Combining Radiation Therapy with ALK Inhibitors in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer (NSCLC): A Clinical and Preclinical Overview
Combining Radiation Therapy with ALK Inhibitors in Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer (NSCLC): A Clinical and Preclinical Overview

Over the past years, the identification of genetic alterations in oncogenic drivers in non-small cell lung cancer (NSCLC) has significantly and favorably transformed the outcome of patients who can benefit from targeted therapies such as tyrosine kinase inhibitors. Among these genetic alterations, anaplastic lymphoma kinase (ALK) rearrangements were discovered in 2007 and are present in 3–5% of patients with NSCLC. In addition, radiotherapy remains one of the cornerstones of NSCLC treatment. Moreover, improvements in the field of radiotherapy with the use of hypofractionated or ablative stereotactic radiotherapy have led to a better outcome for localized or oligometastatic NSCLC. To date, the effects of the combination of ALK inhibitors and radiotherapy are unclear in terms of safety and efficacy but could potently improve treatment. In this manuscript, we provide a clinical and preclinical overview of combining radiation therapy with ALK inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13102394

Authors: Delphine Antoni, Hélène Burckel, and Georges Noe

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Review PaperKirk SmithNSCLC, ALK, TKI, radiotherapy
Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib
Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib

Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study. READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2021.113335

Authors: Chaowei Ren, Ning Sun, Ying Kong, Xiaojuan Qu, Haixia Liu, Hui Zhong, Xiaoling Song, Xiaobao Yang, Biao Jiang

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Pre-ClinicalKirk SmithAnaplastic lymphoma kinase (ALK), Proteolysis targeting chimeras, Alectinib, CRBN, Anaplastic large-cell lymphomas (ALCL), Oral bioavailability
Impact of ALK Inhibitors in Patients With ALK-Rearranged Non lung Solid Tumors
Impact of ALK Inhibitors in Patients With ALK-Rearranged Non lung Solid Tumors

We identified seven patients (inflammatory myofibroblastic tumors, n = 3; ALK-positive histiocytosis, n = 1; histiocytic sarcoma, n = 1; osteosarcoma, n = 1; and parotid adenocarcinoma, n = 1), with a median age of 17 years. Two rare ALK fusions, namely, CTNNA1-ALK and ITSN2-ALK, were identified. As initial ALK-TKI therapy, five patients received alectinib and two received crizotinib. The objective response rate for the initial ALK-TKI therapy was 85.7% (95% CI, 44 to 97), including two patients who received alectinib and achieved complete response. The median progression-free survival was 8.1 months (range, 1.7 to not estimable). There were no treatment interruptions or dose reductions because of adverse events caused by alectinib. This study highlights the potential benefit of ALK-TKIs, especially alectinib, in patients with ALK-rearranged nonlung solid tumors.

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Journal of Clinical Oncology: Precision Oncology DOI:10.1200/PO.20.00383

Authors: Yuki
Takeyasu; Hitomi S. Okuma; Yuki Kojima; Tadaaki Nishikawa; Maki Tanioka; Kazuki Sudo; Tatsunori Shimoi; Emi Noguchi; Ayumu Arakawa; Taisuke Mori; Kuniko Sunami, Takashi Kubo; Takashi Kohno; Yoshida Akihiko; Noboru Yamamoto; and Kan Yonemori

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Real-World OutcomesKirk SmithCTNNA1-ALK, ITSN2-ALK, alternative ALKfusion, TKI
Next-Generation Sequencing Identified a Novel Crizotinib-Sensitive PLB1-ALK Rearrangement in Lung Large-Cell Neuroendocrine Carcinoma
Next-Generation Sequencing Identified a Novel Crizotinib-Sensitive PLB1-ALK Rearrangement in Lung Large-Cell Neuroendocrine Carcinoma

... We report a case of LCNEC harboring a novel PLB1-ALK rearrangement sensitive to crizotinib by next-generation sequencing (NGS). The patient’s disease responded to crizotinib for > 5 months... NGS demonstrates an additional advantage of being able to concurrently detect different mutations in genetic testing and plays an important role in detecting ALK-rearranged non–small-cell lung cancer. Screening for ALK rearrangement by NGS in patients with LCNEC may help in selecting potential candidates for targeted therapy. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2020.05.026

Authors: Shuai Wang, Xuan Wu, Jiuzhou Zhao, Haiyang Chen, Zhe Zhang, Mingyue Wang, Cong Xu, Yongsen Wang, Lili Wang, Zhen He, Qiming Wang

