smoker, Non-small-cell lung cancer, Prognosis, Family history, EGFR, ALK

The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase involved in neuronal and gut development. Initially discovered in T cell lymphoma, ALK is frequently affected in diverse cancers by oncogenic translocations. These translocations involve different fusion partners that facilitate multimerisation and autophosphorylation of ALK, resulting in a constitutively active tyrosine kinase with oncogenic potential. ALK fusion proteins are involved in diverse cellular signalling pathways, such as Ras/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt and Janus protein tyrosine kinase (JAK)/STAT. Furthermore, ALK is implicated in epigenetic regulation, including DNA methylation and miRNA expression, and an interaction with nuclear proteins has been described. Through these mechanisms, ALK fusion proteins enable a transcriptional programme that drives the pathogenesis of a range of ALK-related malignancies. READ ARTICLE

Cancers (Basel) DOI:10.3390/cancers11081074

Authors: Stephen P Ducray, Karthikraj Natarajan, Gavin D Garland, Suzanne D Turner, Gerda Egger

EditorialKirk SmithJuly 30, 2019ALCL, ALK, ALK-translocation proteins, EML4-ALK, NPM-ALK, NSCLC, epigenetics

Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden

Introduction: The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples. Conclusions: High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.07.017

Authors: Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kazuya Nishii, Takehiro Matsubara, Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Akiko Sato, Hiromi Watanabe, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Minoru Takata, Yoshinobu Maeda, Katsuyuki Kiura

Case StudyKirk SmithJuly 30, 2019NSCLC, Alectinib, ALK G1202R, MET, Amphiregulin

Short progression-free survival of ALK inhibitors sensitive to secondary mutations in ALK-positive NSCLC patients

Most non-small cell lung cancer (NSCLC) patients relapse on anaplastic lymphoma kinase-tyrosine kinase inhibitor (ALK-TKI) therapy because of acquired resistance. Rebiopsy is recommended to provide optimal therapy after relapse for some ALK-TKI therapies; however, little clinical data exists on the clinical efficacy of ALK-TKI tailored to secondary mutation. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13143

Authors: Naoki Haratake, Takashi Seto, Shinkichi Takamori, Ryo Toyozawa, Kaname Nosaki, Naoko Miura, Taro Ohba, Gouji Toyokawa, Kenichi Taguchi, Masafumi Yamaguchi, Mototsugu Shimokawa, Mitsuhiro Takenoyama

Curcumin as tyrosine kinase inhibitor in cancer treatment

Curcumin is a natural substance known for ages, exhibiting a multidirectional effect in cancer prevention and adjuvant cancer therapies. The great advantage of using nutraceuticals of vegetable origin in comparison to popular cytostatic drugs is the minimized side effect and reduced toxicity. The targets in oncological therapy are, among others, tyrosine kinases, important mediators of signaling pathways whose impaired expression is observed in many types of cancer. Unfortunately, the hydrophobic nature of the curcumin molecule often limits its bioavailability, which is why many studies focus on the chemical modification of this compound. Current research is aimed at modifying structures that improve the pharmacokinetic parameters of curcumin, e.g. the formation of nanoparticles, complexes with metals or the synthesis of curcumin derivatives with functional substituents that allow tumor targeting. The article is a review and analysis of current literature on the properties of curcumin ..... READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2019.07.015

Authors: A. Golonko, H. Lewandowska, R. Świsłocka, U.T. Jasińska, W. Priebe, W. Lewandowski

ALK-Positive NSCLC: ALEX Trial

Review the study design and results of the ALEX trial, comparing alectinib and crizotinib in treatment-naïve ALK-positive patients with non–small cell lung cancer. WATCH VIDEO

OncLiveTV

Authors: Dr. David Spigel

VideoKirk SmithJuly 11, 2019ALK, ALEX trial

Evaluation of drug-induced lung injury by ALK inhibitor: a single center retrospective analysis

Background: Although lung cancer with ALK or ROS-1 gene fusion is rare, antitumor effect by ALK inhibitor can be highly expected. However, details of drug-induced lung injury (DILI), which can be serious side effect, remain unclear. Conclusion: Elderly people and lower renal function may require caution of DILI caused by ALK inhibitor. Images findings were subjected to OP pattern. The clinical course was not probably critical. READ ARTICLE

European Respiratory Journal DOI:10.1183/13993003.congress-2019.PA4734

Authors: Ken Koshikawa, Jiro Terada, Mitsuhiro Abe, Shunichiro Iwasawa, Masashi Sakayori, Kenji Tsushima, Koichiro Tatsumi

Case StudyKirk SmithJuly 11, 2019Drug-induced lung injury, ALK inhibitor, Pneumonia

Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026

Our effort toward the process improvement of anaplastic lymphoma kinase (ALK) inhibitor ASP3026 (1) is described. A cost-effective and practical synthesis of 1 was accomplished as a result of the change of starting material from 2,4-dichloro-1,3,5-triazine (6) to cyanuric chloride (9) and late-stage introduction of a highly reactive N-methyl piperazine moiety by reductive amination of intermediate ketone 13. The modified process avoided the challenges with the original synthesis and furnished the several hundred kilograms of high-quality API with high economic efficiency, operability, and reproducibility. Furthermore, a sequence of investigation of polymorphic control in the second-generation synthetic route to obtain the thermodynamically desired, most stable polymorph Form A04 is also discussed. READ ARTICLE

Organic Process Research & Development DOI:10.1021/acs.oprd.8b00427

Authors: Yuji Takahama, Kazuyoshi Obitsu, Kazuhiro Takeguchi, Shun Hirasawa, Koji Kobayashi, Takahiro Akiba, Norihiro Ueda, Ryoki Orii, Atsushi Ohigashi, Takumi Takahashi, Minoru Okada, Shigeru Ieda

EditorialKirk SmithJuly 11, 2019ALK inhibitor, SNAr reaction, 1, 3, 5-triazine, polymorph

Chapter 4 - ALK Tyrosine Kinase Inhibitors in Drug Sensitization

Since the genomic aberrations of anaplastic lymphoma kinase (ALK) promote cancer cell proliferation and survival, specific tyrosine kinase inhibitors (TKIs) targeting these molecules have been developed. Besides its original targeting ALK effect, several studies have reported that ALK inhibitors can modulate the ATP-binding cassette (ABC) transporter to reverse the multiple drug resistance (MDR), which is one of the major obstacles for the successful cancer chemotherapy. In this chapter, we highlight reports manifesting that ALK inhibitors, including crizotinib, ceritinib, alectinib, and lorlatinib to antagonize ABC transporters to re-sensitize the anticancer drug in vitro and in vivo. These results give us some hints that specific ALK TKIs in combination with conventional anticancer drugs may be a good strategy to overcome the MDR in the clinic. READ ARTICLE

Protein Kinase Inhibitors as Sensitizing Agents for Chemotherapy DOI:10.1016/B978-0-12-816435-8.00004-3

Authors: Tong Wu, Liwu Fu

New promising circulating RNA biomarkers for early diagnosis of lung adenocarcinoma

Clinical practice relies in the use of specific biological parameters which can be correlated with the onset, establishment, development and therapeutic response of diseases. Biomarkers have becoming even a more relevant research topic in clinics since the foundation of the precision medicine initiatives worldwide. The choice of specific biomarkers is dependent on their sensitivity and specificity for a particular disease, but also on technical aspects related with their collection protocol, stability and detection from biological samples. In clinical oncology, early diagnosis biomarkers are very important for the prevention of the incidence of cancers, but also for the establishment of proper therapeutic strategies... Despite of the lack of knowledge about the subjacent molecular mechanisms involved in the secretion of circRNAs by cancer cells, there is increased evidence about their use as molecular circulating biomarkers for the stratification and prognosis of tumors, as illustrate..... READ ARTICLE

Annals of Translational Medicine
DOI:10.21037/atm.2019.05.70

Authors: Francisco J. Enguita

Review PaperKirk SmithJuly 1, 2019Circulating RNA biomarkers, lung adenocarcinoma

MPRIP-ALK, a Novel ALK Rearrangement That Responds to ALK Inhibition in NSCLC

Oncogenic rearrangements of the ALK receptor tyrosine kinase (ALK) gene are detected in approximately 7% of NSCLC patients.1 However, novel partner genes for ALK fusion and their clinical significance are not fully defined. Herein we describe the first case of ALK fusion with the myosin phosphatase Rho interacting protein gene (MPRIP) via next-generation sequencing (NGS), whose oncogenicity was further validated in vitro. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.02.030

Authors: Wenfeng Fang, Jiadi Gan, Shaodong Hong, Feng Lu, Li Zhang.

EditorialKirk SmithJuly 1, 2019MPRIP-ALK, ALK, Inhibition, NSCLC

Concomitant EGFR Mutation and EML4-ALK Rearrangement in Lung Adenocarcinoma Is More Frequent in Multifocal Lesions

Background: The coexistence of epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement in patients with multifocal lung adenocarcinomas (LUAC) constitutes a rare molecular subtype of lung cancer. We aimed to investigate the intertumoral heterogeneity of pathologic and genetic characteristics of multifocal LUAC with EGFR/ALK co-alterations. Conclusion: The results highlight the importance of distinguishing synchronous primary tumors from intrapulmonary metastases, and of assessing the relative abundance of EGFR mutation and ALK rearrangement in patients with multifocal adenocarcinomas with EGFR/ALK co-alterations. READ ARTICLE

Clinical Lung Cancer DOI:doi.org/10.1016/j.cllc.2019.04.008

Authors: Jun Fan, Xiaofang Dai, Zhenkao Wang, Bo Huang, Heshui Shi, Danju Luo, Jiwei Zhang, Weijing Cai, Xiu Nie, Fred R.Hirsch