Clinical implications of an analysis of pharmacokinetics of crizotinib coadministered with dexamethasone in patients with non-small cell lung cancer

Purpose: Dexamethasone is a systemic corticosteroid and a known cytochrome P450 (CYP)3A inducer. Crizotinib is a selective tyrosine kinase inhibitor of ALK, ROS1, and MET and a substrate of CYP3A. This post hoc analysis characterized the use of concomitant CYP3A inducers with crizotinib and estimated the effect of dexamethasone use on crizotinib pharmacokinetics at steady state. Conclusions: Crizotinib plasma exposure following coadministration with dexamethasone was similar to that when crizotinib was administered without dexamethasone, indicating dexamethasone has no effect on crizotinib exposure or efficacy. Other CYP3A inducers with similar potency would likewise have no clinically relevant effect on crizotinib exposure. READ ARTICLE

Cancer Chemotherapy and Pharmacology DOI:10.1007/s00280-019-03861-y

Authors: Swan Lin, Dana J. Nickens, Maulik Patel, Keith D. Wilner & Weiwei Tan

Kirk SmithMay 24, 2019

Frequency, clinical features and differential response to therapy of concurrent ALK/EGFR alterations in Chinese lung cancer patients

Purpose: EGFR and anaplastic lymphoma kinase (ALK) alterations have been regarded as oncogenic drivers and incorporated into clinical practices to manage nonsmall cell lung cancer (NSCLC). Alterations of these two genes were traditionally considered to be mutually exclusive, but recent studies have suggested that they can occur concomitantly. Here, we investigated the prevalence, clinical features and outcomes in response to the treatment of NSCLC patients who harbor EGFR and ALK co-alterations. Conclusion: EML4-ALK/EGFR and non-EML4-ALK/EGFR co-alterations displayed distinct clinical features and responses to EGFR-TKIs, suggesting that non-EML4-ALK co-alterations are likely to occur as a resistance mechanism to EGFR-TKI. In addition, dual-TKI therapy might be a better choice than single-TKI treatments for these co-altered patients. To the best of our knowledge, this is the largest dual-positive EGFR/ALK cohort study in People's Republic of China. READ ARTICLE

Drug Design and Development Therapies DOI:10.2147/DDDT.S196189

Authors: Jixian Liu, Zhimin Mu, Li Liu, Kang Li, Richeng Jiang, Peng Chen, Qiang Zhou, Meiling Jin, Yuxiang Ma, Yuancai Xie, Jianxing Xiang, Bing Li, Yafeng Ma, Xinru Mao, Lu Zhang, Tengfei Zhang, Da Wu

Meta-analysis comparing incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with non-small-cell lung cancer

Aim: Using the available literature, this meta-analysis aimed to compare reports of the incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with ALK-positive NSCLC. Conclusion: This meta-analysis of Phase III randomized clinical trials found no significant difference in the incidence of grade 3–4 neutropenia among patients with ALK-positive NSCLC treated with either an ALK inhibitor or chemotherapy, and this was not affected by adjusting for baseline tumor stage. READ ARTICLE

FUTURE ONCOLOGY
DOI:10.2217/fon-2018-0863

Authors: Bernardo Rapoport, Ramin B Arani, Nicola Mathieson, Andriy Krendyukov

Computed Tomography Imaging Characteristics of Non–Small-Cell Lung Cancer With Anaplastic Lymphoma Kinase Rearrangements: A Systematic Review and Meta-Analysis

Background: Young patients are rarely diagnosed with non-small cell lung cancer (NSCLC), and little is known about its predisposing genomic alterations and survival. Conclusions: Younger patients with NSCLC had a higher frequency of gene fusions than older patients and had a trend of worse OS. READ ARTICLE

Annals of Translational Medicine DOI:10.21037/atm.2019.03.39

Authors: Shifeng Yang, Zhengbo Song, Guoping Cheng

A Complex Renal Cyst in a Patient on Crizotinib: Case Report

Crizotinib is a first generation tyrosine kinase inhibitor for ALK gene positive nonsmall cell lung cancer (ALK + NSCLC). The FDA approved its use in 2011. 1 There has been a recent recognition of crizotinib-associated renal cysts (CARCs). READ ARTICLE

