Detection of genomic rearrangements like ALK fusions are of great interest in non-small cell lung cancer (NSCLC) as those alterations can be targeted by an increasing number of drugs. To overcome tissue limitations, detection of these alterations from liquid biopsies is an unmet need, despite the development of novel NGS-based tests. To allow the detection of ALK rearrangements from circulating-free RNA (cfRNA) from NSCLC patients, we have evaluated a novel RT-PCR based assay and compared the results to tissue-based testing using immunohistochemistry (IHC) or fluorescence in-situ hybridization (FISH).The prototype cobas ALK/RET/ROS1 Fusion Panel assay was able to detect ALK fusion transcripts in the plasma of NSCLC patients at baseline as well as at disease progression. Limited sensitivity could be explained by biological factors influencing nucleic acid shedding by tumours, as well as the presence of fusions not covered by the assay. However, the assay demonstrated high specificity. T..... READ ARTICLE
Cancer Research DOI:10.1158/1538-7445.AM2020-5299
Authors: Simon Heeke, Marius Ilié, Maryline Allegra, Audrey Vallée, Carole Salacroup, Virginie Tanga, Véronique Hofman, Jaya Rajamani, Michael Lee, Ellen Ordinario, Marc G. Denis and Paul Hofman
KEY POINTS:
Most epidermal growth factor receptor (EGFR)-mutated NSCLC (exon 19 del and L858R) should be
initially treated with osimertinib.
Anaplastic lymphoma kinase (ALK) fusion-positive NSCLC should be initially treated with alectinib,
brigatinib, or ceritinib; however, tolerability issues limit the use of ceritinib.
ROS1 fusion-positive NSCLC should be initially treated with entrectinib over crizotinib given central
nervous system activity.
BRAF V600E-mutated NSCLC should be initially treated with dabrafenib plus trametinib.
Neurotrophic tropomyosin receptor kinase fusion-positive NSCLC should be initially treated with
entrectinib or larotrectinib.
Patients with HER2 or EGFR exon 20 insertions, RET fusions, NRG1 fusions, MET amplification and
exon 14 skipping mutations, and KRAS G12C mutations should be initially treated with standard-ofcare chemoimmunotherapy; however, there are targeted therapies under investigation showing
promise. READ ARTICLE
Clinics in Chest Medicine DOI:10.1016/j.ccm.2020.02.003
Authors: Nicholas P. Giustini, Ah-Reum Jeong, James Buturla, Lyudmila Bazhenova
Background: TQ-B3139 is a novel ALK inhibitor with activity 3-7 folds higher than Crizotinib against a broad range of ALK mutations. This phase I study (NCT03099330) is to investigate the safety, and determine the recommended phase II dose (RP2D), and pharmacokinetic (PK), clinical efficacy of TQ-B3139 in Chinese NSCLC patients... Background: TQ-B3139 is a novel ALK inhibitor with activity 3-7 folds higher than Crizotinib against a broad range of ALK mutations. This phase I study (NCT03099330) is to investigate the safety, and determine the recommended phase II dose (RP2D), and pharmacokinetic (PK), clinical efficacy of TQ-B3139 in Chinese NSCLC patients. READ ARTICLE
Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9585
Authors: Yuxiang Ma, Nong Yang, Su Li, Hongyun Zhao, Liu Li, Haiyan Yang, Wenfeng Fang, Yang Zhang, Shaodong Hong, Yi Xiong, Chunhua Zhou, Yongchang Zhang, Liang Zeng, Li Zhang
Background: Lorlatinib, a third-generation tyrosine kinase inhibitor targeting ALK and ROS1, has been made available in France starting October 2015 through an EAP for advanced, refractory, ALK+ NSCLC after the failure of chemotherapy and TKIs. Besides the landmark, multi-cohort phase II trial that assessed lorlatinib in ALK+ NSCLC, real-life evidence regarding the efficacy and safety, as well as treatment sequences including lorlatinib, is lacking. Methods: We report the cohort of consecutive patients with advanced, refractory, ALK or ROS1+ NSCLC enrolled in the French EAP of lorlatinib from October 2015 to October 2019. Data were collected from medical records by French Cooperative Thoracic Intergroup (IFCT) research study assistants on site. Primary endpoint was progression-free survival... Conclusions: These real-life results confirmed lorlatinib as a major treatment option for patients with advanced refractory ALK or ROS1+ NSCLC. READ ARTICLE
Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9615
