Discovery of 2-aminopyridines bearing a pyridone moiety as potent ALK inhibitors to overcome the crizotinib-resistant mutants

Despite the initial benefit demonstrated in clinical setting with ALK inhibitors, the challenging resistant mutants (F1174L, L1196M and G1202R) invariably developed. In this work, a series of 2-aminopyridine derivatives were designed and synthesized by C-5 position incorporation of a 2-pyridone moiety and bioisosteric replacement of the C-3 position linkers. Optimization of the 2-aminopyridine derivatives led to the identification of hit 18d displaying a significant growth inhibition against a variety of ALK-addicted cancer cells. Especially in the case of ALK-positive Karpas-299 cell, 18d exhibited excellent anti-proliferative potency with an IC50 value of about 40 nM. Moreover, 18d demonstrated encouraging activities against wild-type ALK (19 nM), ROS1 (2.3 nM) as well as challenging crizotinib-resistant ALKL1196M and ALKG1202R mutants with IC50 values of 45 nM and 22 nM, respectively. Additionally flow cytometric analysis indicates that 18d inhibited Karpas-299 cell viability via G1 phase arrest. Taken together, this work provided a promising ALK inhibitor to circumvent the clinical crizotinib-resistant mutants. READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2019.111734

Authors: Wenteng Chen, Xiao Guo, Can Zhang, Di Ke, Guolin Zhang, Yongping Yu

Afatinib Overcomes Pemetrexed-Acquired Resistance in Non-Small Cell Lung Cancer Cells Harboring an EML4-ALK Rearrangement

Background: The aim of this study is to elucidate the mechanisms of acquired resistance to pemetrexed in echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) rearranged non-small cell lung cancer. Methods: We analyzed the sensitivity to pemetrexed and the expression patterns of various proteins after pemetrexed treatment in the cell lines, A549, NCI-H460, NCI-H2228 harboring EML4-ALK variant 3, and NCI-H3122 harboring EML4-ALK variant 1. Pemetrexed-resistant cell lines were also generated through long-term exposure to pemetrexed. Results: The EML4-ALK variant 1 rearranged NCI-H3122 was found to be more sensitive than the other cell lines. Cell cycle analysis after pemetrexed treatment showed that the fraction of cells in the S phase increased in A549, NCI-H460, and NCI-H2228, whereas the fraction in the apoptotic sub-G1 phase increased in NCI-H3122. The pemetrexed-resistant NCI-H3122 cell line showed increased expression of EGFR and HER2 compared to ..... READ ARTICLE

Cells DOI:10.3390/cells8121538

Authors: Ji-Hyun Kwon, Kui-Jin Kim, Ji Hea Sung, Koung Jin Suh, Ji Yun Lee, Ji-Won Kim, Se Hyun Kim, Jeong-Ok Lee, Jin Won Kim, Yu Jung Kim, Keun-Wook Lee, Jee Hyun Kim, Soo-Mee Bang, Soyeon Kim, Sung-Soo Yoon, Jong Seok Lee

Pre-ClinicalKirk SmithNovember 28, 2019Pemetrexed, drug resistance, afatinib, lung cancer, EML4-ALK rearrangement

Final progression-free survival results from the J-ALEX study of alectinib versus crizotinib in ALK-positive non-small-cell lung cancer

Objectives: The J-ALEX study compared the efficacy and safety of alectinib with crizotinib in Japanese patients with advanced ALK-positive non-small-cell lung cancer (NSCLC). Superiority in independent review facility (IRF)-assessed progression-free survival (PFS) was demonstrated for alectinib at the second pre-planned interim PFS analysis (data cutoff: December 3, 2015; hazard ratio [HR] 0.34, 99.7 % confidence interval [CI]: 0.17–0.71, P < 0.0001). We report final PFS data and the second pre-planned interim analysis of overall survival (OS) and safety (data cutoff: June 30, 2018). Conclusions: At the final PFS analysis, alectinib continued to demonstrate superiority in IRF-assessed PFS versus crizotinib in ALK-inhibitor-naïve ALK-positive NSCLC, with a favorable safety profile. OS follow-up continues. READ ARTICLE