Urology DOI:10.1016/j.urology.2019.04.035

Authors: Christine W. Liaw, Michael Palese, Larry Di Fabrizio

Case StudyKirk SmithMay 9, 2019Renal, Cyst, Crizotinib

Discovery of novel mutant-combating ALK and ROS1 dual inhibitors bearing imidazolidin-2-one moiety with reasonable PK properties

Aiming to identify novel potent ALK and ROS1 dual inhibitors, the relatively bulky piperidine fragment in ceritinib was replaced with substituted imidazolidin-2-one moiety which gave rise to a series of 2,4-diaryl-aminopyrimidine (DAAP) analogs (6–33). SAR studies were conducted based on cellular assays on five cell lines and most compounds exerted moderated to excellent activities. Among them, 15 showed excellent inhibitory activities against ROS1 and ALK positive cell lines, especially Ba/F3G1202R, with IC50 values ranging from 14 to 37 nM. As a continuation, several compounds were tested in enzymatic assays and 15 displayed encouraging activities against wild-type ALK (1.2 nM), ROS1(0.43 nM) as well as extremely resistant ALKL1196M and ALKG1202R mutants with IC50 values of 0.73 nM and 6.7 nM, respectively. To our delight, both cellular and enzymatic results of 15 were in good accordance with western blot assays on H2228 and HCC78 cell lines. Importantly, pharmacokinetic (PK) profile..... READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2019.03.038

Authors: Hongrui Lei, Nan Jiang, Xiuqi Miao, Lingyun Xing, Ming Guo, Yang Liu, Haowen Xu, Ping Gong, Daiying Zuo, Xin Zhai

The safety and serious adverse events of approved ALK inhibitors in malignancies: a meta-analysis

Background: A total of 2%–7% of non-small cell lung cancer (NSCLC) patients have anaplastic lymphoma kinase (ALK) mutations. At present, three or more generations of ALK inhibitors have been used for ALK-positive NSCLC treatment, including crizotinib, alectinib, ceritinib, and brigatinib. Although most adverse events (AEs) of ALK inhibitors are grades 1 to 2 and generally can be well tolerated, serious adverse events (SAEs) of ALK inhibitors lack data analysis, and the lung toxicity of ALK inhibitors needs attention. Thus, we performed this meta-analysis to evaluate the safety of ALK inhibitors, especially in terms of drug-related SAEs. Conclusion: ALK-related SAEs should draw attention, especially in terms of lung toxicity. According to this meta-analysis, alectinib seems to be the safest ALK inhibitor. Physicians should focus on related SAEs when prescribing ALK inhibitors. Given that lung cancer patients have poor pulmonary function at baseline, the lung toxicity risk of ALK inhibi..... READ ARTICLE

Cancer Management and Research
DOI:10.2147/CMAR.S190098

Authors: Helei Hou, Dantong Sun, Kewei Liu, Man Jiang, Dong Liu, Jingjuan Zhu, Na Zhou, Jing Cong, Xiaochun Zhang

Indoor Radon in EGFR- and BRAF-Mutated and ALK-Rearranged Non–Small-Cell Lung Cancer Patients

Background: Radon gas is the leading cause of lung cancer in the nonsmoking population. The World Health Organization (WHO) recommends indoor concentrations of < 100 Bq/m³. Several molecular alterations have been described in non–small-cell lung cancer (NSCLC), mainly in nonsmokers, with no risk factors identified. We studied the role of indoor radon in NSCLC patients harboring specific driver alterations. Conclusion: The median indoor radon concentration was above the WHO recommendations, with no differences between EGFR, ALK, and BRAF patients. Concentrations above the WHO recommendations were most common with ALKr and BRAFm. These findings should be validated in larger studies. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.04.009