Authors: Simon Baldacci, Virginie Avrillon, Benjamin Besse, Bertrand Mennecier, Michael Duruisseaux, Julien Mazieres, Renaud Descourt, Helene Doubre, Pascale Dubray-Longeras, Jacques Cadranel, Denis Moro-Sibilot, Charles Ricordel, Sigolène Galland-Girodet, Isabelle Monnet, Josiane Otto, Sophie Schneider, Pascale Missy, Franck Morin, Virginie Westeel, Nicolas Girard
Background: ROS proto-oncogene 1 (ROS1) rearrangements are a known molecular target in non–small-cell lung cancer (NSCLC). Our goal was to determine whether ROS1-rearranged NSCLC has imaging features and patterns of metastasis, which differ from those of anaplastic lymphoma kinase (ALK)-rearranged or epidermal growth factor receptor (EGFR)-mutant NSCLC... Conclusion: Although considerable overlap exists in the imaging features of ROS1-rearranged, ALK-rearranged, and EGFR-mutant NSCLC, we found that ROS1-rearranged NSCLC has certain distinct imaging features and patterns of spread. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2019.10.006
Authors: Subba R. Digumarthy, Dexter P. Mendoza, Jessica J. Lin, Tianqi Chen, Marguerite M. Rooney, Emily Chin, Lecia V. Sequist, Jochen K. Lennerz, Justin F. Gainor, Alice T. Shaw
Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) and MET proto-oncogene, receptor tyrosine kinase (MET). Unfortunately, hepatotoxicity is a serious limitation in its clinical application, and the reason remains largely unknown. In this study, we tested the effect of crizotinib in human hepatocyte cell line HL-7702 and human primary hepatocytes, and the results showed that crizotinib treatment caused hepatocyte damage, suggesting that crizotinib induced liver injury by causing hepatocyte death, consistent with the clinical cases. Mechanistically, crizotinib induced hepatocyte death via the apoptotic pathway, and cleaved PARP (c-PARP) was observed as a signaling protein. Moreover, mitochondrial membrane potential (MMP) decrease contributed to crizotinib-induced hepatocyte apoptosis accompanied by hepatocyte DNA damage and reactive oxygen species (ROS) generation. Importantly, crizotinib induced hepatocyte apoptosis independent of its targets, ALK, ROS1 and MET. In conclusion, our data showed that crizotinib induced liver injury through hepatocyte death via the apoptotic pathway which was independent of ALK, ROS1 and MET. And we also found that MMP decrease, DNA damage and ROS generation were involved in the process. READ ARTICLE
Toxicology and Applied Pharmacology DOI: 10.1016/j.taap.2019.114768
AUTHORS: Hao Yan, Jiangxia Du, Xueqin Chen, Bo Yang, Qiaojun He, Xiaochun Yang, Peihua Luo
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WX-0593 is a potent ALK inhibitor against ALK and ROS1 rearrangement and a series of crizotinib (CRZ)-resistant mutants. We explored the safety and efficacy of WX-0593 in patients (pts) diagnosed with ALK+ or ROS-1+ malignancies, including non-small cell lung cancer (NSCLC). READ ARTICLE
Annals of Oncology DOI:https://doi.org/10.1093/annonc/mdz260.007
Authors: Y-K Shi, J. Fang, S. Zhang, Y. Liu, L. Wang, M. Si, M. Ge and H Geng
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
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
This study aims to determine whether advanced ROS1 gene-rearranged NSCLC (ROS1+ NSCLC) has a higher than expected thromboembolic event (TEE) rate.
The risk of peridiagnostic TEEs is significantly elevated in patients with advanced ROS+ NSCLC compared to EGFR+ and KRAS+ cases. TEE risk may be similarly elevated in ALK+ NSCLC. READ ARTICLE
Journal of Thoracic Oncology DOI:10.1016/j.jtho.2018.12.001
Authors: Terry L Ng, Derek E Smith, Rao Mushtaq, Tejas Patil, Anastasios Dimou, Shuo Yang, Qian Liu, Xuefei Li, Caicun Zhou, Robert T Jones, Megan M Tu, Flora Yan, I Alex Bowman, Stephen V Liu, Siera Newkirk, Joshua Bauml, Robert C Doebele, Dara L Aisner, Dexiang Gao, Shengxiang Ren, D Ross Camidge
Non–small-cell lung cancer (NSCLC) patients harboring ALK or ROS1 rearrangements invariably acquire resistance to the first- and second-generation tyrosine kinase inhibitors (TKIs), most notably ALK G1202R and ROS1 G2032R. Lorlatinib, a novel third-generation TKI, produced remarkable results from the first-in-man phase 1 trial: an overall response rate of 46% and 50% for previously treated ALK- and ROS1-positive patients, respectively. However, the efficacy of lorlatinib has not been widely validated in Asian patients.