Lung Cancer. DOI: 10.1016/j.lungcan.2019.11.025

Authors: Kazuhiko Nakagawa, Toyoaki Hida, Hiroshi Nokihara, Masahiro Morise, Koichi Azuma, Young Hak Kim, Takashi Seto, Yuichi Takiguchi, Makoto Nishio, Hiroshige Yoshioka, Toru Kumagai, Katsuyuki Hotta, Satoshi Watanabe, Koichi Goto, Miyako Satouchi, Toshiyuki Kozuki, Ryo Koyama, Tetsuya Mitsudomi, Nobuyuki Yamamoto, Takashi Asakawa, Morihiko Hayashi, Wakako Hasegawa, Tomohide Tamura

Clinical TrialsKirk SmithNovember 28, 2019Alectinib, ALK-positive, Crizotinib, J-ALEX, NSCLC, PFS

Driver genes as predictive indicators of brain metastasis in patients with advanced NSCLC: EGFR, ALK, and RET gene mutations

Background: A retrospective analysis verified the role of gene mutations in brain metastasis in patients with non-small cell lung cancer (NSCLC). Conclusions: An EGFR mutation, ALK gene fusion, and RET gene fusion in advanced NSCLC patients play roles in brain metastasis as positive driver genes. Impact: An EGFR mutation, and ALK and RET gene fusions are risk factors for brain metastasis in advanced NSCLC patients. READ ARTICLE

Cancer Medicine. DOI: 10.1002/cam4.2706

Authors: Huijuan Wang, Ziqi Wang, Guowei Zhang, Mina Zhang, Xiaojuan Zhang, Haixia Li, Xuanxuan Zheng, Zhiyong Ma

Final Overall Survival and Other Efficacy and Safety Results From ASCEND-3: Phase II Study of Ceritinib in ALKi-Naive Patients With ALK-Rearranged NSCLC

Introduction: The phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)–naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results. Conclusions: Ceritinib exhibited prolonged and clinically meaningful OS, PFS, and duration of response in chemotherapy-pretreated (at least three lines), ALKi-naive patients with ALK+ NSCLC. The safety profile was consistent with that reported in previous studies. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.006

Authors: Makoto Nishio, Enriqueta Felip, Sergey Orlov, Keunchil Park, Chong-Jen Yu, Chun-Ming Tsai, Manuel Cobo, Mark McKeage, Wu-Chou Su, Tony Mok, Giorgio V. Scagliotti, David R. Spigel, Kalyanee Viraswami-Appanna, Zhe Chen, Vanessa Q. Passos, Alice T. Shaw

Clinical TrialsKirk SmithNovember 25, 2019Ceritinib, ALK, NSCLC, Phase II, ASCEND-3

Sequential ALK inhibitor treatment benefits patient with leptomeningeal metastasis harboring non-EML4-ALK rearrangements detected from cerebrospinal fluid: A case report

A 47-year-old female with ALK-rearranged lung adenocarcinoma developed leptomeningeal metastasis (LM) after progression on first-line crizotinib. Alectinib 300 mg was commenced and the patient achieved clinical and radiographic improvements. After nine months of alectinib 300 mg, she started to experience symptomatic LM. Two concurrent non-EML4-ALK rearrangements, LOC388942-ALK and LINC00211-ALK, were identified from the CSF but not from the plasma samples. With the primary lung lesions remaining stable, the alectinib dose was increased to 600 mg twice daily which alleviated the clinical symptoms of symptomatic LM. After 7.6 months of alectinib 600 mg, the patient again experienced CNS progression. With both CSF and plasma samples revealing no druggable mutations, the alectinib dose was re-escalated to 900 mg twice daily, resulting in clinical benefits lasting for two months. Her therapy was then switched to lorlatinib which controlled the disease for 8.7 months until her demise. The L..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13259

Authors: Zhaona Li, Pupu Li, Bing Yan, Qiongqiong Gao, Xiangli Jiang, Zhongli Zhan, Qingna Yan, Analyn Lizaso, Chun Huang

$Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial$

Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial

Introduction: We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase–positive NSCLC. Conclusions: Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.004

Authors: Rudolf M. Huber, MD, Karin H. Hansen, Luis Paz-Ares Rodríguez, Howard L. West, Karen L. Reckamp, Natasha B. Leighl, Marcello Tiseo, Egbert F. Smit, Dong-Wan Kim, Scott N. Gettinger, Maximilian J. Hochmair, Sang-We Kim, Corey J. Langer, Myung-Ju Ahn, Edward S. Kim, David Kerstein, Harry J.M. Groen, D. Ross Camidge

