Brigatinib versus Crizotinib in Anaplastic Lymphoma Kinase (ALK) Inhibitor–Naive Advanced ALK-Positive Non–Small Cell Lung Cancer: Final Results of the Phase 3 ALTA-1L Trial

In the phase 3 ALTA-1L study of brigatinib in anaplastic lymphoma kinase (ALK) inhibitor–naive advanced ALK+ NSCLC, brigatinib demonstrated superior progression-free survival (PFS) versus crizotinib in 2 planned interim analyses. We report final efficacy, safety, and exploratory results. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.07.035

Authors: D. Ross Camidge, Hye Ryun Kim, Myung-Ju Ahn, James CH. Yang, Ji-Youn Han, Maximilian J. Hochmair, Ki Hyeong Lee, Angelo Delmonte, Maria Rosario Garcia Campelo, Dong-Wan Kim, Frank Griesinger, Enriqueta Felip, Raffaele Califano, Alexander I. Spira, Scott N. Gettinger, Marcello Tiseo, Huamao M. Lin, Yuyin Liu, Florin Vranceanu, Huifeng Niu, Pingkuan Zhang, Sanjay Popat

Addition of Metformin to Concurrent Chemoradiation in Patients With Locally Advanced Non–Small Cell Lung Cancer

In this randomized clinical trial, the addition of metformin to concurrent chemoradiation was well tolerated but did not improve survival among patients with unresectable stage III NSCLC. ClinicalTrials.gov Identifier: NCT02186847 READ ARTICLE

JAMA: Journal of American Medical Association DOI:10.1001/jamaoncol.2021.2318

Authors: Heath Skinner, MD,PhD; Chen Hu, PhD; Theodoros Tsakiridis, MD, PhD; Rafael Santana-Davila, MD; Bo Lu, MD; Jeremy J. Erasmus, MD; Anthony J. Doemer, MS; Gregory M. M. Videtic, MD; James Coster, MD; Alex Xuezhong Yang, MD; Richard Y. Lee, MD, PhD; Maria Werner-Wasik, MD; Philip E. Schaner, MD, PhD; Steven E. McCormack, MD; Benjamin T. Esparaz, MD; Ronald C. McGarry, MD,PhD; Jose Bazan, MD; Timothy Struve, MD; Rebecca Paulus, BS and Jeffrey D. Bradley, MD

Clinical Trials, group4Kirk SmithJuly 29, 2021NSCLC, metformin, chemoradiation

Mutations

A video on "what is a mutation" by Vanderbilt University Medical Center. Basic background with clear graphic depictions. SEE VIDEO

Vanderbilt University Medical Center

Video, group4Kirk SmithJuly 24, 2021mutations

Comparative Efficacy and Safety of Lorlatinib and Alectinib for ALK-Rearrangement Positive Advanced Non-Small Cell Lung Cancer in Asian and Non-Asian Patients

The treatment of anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p) advanced non-small cell lung cancer (NSCLC) remains a challenge. We compared the safety and efficacy of lorlatinib and alectinib in patients with ALK-p ALK-inhibitor‒naïve advanced NSCLC (in overall participants and in the Asian and non-Asian subgroups). The results showed that in the overall participant group, the efficacy of lorlatinib and alectinib was not significantly different in terms of progression-free survival (PFS) and overall survival (OS). Although in the Asian subgroup, PFS was not significantly different upon treatment with lorlatinib or alectinib, in the non-Asian subgroup, PFS was significantly better in response to lorlatinib than with alectinib. Grade 3 or higher adverse events in the overall participant group were significantly more frequent with lorlatinib than with alectinib. These results will provide valuable information that would enable the improvement of treatment strategies for ALK-p ALK-inhibitor‒naïve advanced NSCLC. READ ARTICLE

Cancers DOI:10.3390/cancers13153704

Authors: Koichi Ando, Ryo Manabe,Yasunari Kishino, Sojiro Kusumoto,Toshimitsu Yamaoka, Akihiko Tanaka, Tohru Ohmori and Hironori Sagara

Real-World Outcomes, group4Kirk SmithJuly 23, 2021alectinib, ALK rearrangement, lorlatinib

Development and validation of UPLC–MS/MS method for the simultaneous quantification of anaplastic lymphoma kinase inhibitors, alectinib, ceritinib, and crizotinib in Wistar rat plasma...