This study is the first to report that lorlatinib is an important novel therapeutic option for Asian patients who have advanced NSCLC harboring ALK/ROS1 mutations whose disease progressed during treatment with first- and second-generation TKIs. READ ARTICLE
Clinical Lung Cancer DOI:10.1016/j.cllc.2018.12.020
Authors: Jiyun Lee, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Yoon La Choi, Myung-Ju Ahn
Convex probe endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) is a minimally invasive technique with high sensitivity in the mediastinal staging of non-small cell carcinoma (NSCLC). The aim of this study was to evaluate the adequacy of EBUS-TBNA in providing adequate size specimens for EGFR, ALK and ROS1 genetic mutation analysis in patients with adenocarcinoma or not otherwise specified (NOS) lung cancer.
The study demonstrated that EBUS-TBNA provides adequate material for mutation analysis in patients with newly diagnosed adenocarcinoma or NOS lung cancer. READ ARTICLE
The Clinical Respiratory Journal DOI:10.1111/crj.12985
Authors: Tugba Cicek, Ayperi Ozturk, Aydın Yılmaz, Zafer Aktas, Funda Demirag, Nalan Akyurek
Immune checkpoint inhibitors (ICIs) have been incorporated in the treatment strategy of advanced non-small cell lung cancer (NSCLC) in first- and second-line setting improving the prognosis of these patients. However, the treatment landscape has been also drastically overturned with the advent of targeted therapies in oncogenic-addicted advanced NSCLC patients. Despite ICIs represent an active and new treatment option for a wide range of advanced NSCLC patients, the efficacy and the optimal place of ICI in the treatment strategy algorithm of oncogenic-addicted tumors remains still controversial, as only a minority of trials with ICI enrol oncogenic-addicted NSCLC patients previously treated with standard therapy. Therefore, there are still several open questions about ICI in oncogenic-driven NSCLC, such as the efficacy and toxicities, which need to be addressed before considering treatment with ICI as a standard approach in this population. It is in this framework, we provide a thoroug..... READ ARTICLE
Cancer Treatment Reviews DOI:10.1016/j.ctrv.2018.10.006
Authors: J. Remon, L.E. Hendriks, C. Cabrera, N. Reguart, B. Besse
ALK and ROS1 are prognostic and predictive tumor markers in non-small cell lung carcinoma (NSCLC), which are more often found in lung adenocarcinomas as with other oncogenes such as EGFR, KRAS, or C-MET. Their positivity is 2.6% and 1.3%, respectively, and patients who have mutations in both genes are extremely rare. Here, we report a 61-year-old male diagnosed with acinar adenocarcinoma, who was shown to have both ALK and ROS1 rearrangements but was EGFR- and C-MET mutation-negative. He was treated surgically and received targeted therapy. Our review of the literature revealed that few such cases of concurrent ALK and ROS1 rearrangements have been reported. This information furthers our understanding of the molecular biology underlying NSCLC which will aid the selection of optimal treatment for patients with more than one driver mutation. READ ARTICLE
Pathology - Research and Practice DOI:10.1016/j.prp.2018.09.028
Authors: Huiyan Deng, Chang Liu, Guoliang Zhang, Xiaoling
Wang, Yueping Liu
Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion–positive and 13 ROS1-fusion–positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion–positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥50 years, male sex, high pathological stage and negative kinase-fusion status. READ ARTICLE
Nature Medicine DOI: 10.1038/nm.2658
Authors: Kengo Takeuchi, Manabu Soda, Yuki Togashi, Ritsuro Suzuki, Seiji Sakata, Satoko Hatano, Reimi Asaka, Wakako Hamanaka, Hironori Ninomiya, Hirofumi Uehara, Young Lim Choi, Yukitoshi Satoh, Sakae Okumura, Ken Nakagawa, Hiroyuki Mano, Yuichi Ishikawa
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