PLEKHM2-ALK: A novel fusion in small-cell lung cancer and durable response to ALK inhibitors

Objectives: In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement identifies a subgroup of patients who are sensitive to ALK tyrosine kinase inhibitors (TKIs). ALK fusion is extremely rare in small-cell lung cancer (SCLC). To the best of our knowledge, only two cases of SCLC harboring ALK fusion mutation has been reported previously, both of whom carrying EML4-ALK fusion. There are no standard treatment options for SCLC patients with ALK fusion mutations. Herein, we described a rare case of ALK-rearranged SCLC responding to ALK inhibitors. Conclusion: This case provides a meaningful reference for the treatment of SCLC patients with ALK fusion mutations. This case also provides valuable information on the response to ALK inhibitors of patients with PLEKHM2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS may be used as a routine test to explore more treatment opportunities for tumor SCLC patients. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.11.002

Authors: Tao Li, Fan Zhang, Zhaozhen Wu, Longgang Cui, Xiaochen Zhao, Jinliang Wang, Yi Hu

Case StudyKirk SmithNovember 16, 2019Small-cell lung cancer, Novel ALK fusion, Durable clinical benefit, NGS

Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity

Purpose: Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary ALK mutations. Here, we investigated utility of plasma genotyping for identifying ALK resistance mutations at relapse on next-generation ALK TKIs.
Experimental design: We analyzed 106 plasma specimens from 84 patients with advanced ALK-positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify ALK mutations.
Results: By genotyping plasma, we detected an ALK mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of ALK mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 ALK mutations (24% vs. 2%, P = 0.004). Among 29 patients relapsing on lorlatinib, plasm..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-19-1436

Authors: Dagogo-Jack I, Rooney M, Lin JJ, Nagy RJ, Yeap BY, Hubbeling H, Chin E, Ackil J, Farago AF, Hata AN, Lennerz JK, Gainor JF, Lanman RB, Shaw AT.

Real-World OutcomesKirk SmithNovember 15, 2019Next-Generation ALK Inhibitors, Plasma, Mutation Diversity

ROS-dependent DNA damage contributes to crizotinib-induced hepatotoxicity via the apoptotic pathway

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

Novel derivatives of anaplastic lymphoma kinase inhibitors: Synthesis, radiolabeling, and preliminary biological studies of fluoroethyl analogues of crizotinib, alectinib, and ceritinib

Novel derivatives of anaplastic lymphoma kinase inhibitors: Synthesis, radiolabeling, and preliminary biological studies of fluoroethyl analogues of crizotinib, alectinib, and ceritinib

Anaplastic lymphoma kinase (ALK), an oncogenic receptor tyrosine kinase, is a therapeutic target in various cancers, including non-small cell lung cancer. Although several ALK inhibitors, including crizotinib, ceritinib, and alectinib, are approved for cancer treatment, their long-term benefit is often limited by the cancer's acquisition of resistance owing to secondary point mutations in ALK. Importantly, some ALK inhibitors cannot cross the blood-brain barrier (BBB) and thus have little or no efficacy against brain metastases. The introduction of a lipophilic moiety, such as a fluoroethyl group may improve the drug's BBB penetration. Herein, we report the synthesis of fluoroethyl analogues of crizotinib 1, alectinib 4, and ceritinib 9, and their radiolabeling with 18F for pharmacokinetic studies. The fluoroethyl derivatives and their radioactive analogues were obtained in good yields with high purity and good molar activity. A cytotoxicity screen in ALK-expressing H2228 lung cancer cells showed that the analogues had up to nanomolar potency and the addition of the fluorinated moiety had minimal impact overall on the potency of the original drugs. Positron emission tomography in healthy mice showed that the analogues had enhanced BBB penetration, suggesting that they have therapeutic potential against central nervous system metastases. READ ARTICLE

European Journal of Medicinal Chemistry DOI: 10.1016/j.ejmech.2019.111571

Authors: Bhasker Radaram, Federica Pisaneschi, Yi Rao, Ping Yang, David Piwnica-Worms, Mian M.Alauddin

A novel ALK inhibitor ZYY inhibits Karpas299 cell growth in vitro and in a mouse xenograft model and induces protective autophagy