Bromelain, the aqueous extract of pineapple, has been used as a food supplement with reported nutritional and therapeutic benefits. Bromelain has anti-cancer, anti-inflammatory, antithrombotic, and fibrinolytic effects. Anaplastic lymphoma kinase (ALK) inhibitors, including alectinib (ALC), ceritinib (CER), and crizotinib (CRZ), have been efficiently used in the management of non-small cell lung cancer (NSCLC). The solubility of ALC, CER, and CRZ is much higher at low acidic pH (pH 1) and it decreases as the pH increases affecting their absorption with a subsequent decrease in their bioavailability. It was thought that the intake of bromelain could result in a decrease in the bioavailability of ALC, CER, and CRZ due to bromelain-induced alkalizing effect following digestion. On the contrary, bromelain could possibly increase plasma exposure of the cited drugs due to its known muco-permeation enhancing effect. The therapeutic-anticancer effect of bromelain can be possibly increased/enha..... READ ARTICLE

Journal of Pharmaceutical and Biomedical Analysis DOI:10.1016/j.jpba.2021.114276

Authors: Hadir M. Maher, Aliyah Almomen, Nourah Z. Alzoman, Shereen M. Shehata, Ashwaq A. Alanazi

Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile

Proteolysis-targeting chimera (PROTAC) is an attractive technology in drug discovery. Canonically, targets act as a basic starting point in the most previous PROTAC design. Here, we designed degraders considering from the view of clinical benefits. With this novel design, Brigatinib was turned into a degrader SIAIS164018 and endowed with unique features. First, SIAIS164018 could degrade not only ALK fusion proteins in activating or G1202R-mutated form but also mutant EGFR with L858R + T790M, which are two most important targets in non-small-cell lung cancer. Second, SIAIS164018 strongly inhibited cell migration and invasion of Calu-1 and MDA-MB-231. Third and surprisingly, SIAIS164018 degrades several important oncoproteins involved in metastasis such as FAK, PYK2, and PTK6. Interestingly, SIAIS164018 reshuffled the kinome ranking profile when compared to Brigatinib. Finally, SIAIS164018 is orally bioavailable and well tolerated in vivo. SIAIS164018 is an enlightening degrader for us to excavate the charm of protein degradation. READ ARTICLE

Journal of Medicinal Chemistry DOI:10.1021/acs.jmedchem.1c00373

Authors: Chaowei Ren, Ning Sun, Haixia Liu, Ying Kong, Renhong Sun, Xing Qiu, Jinju Chen, Yan Li, Jianshui Zhang, Yuedong Zhou, Hui Zhong, Qianqian Yin

Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

Gatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed hi..... READ ARTICLE

Precision Oncology DOI:10.1038/s41698-021-00203-1

Authors: Marianne Oulhen, Patrycja Pawlikowska, Tala Tayoun, Marianna Garonzi, Genny Buson, Claudio Forcato, Nicolò Manaresi, Agathe Aberlenc, Laura Mezquita, Yann Lecluse, Pernelle Lavaud, Charles Naltet, David Planchard, Benjamin Besse & Françoise Farace

Pre-Clinical, group4Kirk SmithJuly 16, 2021ALK, heterogeneity, single circulating tumor cells, RTK/RAS, EMT

Real-world insights into patients with advanced NSCLC and MET alterations

Heterogeneous treatments reflect the changing landscape and availability of new treatments, as well as the high unmet medical need in older, METex14 patients who had more advanced disease at diagnosis. MET-targeted therapies could be beneficial in patients with these rare MET alterations. RE AD ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2021.06.015

Authors: Marisa Bittonia James Chih-Hsin Yang, Jin-Yuan Shih, Nir Peled, Egbert F. Smite, D. Ross Camidge, Rajeswara Rao Arasada, Dina Okseng, Emmanuelle Boutmy, Christopher Stroh, Andreas Johne, David P. Carbonea and Paul K. Paik

Structural and functional analysis of lorlatinib analogs reveals roadmap for targeting diverse compound resistance mutations in ALK-positive lung cancer

The treatment approach to advanced, ALK-positive non-small cell lung cancer (NSCLC) utilizing sequential ALK tyrosine kinase inhibitors (TKIs) represents a paradigm of precision oncology. Lorlatinib is currently the most advanced, potent and selective ALK tyrosine kinase inhibitor (TKI) in the clinic. However, tumors invariably acquire resistance to lorlatinib, and after sequential ALK TKIs culminating with lorlatinib, diverse refractory compound ALK mutations can emerge. Here, we determine the spectrum of lorlatinib-resistant compound ALK mutations identified in patients after treatment with lorlatinib, the majority of which involve ALK G1202R or I1171N/S/T. By assessing a panel of lorlatinib analogs against compound ALK mutant in vitro and in vivo models, we identify structurally diverse lorlatinib analogs that harbor differential selective profiles against G1202R- versus I1171N/S/T-based compound ALK mutations. Structural analysis revealed that increased potency against compound mut..... READ ARTICLE