Authors: Laura Mezquita, Amparo Benito, Alberto Ruano-Raviña, Javier Zamora,Maria Eugenia Olmedo, Pablo Reguera, Ainhoa Madariaga, María Villamayor, Silvia Patricia Cortez, Luis Gorospe, Almudena Santón, Sagrario Mayoralas, Raúl Hernanz, Alberto Cabañero, Edouard Auclin, Alfredo Carrato, Pilar Garrido

Case StudyKirk SmithMay 3, 2019Driver oncogene, Radioactivity, Radon gas, NSCLC

Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC

Introduction: Leptomeningeal metastases (LMs) indicated a poor prognosis in NSCLC. LMs were more frequent in driver gene–mutated patients, and cerebrospinal fluid (CSF) cell-free DNA has shown unique genetic profiles of LM in EGFR-mutated LM. However, studies in patients with ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC with LMs are scarce. Conclusion: Liquid biopsy of CSF is more sensitive than liquid biopsy of plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in patients with ALK-rearranged NSCLC with LM. Thus, CSF might be promising as a medium of liquid biopsy in LM. READ ARTICLE

Journal of Thoracic Oncology
DOI:10.1016/j.jtho.2019.01.007

Authors: Mei-Mei Zheng, Yang-Si Li, Ben-Yuan Jiang, Hai-Yan Tu, Wen-Fang Tang, Jin-Ji Yang, Xu-Chao Zhang, Jun-Yi Ye, Hong-Hong Yan, Jian Su, Qing Zhou, Wen-Zhao Zhong, Xue-Ning Yang, Wei-Bang Guo, Shannon Chuai, Zhou Zhang, Hua-Jun Chen, Zhen Wang, Chao Liu, Yi-Long Wu

Isolated 5′ Signals Are an Atypical Pattern To Be Considered as Positive for ALK Rearrangement: A Brief Report of Three Cases and Review of the Literature

Anaplastic lymphoma kinase (ALK) rearrangement is reported in 3% to 8% of patients with lung adenocarcinoma and can be detected by fluorescent in situ hybridization (FISH) or indirectly by immunohistochemistry. In FISH assay, isolated 5′ signal (loss of 3′ signal) is usually considered negative. We report three young nonsmoking patients with stage IV lung adenocarcinoma. Strong ALK expression in tumor cells detected by immunohistochemistry was observed in all cases, but FISH revealed an isolated 5′ signal pattern. Massive parallel “next-generation” sequencing was performed in two patients and confirmed ALK rearrangement. The three patients were treated and responded to crizotinib after 14, 10, and 31 months. READ ARTICLE

Translational Oncology DOI:10.1016/j.tranon.2019.02.015

Authors: Alice Guyard, Cécile Charpy, Nathalie Théou-Anton,Anne Cremades, Frédéric Grassin, Anaïs Bourgogne, Karen Leroy, Anaïs Pujals, Christiane Copie-Bergman, Christos Chouaid, Audrey Mansuet-Lupo

Case StudyKirk SmithMay 1, 2019Isolated 5′ Signals, ALK Rearrangement

Expanding the Molecular Characterization of Thoracic Inflammatory Myofibroblastic Tumors beyond ALK Gene Rearrangements

Introduction: Half of inflammatory myofibroblastic tumors (IMTs) regardless of anatomic location harbor anaplastic lymphoma kinase gene (ALK) rearrangements and overexpress anaplastic lymphoma kinase protein. The wide application of next-generation sequencing and the clinical benefit to tyrosine kinase inhibitors have opened new opportunities for investigation of ALK-negative IMTs. Conclusions: By using a battery of complementary molecular techniques, we have shown that all the thoracic IMTs harbored a tyrosine kinase abnormality, with 30% involving a kinase gene other than ALK, including ROS1, NTRK3, and RET gene fusions. We have also described for the first time ALKATI-induced ALK oncogenic activation in IMTs. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.12.003

Authors: Jason C. Chang, Lei Zhang, Alexander E. Drilon, Ping Chi, Rita Alaggio, Laetitia Borsu, Ryma Benayed, William D. Travis, Marc Ladanyi, Cristina R. Antonescu