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Case StudyKirk SmithCrizotinib, Generation sequencing, Lung large-cell neuroendocrine carcinoma, PLB1-ALK, Sensitivity
Thromboembolism in ALK+ and ROS1+ NSCLC patients: A systematic review and meta-analysis
Thromboembolism in ALK+ and ROS1+ NSCLC patients: A systematic review and meta-analysis

In this study, we confirmed that there is an increased incidence of TTE in both ALK+ and ROS1+ NSCLC patients as compared to controls (non-ALK+ and non-ROS1+) by meta-analysis. Additionally, time-to-event analysis in this study served as a second meta-analytic method to provide dual sensitivity and confirmed similar elevated TTE risks among ALK+ and ROS1+ NSCLC patients. VTE (primarily PE and DVT) is the primary TE event of interest investigated in the studies included in this systematic review. In general, this meta-analysis indicated there is about a 2.5-fold and slightly higher than 3-fold increase in VTE among ALK+ and ROS1+ patients, respectively when compared to non-ALK+ and non-ROS1+ NSCLC patients. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.05.019

Authors: Viola W. Zhu, Joseph J. Zhao, Yanfei Gao, Nicholas L. Syn, Shannon S. Zhang, Sai-Hong Ignatius Ou, Kenneth A. Bauer, Misako Nagasaka

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Review PaperKirk SmithALK+ NSCLC, Meta-analysis, Systematic review, Cumulative incidence, Thromboembolism, Pulmonary embolism, Deep vein thrombosis
Significance of TP53 Mutation in Cellular Process and Disease Progression in Lung Adenocarcinoma
Significance of TP53 Mutation in Cellular Process and Disease Progression in Lung Adenocarcinoma

Analysis of the TCGA data showed TP53 mutations in 22% of LUAD patients. Clinicopathological analyses demonstrated that TP53 mutation was correlated with the disease progression but not prognosis. We identified 1935 differentially expressed genes (DEGs). Functional enrichment analysis showed that the DEGs were mainly concentrated in metabolism, cell differentiation, and cancer-related pathways. The top hub genes were identified and disease analysis revealed the most critical genes related to disease progression and prognosis. The expression levels of several of these genes were then tested in tumor tissues. Our results showed that TP53 mutation plays a critical role in cellular process and the clinicopathological findings in LUAD. We also identified potential key genes, which could provide novel evidence for individualized treatment. READ ARTICLE

Genetic Testing and Molecular Biomarkers DOI:10.1089/gtmb.2020.0304

Authors: Yongbo Hou, Sheng Tan, Guoxiang Wang

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Real-World OutcomesKirk SmithTP53, adenocarcinoma, lung
Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing
Decoding the Evolutionary Response to Ensartinib in Patients With ALK-Positive NSCLC by Dynamic Circulating Tumor DNA Sequencing

By implementing dynamic circulating tumor DNA (ctDNA) analysis, we explored the impact of TP53 mutations on tumor evolution and resistance mechanisms to ensartinib in patients with ALK-positive NSCLC. Our study highlighted the advantage of ctDNA analysis for monitoring tumor evolution. TP53 mutations promoted genetic evolution and accelerated occurrence of resistance. We also unveiled ALK-dependent resistance mechanisms, mainly by G1269A, G1202R, and E1210K mutations, and ALK-independent resistance mechanisms to ensartinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.01.1615

Authors: Yunpeng Yang, Jie Huang, Tao Wang, Jianya Zhou, Jing Zheng, Jifeng Feng, Wu Zhuang, Jianhua Chen, Jun Zhao, Wei Zhong, Yanqiu Zhao, Yiping Zhang, Yong Song, Yi Hu, Zhuang Yu, Youling Gong, Yuan Chen, Feng Ye, Shucai Zhang, Lejie Cao, Yun Fan, Gang Wu, Yubiao Guo, Chengzhi Zhou, Kewei Ma, Jian Fang, Weineng Feng, Yunpeng Liu, Zhendong Zheng, Gaofeng Li, Huijie Wang, Shundong Cang, Ning Wu, Wei Song, Xiaoqing Liu, Shijun Zhao, Lieming Ding, Li Mao, Giovanni Selvaggi, Larry Zhu, Shanshan Xiao, Xiaobin Yuan, Zhilin Shen, Li Zhang