In recent years, anaplastic lymphoma kinase (ALK) rearrangement-positive anaplastic large cell lymphoma (ALCL) has rising morbidity and mortality. Unfortunately, no ALK inhibitor has been approved by the FDA for single treatment of ALK rearrangement-positive ALCL. In this study, we investigated the antitumor effect of ZYY, a novel ALK inhibitor, showing a strong growth inhibitory effect on Karpas299 cells in vitro and in vivo. Specifically, ZYY significantly reduced the mRNA and protein expression of ALK and its downstream signaling proteins in Karpas299 cells. Furthermore, ZYY induced G1 phase arrest and promoted apoptosis in Karpas299 cells. Furthermore, we demonstrated that ZYY-induced apoptosis was mainly related to the mitochondria-dependent endogenous pathway. In vitro studies further showed that ZYY induced autophagy in Karpas299 cells, along with increased levels of the autophagy-related proteins, including LC3II and Beclin-1. Moreover, knockdown Beclin-1 and application of autophagy inhibitor chloroquine potentiated ZYY-induced cytotoxicity and apoptosis in vitro, indicating that cytoprotective autophagy might be triggered by ZYY in Karpas299 cells. Taken together, the novel ALK inhibitor ZYY has tremendous potential for treating human ALCL, and a combination of autophagy and ALK inhibition could effectively elicit potent antitumor effects. READ ARTICLE

Toxicology and Applied Pharmacology DOI: 10.1016/j.taap.2019.114781

AUTHORS: Jiwei Shen, Junfang Wang, Jianan Du, Lijing Wang, Xuejiao Zhou, Xing Chang, Zengqiang Li, Xin Zhai, Daiying Zuo, Yingliang Wu

Kirk SmithNovember 15, 2019

Identification of EML4-ALK fusion in a sporadic case of cholangiocarcinoma

•Patients with cholangiocarcinoma have extremely poor prognoses.
•No molecular targeted agents have been still approved for cholangiocarcinoma treatment.
•RNA sequencing disclosed the fusion transcript EML4-ALK in a patient with cholangiocarcinoma.
•Cholangiocarcinoma share some driver targetable mutations with other solid tumors. READ ARTICLE

European Journal of Internal Medicine DOI:10.1016/j.ejim.2019.10.030

Authors: Domenico Trombetta, Paola Parente, Tiziana Pia Latiano, Federico Pio Fabrizio, Lucia Anna Muscarella

EditorialKirk SmithNovember 9, 2019Cholangiocarcinoma, EML4-ALK, Gene fusion

ALK Mutation Status Before and After Alectinib Treatment in Locally Advanced or Metastatic ALK-Positive NSCLC: Pooled Analysis of Two Prospective Trials

Introduction: The effectiveness of ALK receptor tyrosine kinase (ALK) inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with NSCLC and ALK point mutations using pooled data from two single-arm phase II studies. Conclusions: Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cell-free DNA in plasma samples may be an alternative noninvasive method for monitoring resistance mutations during therapy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.10.015

Authors: Johannes Noé, Alex Lovejoy, Sai-Hong Ignatius Ou, Stephanie J. Yaung, Walter Bordogna, Daniel M. Klass, Craig A. Cummings, Alice T. Shaw

Review PaperKirk SmithNovember 8, 2019Alectinib, ALK-positive, NSCLC, Mutation analysis, Resistance

Intracranial remission with brigatinib rechallenge as fifth-line ALK inhibition therapy in a lung cancer patient

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors have been developed for the treatment of EML4-ALK-rearranged non-small-cell lung cancer, with the newer generation agents brigatinib, alectinib and lorlatinib showing pronounced central nervous system activities. Intracranial efficacy is an important feature for these agents, as metastatic lesions frequently occur in the central nervous system in the ALK-positive setting. Here, we report on an updated case of a patient who received her diagnosis in 2005 and has had disease progression with new lesions on six occasions over the last 8 years. During the first two progressions, only local recurrence was observed. After that, the lungs stayed clear and the patient progressed exclusively in the brain and spinal cord. Initial treatments consisted of chemotherapy and radiotherapy. In 2012, ALK-directed targeted therapy became available, and crizotinib was administered. The treatment was switched to brigatinib 3 years later be..... READ ARTICLE

Anti-Cancer Drugs
DOI:10.1097/CAD.0000000000000800

Authors: Hochmair, Maximiliana; Weinlinger, Christopha; Prosch, Helmut

A Compound L1196M/G1202R ALK Mutation in a Patient with ALK-Positive Lung Cancer with Acquired Resistance to Brigatinib Also Confers Primary Resistance to Lorlatinib

