Posts tagged TKI
High Tumor Mutation Burden and DNA Repair Gene Mutations are Associated with Primary Resistance to Crizotinib in ALK-Rearranged Lung Cancer
High Tumor Mutation Burden and DNA Repair Gene Mutations are Associated with Primary Resistance to Crizotinib in ALK-Rearranged Lung Cancer

About 20% of patients with ALK-rearranged non-small cell lung cancer (NSCLC) develop acquired resistance to tyrosine kinase inhibitor (TKI) during the first 6 months. This study aimed to examine the molecular mechanisms of early TKI resistance and prognosis in ALK-rearranged NSCLC.Ten patients with ALK-rearranged NSCLC were included: five who developed rapid resistance to crizotinib (progression-free survival (PFS) ≤3 months) and five who exhibited a good response to crizotinib (PFS ≥36 months). The study finds a higher mutation burden and mutations in DNA repair gene, including TP53, were potentially associated with primary resistance to crizotinib in ALK-rearranged NSCLC. An immune-checkpoint inhibition strategy could be examined, which might overcome primary resistance to crizotinib in ALK-rearranged NSCLC. READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S325443

Authors: Dakai Xiao, Qiuhua Deng, Dongyun He, Ying Huang, Wenchi Liang, Fengnan Wang, Haihong Yang

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Case StudyKirk SmithALK, non-small cell lung cancer, TKI, resistance, prognosis
SPP1 overexpression is associated with poor outcomes in ALK fusion lung cancer patients without receiving targeted therapy
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

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Pre-Clinical, group4Kirk SmithSPP1, ALK, lung cancer, TKI, chemotherapy
An overview of alectinib hydrochloride as a treatment option for ALK positive non-small cell lung cancer
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.

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Review Paper, group4Kirk SmithALESIA, ALEX, ALUR, alectinib, J-ALEX, anaplastic lymphoma kinase (ALK), non-small cell lung cancer (NSCLC), TKI
Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib
Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib

Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dramatically reduced ALK and c-MET kinase-inhibitory potential. Furthermore, the prodrugs showed high stability in serum and release of crizotinib in an enzymatic nitroreductase-based cleavage assay was observed for prodrug A. The in vitro activity of both prodrugs was investigated against ALK- and c-MET-dependent or –overexpressing cells, revealing a distinct hypoxia-dependent activation for prodrug A. Finally, inhibition of c-MET phosphorylation and cell proliferation could also be proven in vivo. In summary of the theoretical, chemical and biological studies, prodrug derivatization of the 2-aminopyridine position can be considered as a promising strategy to reduce the side effects and improve the anticancer activity of crizotinib. READ ARTICLE

Bioorganic Chemistry DOI: 10.1016/j.bioorg.2020.103778

Authors: Bjoern Bielec, Hemma Schueffl, Alessio Terenzi, Walter Berger, Petra Heffeter, Bernhard K. Keppler and Christian R. Kowol

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Pre-Clinical, group5Kirk SmithTKI, Prodrugs, Hypoxia, crizotinib, Nitroimidazole
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
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
Brigatinib-induced tuberculosis reactivation: A case report
Brigatinib-induced tuberculosis reactivation: A case report

Brigatinib is a novel potent tyrosine kinase inhibitor as third-generation therapy for anaplastic lymphoma kinase (ALK) rearrangement positive non-small cell lung cancer (NSCLC). Clinical trials show that brigatinib is potent choice of treatment for the first line and further lines of treatment of ALK rearranged NSCLC with highly potent anti-tumor effect on brain metastasis. The adverse effects of brigatinib are tolerable and managable. However, there is limited data about effects on immune system. The most possible serious adverse effect of brigatinib on immune system might be brigatinib associated grade 3-4 lymphopenia. Here we report a brigatinib-induced tuberculosis reactivation patient who is using third-line brigatinib for metastatic NSCLC and have partial response. READ ARTICLE