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Pre-ClinicalKirk SmithALK+, NSCLC, ctDNA, TP53, Resistance mechanism
Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion–Positive Lung Cancer
Spectrum of Mechanisms of Resistance to Crizotinib and Lorlatinib in ROS1 Fusion–Positive Lung Cancer

We performed molecular profiling of the largest series to date of crizotinib- and lorlatinib-resistant biopsies, finding that ROS1 kinase domain mutations mediate resistance in one third to one half of cases, respectively. Recurrent resistance mutations in ROS1 included G2032R and less well-characterized L2086F. In Ba/F3 models, type I inhibitors, including crizotinib, entrectinib, and lorlatinib, were unable to overcome ROS1L2086F, whereas type II inhibitor, cabozantinib, maintained potency. We additionally detected MET and RAS-MAPK alterations in resistant specimens. Our study highlights the importance of developing novel ROS1 inhibitors with potency against recurrent ROS1 resistance mutations and may inform sequential treatment strategies in ROS1+ lung cancer. ROS1 mutations mediate resistance to crizotinib and lorlatinib in more than one third of cases, underscoring the importance of developing next-generation ROS1 inhibitors with potency against these mutations, including G2032R and L2086F. Continued efforts are needed to elucidate ROS1-independent resistance mechanisms. READ ARTICLE

Cancer Mechanisms and Therapy DOI:10.1158/1078-0432.CCR-21-0032

Authors: Jessica J. Lin, Noura J. Choudhury, Satoshi Yoda, Viola W. Zhu, Ted W. Johnson, Ramin Sakhtemani, Ibiayi Dagogo-Jack, Subba R. Digumarthy, Charlotte Lee, Andrew Do, Jennifer Peterson, Kylie Prutisto-Chang, Wafa Malik, Harper G. Hubbeling, Adam Langenbucher, Adam J. Schoenfeld, Christina J. Falcon, Jennifer S. Temel, Lecia V. Sequist, Beow Y. Yeap, Jochen K. Lennerz, Alice T. Shaw, Michael S. Lawrence, Sai-Hong Ignatius Ou, Aaron N. Hata, Alexander Drilon, Justin F. Gainor

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Real-World OutcomesKirk Smithcrizotinib, lorlatinib, ROS1
Final OS analysis from the phase III j-alex study of alectinib (ALC) versus crizotinib (CRZ) in Japanese ALK-inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC)
Final OS analysis from the phase III j-alex study of alectinib (ALC) versus crizotinib (CRZ) in Japanese ALK-inhibitor naïve ALK-positive non-small cell lung cancer (ALK+ NSCLC)

After a median follow-up of 68.6 months in the ALC arm and 68.0 months in the CRZ arm, death events occurred in 40.8% and 39.4% in the ALC and the CRZ arms, respectively. Five-year survival rates for patients in the ALC and CRZ arm were 60.85% and 64.11%, respectively. The final OS HR was 1.03 (95%CI 0.67-1.58), however, median OS was not reached in either arm. Of note, patients in the CRZ arm tended to have their treatment switched earlier than those in the ALC arm (median time to treatment-switch: 12.3 months vs. NE). Most of the patients (78.8%) in the CRZ arm received ALC as a 1st subsequent therapy, whereas only 10.7% of patients in the ALC arm received CRZ. In this final J-ALEX OS analysis, prolongation of OS in the ALC arm was not observed compared to the CRZ arm. However, OS result may be substantially confounded since 78.8% of the patients in the CRZ arm received ALC as initial, subsequent therapy. Clinical trial information: 132316...... READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9022

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

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Clinical TrialsKirk SmithALEX study, alectinib, crizotinib
Early circulating tumor (ct) DNA dynamics and efficacy of lorlatinib: Analysis from the CROWN study.
Early circulating tumor (ct) DNA dynamics and efficacy of lorlatinib: Analysis from the CROWN study.

Early ctDNA dynamics may predict lorlatinib efficacy in pts with previously untreated ALK-positive NSCLC. The magnitude of reduction in ctDNA at 4 weeks may be associated with better responses and potentially longer PFS. These findings further support the utility of dynamic ctDNA monitoring in ALK-positive NSCLC. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_SUPPL.9011

Authors: Ross A. Soo, Jean-Francois Martini, Anthonie J. van der Wekken, Shunsuke Teraoka, Alice T. Shaw, Deborah Shepard, Anna Maria Calella, Anna Polli, Francesca Toffalorio, Pascale Tomasini, Chao-Hua Chiu, Dariusz Kowalski, Hye Ryun Kim, Benjamin J. Solomon