Case StudyKirk SmithMay 1, 2019Inflammatory myofibroblastic tumor (IMT), ALK, ROS1, NTRK3, Fusion, Kinase

PCN165 ESTIMATION OF THE NUMBER OF ALK-POSITIVE CASES AMONG PEOPLE LIVING WITH CANCERS IN THE UNITED STATES

Objectives: Considering the scarcity of data on anaplastic lymphoma kinase (ALK) cancer biomarker, a review of literature was performed to collate information on its prevalence across all common tumor sites, and the estimates of diagnosed incidence of each tumor were used to determine the total number of incident ALK-positive cases for the year 2018 in the United States (US). Conclusions: ALK-mutations are found in multiple tumor sites, and collectively represent 19,800 cases of cancer in 2018 in US. READ ARTICLE

Value in Health DOI:10.1016/j.jval.2019.04.289

Authors: N. J. Zhang

Real-World OutcomesKirk SmithMay 1, 2019ALK-POSITIVE CANCER, UNITED STATES

Fusion of ALK to the melanophilin gene MLPH in pediatric Spitz nevi

Spitzoid neoplasms typically affect young individuals and include Spitz nevus, atypical Spitz tumor, and Spitzoid melanoma. Spitz tumors can exhibit gene fusions involving the receptor tyrosine kinases NTRK1, NTRK3, ALK, ROS1, RET, or MET, or the serine-threonine kinase BRAF. Because most studies have been based on adult cases, we studied ALK fusions in Spitz nevi occurring in pediatric patients. Twenty-seven cases were screened for ALK expression by immunohistochemistry, and 6 positive cases were identified. These cases were studied further using the TruSight RNA Fusion Panel, and in 4 cases, exon 20 of the ALK gene was found to be fused to exon 14 of the MLPH (melanophilin) gene, a gene fusion that has only been reported in a Spitz nevus in an adult. The remaining 2 cases showed no fusion of ALK with any gene. The cases with the MLPH-ALK fusion showed a similar histology to that described for Spitz nevi with ALK fusions, with spindle-shaped and epithelioid melanocytes in fusiform nes..... READ ARTICLE

Human Pathology DOI:10.1016/j.humpath.2019.03.002

Authors: Catherine T. Chung, Paula Marrano, David Swanson, Brendan C. Dickson, Paul Scott Thorner

Crizotinib enhances anti-CD30-LDM induced antitumor efficacy in NPM-ALK positive anaplastic large cell lymphoma

Combining antibody-drug conjugates (ADCs) with targeted small-molecule inhibitors can enhance antitumor effects beyond those attainable with monotherapy. In this study, we investigated the therapeutic combination of a CD30-targeting ADC (anti-CD30-lidamycin [LDM]) with a small-molecule inhibitor (crizotinib) of nucleophosmin-anaplastic lymphoma kinase NPM-ALK in CD30+/ALK+ anaplastic large cell lymphoma (ALCL). In vitro, anti-CD30-LDM showed strong synergistic antiproliferative activity when combined with crizotinib. Furthermore, treatment with anti-CD30-LDM plus crizotinib resulted in a stronger induction of cell apoptosis than monotherapy with either treatment. Western blot analysis revealed that ERK1/2 phosphorylation was increased in response to anti-CD30-LDM-induced DNA damage. Interestingly, the addition of crizotinib inhibited the expression of phosphorylated ERK1/2 and further augmented anti-CD30-LDM-mediated apoptosis, providing a potential synergistic mechanism for DNA-damagi..... READ ARTICLE

Cancer Letters
DOI:10.1016/j.canlet.2019.02.002

Authors: Rong Wang, Liang Li, Aijun Duan, Yi Li, Xiujun Liu, Qingfang Miao, Jianhua Gong, Yongsu Zhen

Clinical features and therapeutic options in non-small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