Current Problems in Cancer DOI:10.1016/j.currproblcancer.2021.100738

Authors: Volkan Keş, Osman Sütcüoğlu, Fatih Gürler, Ozan Yazıcı, Ahmet Özet

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Case StudyKirk SmithImmunodeficiency, Lung cancer, Lymphopenia, TKI
Successful management of a lung cancer patient harbouring both EGFR mutation and EML4-ALK fusion gene with disseminated intravascular coagulation
Successful management of a lung cancer patient harbouring both EGFR mutation and EML4-ALK fusion gene with disseminated intravascular coagulation

Lung cancer patients harbouring driver oncogene alterations are markedly responsive to molecular target agents, such as epidermal growth factor receptor (EGFR), tyrosine kinase inhibitor (TKI), and echinoderm microtubule-associated protein like 4 - anaplastic lymphoma kinase (EML4-ALK)-TKI. We encountered an exceptionally rare case, harbouring both EGFR mutation and EML4-ALK fusion gene, and suffering from severe disseminated intravascular coagulation. In this case report, we present two notable points. First, our patient was successfully treated with a third-generation EGFR-TKI, osimertinib. Second, osimertinib could manage severe conditions, such as disseminated intravascular coagulation. Third-generation EGFR-TKIs may be a viable option for patients harbouring both EGFR mutations and EML4-ALK fusion genes, even in severe conditions. READ ARTICLE

Respiratory Medicine Case Reports DOI:10.1016/j.rmcr.2021.101393

Authors: Kohei Fujita, Megumi Naka, Takanori Ito, Osamu Kanai, Koichi Maekawa, Koichi Nakatani, Tadashi Mio

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Case StudyKirk Smithalectinib, EGFR mutation, EML4-ALK rearrangement, Lung adenocarcinoma, NSCLC, osimertinib, TKI
Feasibility and challenges for sequential treatment in ALK-rearranged non-small-cell lung cancer
Feasibility and challenges for sequential treatment in ALK-rearranged non-small-cell lung cancer

Despite absence of regulatory obstacles and no requirement for specific acquired mutations, 25-30% of ALK+ NSCLC patients forego subsequent systemic therapy due to rapid clinical deterioration, in several cases (approximately 1/3) associated with an ineffective first next-line choice. These results underline the need for closer patient monitoring and broader profiling in order to support earlier and better directed use of available therapies. READ ARTICLE

Frontiers in Oncology DOI:10.3389/fonc.2021.670483

Authors: Mei Elsayed, Farastuk Bozorgmehr, Daniel Kazdal, Anna-Lena Volckmar, Holger Sültmann, Jürgen Fischer, Mark Kriegsmann, Albrecht Stenzinger, Michael Thomas, Petros Christopoulos

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Real-World OutcomesKirk SmithALK-rearranged, NSCLC, TKI, chemotherapy, Sequential therapies, overall survival
Immunotherapy for ALK-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches
Immunotherapy for ALK-Rearranged Non-Small Cell Lung Cancer: Challenges Inform Promising Approaches

Review Paper describing the mechanisms of ALK aberrations in non-small cell lung cancer by which an immunosuppressed tumor microenvironment is created, leading to host immune evasion. Reports pre-clinical and clinical studies evaluating novel immunotherapeutic approaches and describes the promises and challenges of incorporating immune-based treatments for ALK-rearranged non-small cell lung cancer. READ ARTICLE

Cancers DOI: 10.3390/cancers13061476

Authors: Kamya Sankar, Sunitha Nagrath, Nithya Ramnath

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Review PaperKirk SmithALK, ALK-rearrangements, NSCLC, TKI, immune evasion, immunotherapy, cancer vaccine
Out-of-Pocket Costs for Tyrosine Kinase Inhibitors and Patient Outcomes in EGFR- and ALK-Positive Advanced Non–Small-Cell Lung Cancer
Out-of-Pocket Costs for Tyrosine Kinase Inhibitors and Patient Outcomes in EGFR- and ALK-Positive Advanced Non–Small-Cell Lung Cancer