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Review PaperKirk Smithlorlatinib, CROWN study, ctDNA
Earlier extracranial progression and shorter survival in ALK-rearranged lung cancer with positive liquid rebiopsies
Earlier extracranial progression and shorter survival in ALK-rearranged lung cancer with positive liquid rebiopsies

Background: Liquid rebiopsies can detect resistance mutations to guide therapy of anaplastic lymphoma kinase-rearranged (ALK+) non-small-cell lung cancer (NSCLC) failing tyrosine kinase inhibitors (TKI). Here, we analyze how their results relate to the anatomical pattern of disease progression and patient outcome. Conclusions: Positive blood-based liquid rebiopsies in ALK+ NSCLC characterize biologically more aggressive disease and are common with extracranial, but rare with CNS-only progression or benign radiologic changes. These results reconcile the increased detection of ALK resistance mutations with other features of the high-risk EML4-ALK V3-associated phenotype. Conversely, most oligoprogressive patients with negative liquid biopsies have a more indolent course without need for early change of systemic treatment. READ ARTICLE

Transl Lung Cancer Research DOI:10.21037/tlcr-21-32

Authors: Petros Christopoulos, Steffen Dietz, Arlou K. Angeles, Stephan Rheinheimer, Daniel Kazdal, Anna-Lena Volckmar, Florian Janke, Volker Endris, Michael Meister, Mark Kriegsmann, Thomasz Zemojtel, Martin Reck, Albrecht Stenzinger, Michael Thomas, Holger Sültmann

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Real-World OutcomesKirk SmithAnaplastic lymphoma kinase-rearranged (ALK+), non-small-cell lung cancer (NSCLC), liquid biopsy, extracranial progression, tyrosine kinase inhibitor (TKI), treatment failure, overall survival
Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases
Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases

Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal sero..... READ ARTICLE

The American Journal of Surgical Pathology DOI:10.1097/PAS.0000000000001656

Authors: Argani, Pedram, Lian, Derrick W.Q., Agaimy, Abbas, Metzler, Markus, Wobker, Sara E. Matoso, Andres, Epstein, Jonathan I., Sung, Yun-Shao; Zhang, Lei and Antonescu, Cristina R

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Case StudyKirk Smithmesothelioma, ALK, translocation, pediatric
Alectinib for Miliary Lung Metastasis in ALK-Positive Lung Adenocarcinoma
Alectinib for Miliary Lung Metastasis in ALK-Positive Lung Adenocarcinoma

We have reported a case of ALK-rearranged NSCLC with a miliary pulmonary metastasis pattern that was sensitive to alectinib and in which the serum amylase level decreased in response to treatment with alectinib. Young patients with miliary pulmonary metastasis should be checked for all driver mutations. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S300229

Authors: Satoh H, Okuma Y, Kashima J, Konnno-Yamamoto A, Yatabe Y, Ohe Y

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Case StudyKirk Smithalectinib, ALK rearrangement, NSCLC, miliary pulmonary metastasis
ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells
ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells

In the present study, we asked whether ALK inhibition affects autophagy, and whether this may influence treatment response. Whereas the impact of targeted therapies on autophagic activity previously have been assessed by surrogate marker proteins such as LC3B, we here thoroughly examined effects on functional autophagic activity, i.e. on the sequestration and degradation of autophagic cargo, in addition to autophagic markers. Interestingly, the ALK inhibitor Ceritinib decreased mTOR activity and increased GFP-WIPI1 dot formation in H3122 and H2228 EML4-ALK+ lung cancer cells, suggesting autophagy activation. Moreover, an mCherry-EGFP-LC3B based assay indicated elevated LC3B carrier flux upon ALK inhibition. In accordance, autophagic cargo sequestration and long-lived protein degradation significantly increased upon ALK inhibition. Intriguingly, autophagic cargo flux was dependent on VPS34 and ULK1, but not LC3B. Co-treating H3122 cells with Ceritinib and a VPS34 inhibitor or Bafilomyci..... READ ARTICLE

Scientific Reports DOI:10.1038/s41598-021-87966-6

Authors: Anna M. Schläfli, Igor Tokarchuk, Sarah Parejo, Susanne Jutzi, Sabina Berezowska, Nikolai Engedal, Mario P. Tschan

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Pre-ClinicalKirk Smithceritinib, mTOR, EML4-ALK+, VPS34 inhibitor, Bafilomycin A1, autophagy
Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation
Emerging Lab-on-a-Chip Approaches for Liquid Biopsy in Lung Cancer: Status in CTCs and ctDNA Research and Clinical Validation