Background: Although oncogenic driver mutations were thought to be mutually exclusive in non-small cell lung cancer (NSCLC), certain tumors harbor co-occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients. Conclusion: In this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR-TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options. READ ARTICLE

Cancer Medicine DOI:10.1002/cam4.2183

Authors: Xibin Zhuang, Chao Zhao, Jiayu Li, Chunxia Su, Xiaoxia Chen, Shengxiang Ren, Xuefei Li, Caicun Zhou

Application of time-dependent modeling for the exposure-efficacy analysis of ceritinib in untreated ALK-rearranged advanced NSCLC patients

Purpose: Ceritinib 750 mg/day was approved for the treatment of patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) based on ASCEND-4 study. The objective of this article is to introduce the use of time-dependent modeling approach in the updated exposure-efficacy analysis of ceritinib for the first-line indication. READ ARTICLE

Cancer Chemotherapy and Pharmacology DOI:10.1007/s00280-019-03830-5

Authors: Yvonne Y Lau, Wen Gu, Yu-Yun Ho, Ying Hong, Xinrui Zhang and Patrick Urban

Intra-cranial efficacy of brigatinib in an ALK-positive non-small cell lung cancer patient presenting leptomeningeal carcinomatosis

Objectives: Brigatinib is a second-generation ALK inhibitor which demonstrated activity over crizotinib-resistance, especially on brain metastasis by increased blood-brain penetration. However, its activity on lepto-meningeal disease is unknown and scarcely reported. Conclusion: Our case provides additional data on brigatinib’s intracranial activity, not only on brain metastasis but also on leptomeningeal disease, after experiencing resistance to both crizotinib and ceretinib, 1st and 2nd generation ALK inhibitors. READ ARTICLE

Lung Cancer
DOI:10.1016/j.lungcan.2019.04.013

Authors: Elisabeth Gaye, Margaux Geier, Paul Bore, Marine Guilloïque, Francois Lucia, Gilles Quéré, Sylvie Gouva, Gilles Robinet, Renaud Descourt

Refinement of diagnosis and supporting evidence for the use of immunotherapy through sequential biopsies in a case of EML4-ALK positive lung cancer

In this case report, we describe a tortuous, yet rare, treatment process of the patient. The first biopsy of the patient suggested inflammatory myofibroblastic tumor, ALK (D5F3) positive. Considering the benign progression of the disease, and no indication for surgical resection, oral prednisone was given first. However, the disease rapidly progressed, and a second biopsy revealed a pulmonary sarcomatoid cancer. Since the biopsy was ALK (D5F3) positive, the effect of crizotinib treatment was significant, though crizotinib resistance unfortunately only occurred after 4 months. The third biopsy pathology was performed and confirmed lung adenocarcinoma. After switching to pembrolizumab treatment, the lesions were significantly reduced after four courses of treatment. The current condition of patient persisted in partial response. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S203192

Authors: Peng Song, Jingcheng Zhang, and Li Zhang

Case StudyKirk SmithApril 17, 2019Sequential biopsies, EML4-ALK, immunotherapy, lung adenocarcinoma

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

The incidence of ALK inhibitor-related pneumonitis in advanced non-small-cell lung cancer patients: A systematic review and meta-analysis

Introduction: We evaluated the incidence of pneumonitis in clinical trials of anaplastic lymphoma kinase (ALK) inhibitors in patients with advanced non-small cell lung cancer (NSCLC) and compared the incidence among different cohorts, in order to identify possible predisposing factors for ALK inhibitor-related pneumonitis. Conclusions: The overall incidence of ALK inhibitor pneumonitis was 2.14% in patients with advanced NSCLS. The patients from Japanese cohorts had a higher incidence of ALK-inhibitor pneumonitis, which indicates the need for increased awareness and caution for pneumonitis in Japanese patients treated with ALK inhibitors. READ ARTICLE

Lung Cancer
DOI:10.1016/j.lungcan.2019.04.015

Authors: Chong Hyun Suh, Kyung Won Kim, Junhee Pyo, Hiroto Hatabu, Mizuki Nishino