BioRxiv DOI:10.1101/2021.07.16.452681

Authors: Aya Shiba-Ishii, Ted W Johnson, Ibiayi Dagogo-Jack, Mari Mino-Kenudson, Theodore R Johnson, Ping Wei, Scott L Weinrich, Michele A McTigue, Makeba A Walcott, Linh Nguyen-Phuong, Kristin Dionne, Adam Acker, Lesli Kiedrowski, Andrew Do, Jennifer L Peterson, Jaimie L Barth, Beow Y Yeap, Justin F Gainor, Jessica J Lin, Satoshi Yoda, Aaron N Hata

Pharmacophore screening, molecular docking, ADMET prediction and MD simulations for identification of ALK and MEK potential dual inhibitors

Anaplastic lymphoma kinase (ALK) fusion gene is a common driver gene in non-small cell lung cancer (NSCLC). The activation of mitogen-activated protein kinase (MAPK) and other related signaling pathways cause the proliferation of cancer cells. Mitogen-activated protein kinase kinase (MAPKK, also known as MEK) is a member of the ALK-MAPK signaling cascade. Recent studies have found that the drug resistance in ALK-positive NSCLC is highly dependent on the activation of the MAPK pathway, and the combined inhibition of ALK and MEK can delay or even eliminate the resistance. In this work, dual ALK/MEK inhibitors were designed through computer-aided drug design (CADD). Ten million molecules from ZINC were screened through pharmacophore models, ADMET prediction and molecular docking. Finally, 35 hit compounds were obtained. Among them, compound 1 has the highest dual inhibitory potential. The results of molecular docking, ADMET prediction and molecular dynamics (MD) simulations show that comp..... READ ARTICLE

Journal of Molecular Structure DOI:10.1016/j.molstruc.2021.131066

Authors: Haoran Zhang, Lichuan Zhang, Chenglong Gao, Rilei Yu, Congmin Kang

Driver and novel genes correlated with metastasis of non-small cell lung cancer: A comprehensive analysis

Although mutations of genes are crucial events in tumorigenesis and development, the association between gene mutations and lung cancer metastasis is still largely unknown. The goal of this study is to identify driver and novel genes associated with non-small cell lung cancer (NSCLC) metastasis. Candidate genes were identified using a novel comprehensive analysis, which was based on bioinformatics technology and meta-analysis. Firstly, EGFR, KRAS, ALK, TP53, BRAF and PIK3CA were identified as candidate driver genes. Further meta-analysis identified that EGFR (Pooled OR 1.33, 95% CI 1.19, 1.50; P < .001) and ALK (Pooled OR 1.52, 95% CI 1.22, 1.89; P < .001) mutations were associated with distant metastasis of NSCLC. Besides, ALK (Pooled OR 2.40, 95% CI 1.71, 3.38; P < .001) mutation was associated with lymph node metastasis of NSCLC. In addition, thirteen novel gene mutations were identified to be correlated with NSCLC metastasis, including SMARCA1, GGCX, KIF24, LRRK1, LILRA4, OR2T10, E..... READ ARTICLE

Pathology - Research and Practice DOI:10.1016/j.prp.2021.153551

Authors: Yongfeng Wu, Heng Ni, Dexin Yang, Yuequn Niu, Kelie Chen, Jinming Xu, Fang Wang, Song Tang, Yu Shi, Honghe Zhang, Jian Hu, Dajing Xia, Yihua Wu

Pre-Clinical, group4Kirk SmithJuly 10, 2021Metastasis, Mutation, SMARCA1, EDNRB

Hypoxia in Lung Cancer Management: A Translational Approach

Hypoxia is a common feature of lung cancers. Nonetheless, no guidelines have been established to integrate hypoxia-associated biomarkers in patient management. Here, we discuss the current knowledge and provide translational novel considerations regarding its clinical detection and targeting to improve the outcome of patients with non-small-cell lung carcinoma of all stages. READ ARTICLE

Cancers DOI: 10.3390/cancers13143421

Authors: Ancel J, Perotin J-M, Dewolf M, Launois C, Mulette P, Nawrocki-Raby B, Dalstein V, Gilles C, Deslée G, Polette M and Dormoy V.