We report here the case of a 70-year-old patient with ALK-positive NSCLC treated with crizotinib as part of the ALTA-1L trial.4 The patient relapsed after a partial response. After crizotinib failure, the patient was crossed over to brigatinib, which led to a second partial response lasting 9 months. After progression, the patient was shifted to lorlatinib but the clinical conditions worsened and the patient died. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.06.028

Authors: Geeta G. Sharma, Diego Cortinovis, Francesco Agustoni, Giulia Arosio, Matteo Villa, Nicoletta Cordani, Paolo Bidoli, William H. Bisson, Fabio Pagni, Rocco Piazza, Carlo Gambacorti-Passerini, Luca Mologni

Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer During Crizotinib Treatment

"Background: Central nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment. Conclusion: Although CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.06.013

Authors: Yiming Zhao, Bo Zhang, Shuyuan Wang, Rong Qiao, Jianlin Xu, Lele Zhang, Yanwei Zhang, Baohui Han"

Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing in ALK-Rearranged Non–Small-Cell Lung Cancer

Purpose: Patients with anaplastic lymphoma kinase (ALK)–rearranged non–small-cell lung cancer (NSCLC) inevitably develop resistance to ALK inhibitors. New diagnostic strategies are needed to assess resistance mechanisms and provide patients with the most effective therapy. We asked whether single circulating tumor cell (CTC) sequencing can inform on resistance mutations to ALK inhibitors and underlying tumor heterogeneity in ALK-rearranged NSCLC. Conclusions: Our results highlight the genetic heterogeneity and clinical utility of CTCs to identify therapeutic resistance mutations in ALK-rearranged patients. Single CTC sequencing may be a unique tool to assess heterogeneous resistance mechanisms and help clinicians for treatment personalization and resistance options to ALK-targeted therapies. READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-19-1176

Authors: Emma Pailler, Vincent Faugeroux, Marianne Oulhen, Laura Mezquita, Mélanie Laporte, Aurélie Honoré, Yann Lecluse, Pauline Queffelec, Maud NgoCamus, Claudio Nicotra, Jordi Remon, Ludovic Lacroix, David Planchard, Luc Friboulet, Benjamin Besse and Françoise Farace

The clinical responses of TNIP2-ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma

Objectives: Anaplastic lymphoma kinase (ALK) has been proven to be another driver oncogene that accounts for 3%–7% of non-small-cell lung cancer, and it is more common in young patients and nonsmokers. ALK rearrangements have been previously identified in about 5.1% of lung adenocarcinoma, including EML4-ALK fusion variants, KIF5B-ALK and TFG-ALK. However, a TNIP2-ALK fusion has not been reported in lung adenocarcinoma. Herein, we described a rare case of ALK-rearranged lung adenocarcinoma responding to crizotinib. Conclusion: This case provides valuable information on the response to crizotinib of patients with TNIP2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS is a new method that can offer effective detection of gene fusion and gene mutations. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.08.032

Authors: Tingting Feng, Zhongzhong Chen, Jianjun Gu, Yuxiu Wang, Jun Zhang, Lingfeng Min

Case StudyKirk SmithNovember 1, 2019NSCLC, ALK fusion, TNIP2-ALK, crizotinib, NGS

20P - Detecting therapy-guiding aberrations in platelets and plasma at the transcriptome level in non-small-cell lung cancer

Background: The detection of driver aberrations such as EGFR and ALK, in tumour tissue or plasma has become important for treating lung cancer patients. The aim of this study is to explore the feasibility of detecting therapy-guiding aberrations in RNA, isolated from platelet and plasma samples. Conclusions: In conclusion, the fraction of tumour-derived RNA transcripts in plasma and platelets appears to be very low or undetectable. Our data indicates that plasma and platelet-derived RNA is not a good source to identify tumour cell specific genomic aberrations. READ ARTICLE

Annals of Oncology DOI:10.1093/annonc/mdz413.025

Authors: P. Meng, A. A. Rybczynska, J. Wei, M. M. Terpstra, W. Timens, E. Schuuring, T. J. N. Hiltermann, H. J. M. Groen, K. Kok, A. J. Van der Wekken, A. Van den Berg