Among patients with advanced EGFR- and ALK-positive NSCLC, higher TKI Out-Of-Pocket costs are associated with decreased TKI adherence, a higher likelihood of TKI discontinuation, and inferior survival. READ ARTICLE

Journal of Clinical Oncology: Oncology Practice DOI: 10.1200/OP.20.00692 JCO

Authors: Bernardo H.L. Goulart, Joseph M. Unger, Shasank Chennupati, Catherine R. Fedorenko, Scott D. Ramsey

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Real-World OutcomesKirk SmithCost, TKI, Patient Outcomes, EGFR, ALK, Advanced NSCLC
Therapeutic Sequencing in ALK+ NSCLC
Therapeutic Sequencing in ALK+ NSCLC

Anaplastic lymphoma kinase-rearranged non-small-cell lung cancer (ALK+ NSCLC) is a model disease for the use of targeted pharmaceuticals in thoracic oncology. Due to higher systemic and intracranial efficacy, the second-generation ALK tyrosine kinase inhibitors (TKI) alectinib and brigatinib have irrevocably displaced crizotinib as standard first-line treatment, based on the results of the ALEX and ALTA-1L trials. Besides, lorlatinib and brigatinib are the preferred second-line therapies for progression under second-generation TKI and crizotinib, respectively, based on the results of several phase II studies. Tissue or liquid rebiopsies at the time of disease progression, even though not mandated by the approval status of any ALK inhibitor, are gaining importance for individualization and optimization of patient management. The potential clinical utility of longitudinal ctDNA assays for earlier detection of disease progression and improved guidance of therapy in these patients is a cur..... READ ARTICLE

Pharmaceuticals DOI: 10.3390/ph14020080

Authors: Elsayed M., Christopoulos P.

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Review PaperKirk SmithALK, NSCLC, TKI, EML4-ALK fusion variant 3, chemotherapy, sequential treatment
The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer
The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer

Review providing a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized. READ ARTICLE

Pharmaceuticals (Basel) DOI: 10.3390/ph13120474

Authors: Valerio Gristina, Maria La Mantia, Federica Iacono, Antonio Galvano, Antonio Russo, Viviana Bazan

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Review PaperKirk SmithALK inhibitor, NSCLC, TKI, alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib
Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer
Complex ALK Fusions Are Associated With Better Prognosis in Advanced Non-Small Cell Lung Cancer

The objective response rate and median progression-free survival to crizotinib treatment tended to be better in complex ALK fusion patients.
Notably, patients with complex ALK fusions had significantly improved overall survival after crizotinib treatment especially when compared with the pure canonical EML4-ALK fusion group.
The complex ALK fusion group also tended to respond better to next-generation ALK TKIs, which were used as later-line therapies.
Most identified non-canonical ALK fusions were likely to be expressed in tumors, and some of them formed canonical EML4-ALK transcripts during mRNA maturation.
Diagnosis using CGP is of great value to identify novel ALK fusions and predict prognosis. READ ARTICLE

Frontiers in Oncology DOI: 10.3389/fonc.2020.596937

Authors: Jin Kang,Xu-Chao Zhang,Hua-Jun Chen, Wen-Zhao Zhong, Yang Xu, Jian Su, Qing Zhou, Hai-Yan Tu, Zhen Wang, Chong-Rui Xu, Xue-Ning Yang, Zhi-Hong Chen, Xue Wu, Xian Zhang, Yang Shao, Yi-Long Wu, Jin-Ji Yang

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Real-World OutcomesKirk SmithALK, Fusions, TKI, Comprehensive genomic profiling, CGP, non-canonical ALK fusions, RNA-sequencing
Early serum tumor marker levels after fourteen days of tyrosine kinase inhibitor targeted therapy predicts outcomes in patients with advanced lung adenocarcinoma
Early serum tumor marker levels after fourteen days of tyrosine kinase inhibitor targeted therapy predicts outcomes in patients with advanced lung adenocarcinoma