Lung cancer (LCa) remains the leading cause of cancer-related mortality worldwide,
with late diagnosis and limited therapeutic approaches still constraining patient’s outcome. In recent years,
liquid biopsies have significantly improved the disease characterization and brought new insights into
LCa diagnosis and management. The integration of microfluidic devices in liquid biopsies have shown
promising results regarding circulating biomarkers isolation and analysis and these tools are expected to
establish automatized and standardized results for liquid biopsies in the near future. Herein, we review the
status of lab-on-a-chip approaches for liquid biopsies in LCa and highlight their current applications for
circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) research and clinical validation studies. READ ARTICLE

Cancers DOI:10.3390/cancers13092101

Authors: Carvalho, Â., Ferreira, G., Seixas, D., Guimarães-Teixeira, C., Henrique, R., Monteiro, F.J., Jerónimo, C.

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Review PaperKirk Smithinflammatory myofibroblastic tumors, IMT, rare ALK fusions
EML4-ALK positive lung adenocarcinoma with skeletal muscle metastasis in the right calf which was treatable with lorlatinib after resistance to treatment with alectinib
EML4-ALK positive lung adenocarcinoma with skeletal muscle metastasis in the right calf which was treatable with lorlatinib after resistance to treatment with alectinib

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib. READ ARTICLE

British Medical Journal DOI:10.1136/bcr-2020-240295

Authors: Hironari Matsuda, Munechika Hara, Shin-Ichiro Iwakami, Kazuhisa Takahashi

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Case StudyKirk Smithpost-alectinib, lorlatinib, EML4-ALK
Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer
Safety and feasibility of CRISPR-edited T cells in patients with refractory non-small-cell lung cancer

Clustered regularly interspaced short palindromic repeats (CRISPR)–Cas9 editing of immune checkpoint genes could improve the efficacy of T cell therapy, but the first necessary undertaking is to understand the safety and feasibility. Here, we report results from a first-in-human phase I clinical trial of CRISPR–Cas9 PD-1-edited T cells in patients with advanced non-small-cell lung cancer (ClinicalTrials.gov NCT02793856). Primary endpoints were safety and feasibility, and the secondary endpoint was efficacy. The exploratory objectives included tracking of edited T cells. All prespecified endpoints were met. PD-1-edited T cells were manufactured ex vivo by cotransfection using electroporation of Cas9 and single guide RNA plasmids. A total of 22 patients were enrolled; 17 had sufficient edited T cells for infusion, and 12 were able to receive treatment. All treatment-related adverse events were grade 1/2. Edited T cells were detectable in peripheral blood after infusion. The median progre..... READ ARTICLE

Nature Medicine DOI:10.1038/s41591-020-0973-6

Authors: You Lu, Jianxin Xue, Tao Deng, Xiaojuan Zhou, Kun Yu, Lei Deng, Meijuan Huang, Xin Yi, Maozhi Liang, Yu Wang, Haige Shen, Ruizhan Tong, Wenbo Wang, Li Li, Jin Song, Jing Li, Xiaoxing Su, Zhenyu Ding, Youling Gong, Jiang Zhu, Yongsheng Wang, Bingwen Zou, Yan Zhang, Yanying Li, Lin Zhou, Yongmei Liu, Min Yu, Yuqi Wang, Xuanwei Zhang, Limei Yin, Xuefeng Xia, Yong Zeng, Qiao Zhou, Binwu Ying, Chong Chen, Yuquan Wei, Weimin Li & Tony Mok

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Clinical TrialsKirk Smith
Early Alectinib Resistance From MET Amplification in ALK-Rearranged NSCLC: Response to Crizotinib with Re-Response to Alectinib and Crizotinib
Early Alectinib Resistance From MET Amplification in ALK-Rearranged NSCLC: Response to Crizotinib with Re-Response to Alectinib and Crizotinib

Crizotinib is active as second-line therapy against MET-mediated resistance to alectinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer and can be used in combination.

Repeat molecular analyses including assessment of MET amplification can help guide therapy in ALK-positive non–small-cell lung cancer. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2021.04.008

Authors: Jingran Ji, Anupam Mitra, D. Ross Camidge, Jonathan W. Riess

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Case StudyKirk SmithALK inhibitor resistance, ALK mutation, Non–small-cell lung cancer (NSCLC), MET inhibition, MET amplification, rechallenge