Review Paper, group4Kirk SmithJuly 8, 2021NSCLC, hypoxia, HIF, angiogenesis, oxygen sensing, lung cancer management

Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibition agents

Anaplastic lymphoma kinase (ALK) targeted therapies have demonstrated remarkable efficacy in ALK-positive lung adenocarcinomas. Here we synthesized and evaluated sixteen new 2,4-diaminopyrimidines bearing a sulfoxide moiety as anaplastic lymphoma kinase (ALK) inhibitors. The optimal compound 9e exhibited excellent antiproliferative activity against non-small cell lung cancer NCI-H2228 cells, which is better than that of Brigatinib and similar to Ceritinib. Mechanism study revealed that the optimal compound 9e decreased the mitochondrial membrane potential and arrested NCI-H2228 cells in the G0/G1 phase, finally resulting in cellular apoptosis. It is interesting that 9e could effectively inhibit the migration of NCI-H2228 cells and may be a promising leading compound for chemotherapy of metastatic cancer. READ ARTICLE

Bioorganic & Medicinal Chemistry Letters DOI:10.1016/j.bmcl.2021.128253

Authors: Feng Wu, Han Yao, Wei Li, Niuniu Zhang, Yangyang Fan, Albert S.C. Chan, Xingshu Li, Baijiao An

Targeted therapy in advanced non-small cell lung cancer: current advances and future trends

Lung cancer remains the leading cause of cancer-related mortality in both men and women in the US and worldwide. Non-small cell lung cancer is the most common variety accounting for 84% of the cases. For a subset of patients with actionable mutations, targeted therapy continues to provide durable responses. Advances in molecular and immunohistochemical techniques have made it possible to usher lung cancer into the era of personalized medicine, with the patient getting individualized treatment based on these markers. This review summarizes the recent advances in advanced NSCLC targeted therapy, focusing on first-in-human and early phase I/II clinical trials in patients with advanced disease. We have divided our discussion into different topics based on these agents' mechanisms of action. This article is aimed to be the most current review of available and upcoming targeted NSCLC treatment options. We will also summarize the currently available phase I/II clinical trial for NSCLC patient..... READ ARTICLE

Journal of Hematology & Oncology DOI:10.1186/s13045-021-01121-2

Authors: Umair Majeed, Rami Manochakian, Yujie Zhao & Yanyan Lou

SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy

The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive patients treated with platinum-based chemotherapy had poor outcome (all patients were dead and the mean survival time was 12 months), compared to 72 months for patients with ALK inhibitor therapy. Furthermore, Five ALK-positive cases were analyzed by whole exome sequencing (WES) and via direct transcript counting using a digital probe-base (NanoString) to explore the driver genes. Deregulation of PI3K/AKT signaling pathway in ALK-positive lung cancer was demonstrated by WES analysis, and significantly increased mRNA of ALK, ROS1, MET, SPP1 and PI3K signaling pathway was identified by NanoString assay. The concordance between NanoString, IHC and FISH methodologies for detecting ALK fusion was 100%. Significant overexpression of SPP1 protein in ALK-positive lung cancer was confirmed by IHC compared to paired adjacent normal tissues and ALK-negative cancers. Thus we concluded that SPP1 overexpression is associated with poor outcomes for patients with ALK fusion lung cancer without receiving targeted therapy and PI3K/AKT/SPP1 pathway may become the promising targets in patients with aggressive lung cancer. READ ARTICLE

Scientific Reports DOI: 10.1038/s41598-021-93484-2

Authors: Xiaolin Ji, Yan Liu, Fang Mei, Xinyang Li, Mengxue Zhang, Buwen Yao, Rui Wu, Jiangfeng You and Fei Pei

Pre-Clinical, group4Kirk SmithJuly 7, 2021SSP1, outcome, PI3K/AKT

Precision therapy with anaplastic lymphoma kinase inhibitor ceritinib in ALK-rearranged anaplastic large cell lymphoma

This ceritinib translational study in NPM1-ALK+ ALCL provides a strong rationale for a prospective study of ceritinib in ALK+ T-cell lymphomas and other ALK+ hematologic malignancies. READ ARTICLE

ESMO Open DOI: 10.1016/j.esmoop.2021.100172

Authors: V. Subbiah, S. Kuravi, S. Ganguly, D.R. Welch, C.J. Vivian, M.U. Mushtaq, A. Hegde, S. Iyer, A. Behrang, S.M. Ali, R.W. Madison, J.M. Venstrom, R.A. Jensen, J.P. McGuirk, H.M. Amin and R. Balusu

SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy

The screening of non-small cell lung cancer (NSCLC) tumors for anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements is important because of the dramatically favorable therapy response to ALK inhibitor. However, the exact mechanism of poor survival in ALK fusion lung cancer patients without receiving targeted therapy is unclear. In this study, total of 521 tumor specimens from Chinese patients with lung cancer were screened for ALK fusion by immunohistochemistry (IHC) and confirmed by fluorescence in situ hybridization (FISH). As results, there were no cases of coexisting EGFR and ALK mutations identified. Fourteen cases (2.7%) harbored ALK fusion, including eight solid adenocarcinomas with signet ring cell features, four acinar adenocarcinomas with cribriform pattern containing mucin, one adenosquamous carcinoma and one micropapillary adenocarcinoma with mucin. Six (42.9%) of fourteen patients with ALK-positive lung cancer had stage IV disease, and five ALK-positive p..... READ ARTICLE

Scientific Reports DOI:10.1038/s41598-021-93484-2

Authors: Xiaolin Ji, Yan Liu, Fang Mei, Xinyang Li, Mengxue Zhang, Buwen Yao, Rui Wu, Jiangfeng You & Fei Pei

Pre-Clinical, group4Kirk SmithJuly 7, 2021SPP1, ALK, lung cancer, TKI, chemotherapy

An overview of alectinib hydrochloride as a treatment option for ALK positive non-small cell lung cancer

Introduction: Alectinib is a second-generation inhibitor of anaplastic lymphoma kinase (ALK) and RET. Phase III clinical trials have established its superiority to crizotinib in the first-line ALK inhibitor-naïve setting. Studies also support its use over chemotherapy in the post-crizotinib setting. It is currently one of several FDA- and EMA-approved ALK inhibitors, and it is listed as a preferred initial therapy for treatment-naïve ALK-positive non-small cell lung cancer (NSCLC).Areas covered: Herein, the authors provide the reader with details of the chemical structure, pharmacologic properties, resistance mutations, phase I, II, and III clinical trials, and safety profile of alectinib. Furthermore, the authors provide the reader with the expert opinion and future perspectives on the drug.Expert opinion: Alectinib compares favorably to other second-generation ALK inhibitors with regards to safety, tolerability, and efficacy. Based on currently available data, it is an appropriate first-line option. Ongoing studies will better resolve the ideal sequencing of ALK inhibitors in the treatment of ALK-positive NSCLC. READ ARTICLE

Expert Opinion on Pharmacotherapy DOI: 10.1080/14656566.2021.1948014

Authors: Schokrpur S, Hilburn V, Giustini N and Bazhenova L.

Detection of acquired resistance mutation ALK G1202R after treatment with alectinib and response of lorlatinib

In the era of personalized medicine, the identification of driver mutations has paved the way towards targeted therapy. With the identification of anaplastic lymphoma kinase (ALK) as an oncogenic driver mutation, ALK rearrangements became druggable by tyrosine kinase inhibitors and, thus, have improved the prognosis for patients. Nevertheless, these approaches are limited by resistances occurring within the first or second year of administering ALK inhibitors. Among the different ALK resistant mutations, G1202R is the most common mutation, located in the kinase domain of the ALK protein resulting in resistance to treatment with the first- and second-generation kinase inhibitors (e.g., crizotinib, ceritinib, brigatenib and alectinib). Conflicting reports exist regarding the efficacy of lorlatinib, a next generation ALK inhibitor. The aim of this study is to access the potential impact of lorlatinib as a second-line treatment for a metastatic progressive NSCLC disease harboring genomic a..... READ ARTICLE

Magazine of European Medical Oncology (memo) DOI:

Authors: Louisa Hempel, Jakob Molnar, Andreas Gaumann, Sebastian Robert, Josef Scheiber, Axel Kleespies, Kristina Riedmann, Susanne Schreiber, Beate Gandorfer, Armin Piehler & Dirk Hempel

Case Study, group4Kirk SmithJuly 6, 2021alectinib, ALK rearrangement, lorlatinib

Tumor shrinkage with Combination of Alectinib and Trastuzumab in a Patient with ALK-Rearranged NSCLC Harboring HER2-amplification as an Acquired Resistance Mechanism to ALK Inhibitor Therapy

HER2 amplification is an acquired resistance mechanism in ALK-rearranged non-small cell lung cancer. READ ARTICLE

Clinical Lung Cancer DOI: 10.1016/j.cllc.2021.06.012

Authors: David Chun Cheong Tsui, Dara Aisner, Hala Nijmeh, Liming Bao, Alexander Menter and Ross Camidge

Case Study, group4Kirk SmithJuly 3, 2021ALK, HER2, lung cancer, acquired resistance, trastuzumab