In conclusion, image evaluation strategy with RECIST for patients with lung cancer has difficulty in obtaining the appropriate quantity of diffuse lung nodules, pleural effusions, and bone metastases. The type of 4-TMpc after 14 days TKI targeted therapy is associated with image response and PFS without accounting for mutation status in advanced lung adenocarcinoma patients. Our study results could help early therapeutic decision making by identifying patients who may benefit from gefitinib, erlotinib, afatinib, crizotinib, or ceritinib 14 days after TKI targeted therapy.status, in patients with advanced lung adenocarcinoma. READ ARTICLE

PLOS ONE DOI: 10.1371/journal.pone.0240736

Authors: Chen H-J, Tu C-Y, Huang K-Y, Chien C-R, Hsia T-C

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Real-World OutcomesKirk Smithserum tumor marker, TKI
How to select the best upfront therapy for metastatic disease? Focus on ALK-rearranged non-small cell lung cancer (NSCLC)
How to select the best upfront therapy for metastatic disease? Focus on ALK-rearranged non-small cell lung cancer (NSCLC)

Since then, subsequent generations of ALK inhibitors have demonstrated superior efficacy and better CNS activity compared to crizotinib. Alectinib and brigatinib, both second-generation ALK inhibitors have been compared directly to crizotinib in the first-line setting and has demonstrated improved progression free survival (PFS) and intracranial response. Ceritinib, another second-generation ALK inhibitor has been shown to be superior to chemotherapy in ALK-rearranged disease with good CNS activity. Initial responses to ALK inhibitors are not always durable and resistance can occur as on-target or off-target alterations. Lorlatinib, a third-generation ALK inhibitor, has demonstrated activity in the treatment naïve setting and in resistance to crizotinib and second-generation ALK inhibitors. Lorlatinib has also shown improved PFS in patients harboring EML4-ALK variant 3, which is associated with the development of ALK resistance mutations, specifically G1202R. Another new ALK inhibitor, ensartinib, has demonstrated efficacy in the first-line setting and in alectinib refractory disease. READ ARTICLE

Translational Lung Cancer Research DOI: 10.21037/tlcr-20-331

Authors: Bing Xia, Misako Nagasaka, Viola W. Zhu, Sai-Hong Ignatius Ou, Ross A. Soo

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Real-World OutcomesKirk SmithNSCLC, ALK, TKI, targeted therapy
Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC
Efficacy of Incremental Next-Generation ALK Inhibitor Treatment in Oncogene-Addicted, ALK-Positive, TP53-Mutant NSCLC

Background: The anaplastic lymphoma kinase (ALK) gene fusion rearrangement is a potent oncogene, accounting for 2–7% of lung adenocarcinomas, with higher incidence (17–20%) in non-smokers. ALK-positive tumors are sensitive to ALK tyrosine kinase inhibitors (TKIs), thus ALK-positive non-small-cell lung cancer (NSCLC) is currently spearheading precision medicine in thoracic oncology, with three generations of approved ALK inhibitors in clinical practice. However, these treatments are eventually met with resistance. At the molecular level, ALK-positive NSCLC is of the lowest tumor mutational burden, which possibly accounts for the high initial response to TKIs. Nevertheless, TP53 co-mutations are relatively frequent and are associated with adverse outcome of crizotinib treatment, whereas utility of next-generation ALK inhibitors in TP53-mutant tumors is still unknown. Methods: We report the case of an ALK-positive, TP53-mutant NSCLC patient with about five years survival on ALK TKIs with ..... READ ARTICLE

Journal of Personalized Medicine DOI:10.3390/jpm10030107

Authors: László Urbán, Róbert Dóczi, Barbara Vodicska, Dóra Kormos, László Tóth, István Takács, Edit Várkondi, Dóra Tihanyi,Dóra Lakatos, Anna Dirner, István Vályi-Nagy, István Peták

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Real-World OutcomesKirk SmithNSCLC, ALK rearrangement, TP53 mutation, TKI, personalized treatment