How long does crizotinib work? a rare case of recurrent inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumors (IMTs) are mesenchymal solid tumors, in which anaplastic lymphoma kinase (ALK) gene rearrangement might be detected. A 48-year-old female presented with IMT of lung, treated with surgery. After a 39-month disease-free survival metastatic recurrence was occurred involving soft tissues both infra- and supradiaphragmatic regions. The biopsies obtained from metastatic regions confirmed the recurrence with ALK rearrangement in immunohistochemistry. Initial partial response observed early in treatment course remained as a stable disease with crizotinib treatment. Although an excellent outcome with overall survival of 57 months was observed in our case, there is not enough information about survivals with crizotinib and the treatment options beyond progression. Therefore, every individual case has a unique value paving the way for more effective treatment. READ ARTICLE

Anticancer Drugs DOI:10.1097/CAD.0000000000001137

Authors: Albayrak HC, Gürler F, Sütçüoğlu O, Akyürek N, Özet A.

Fifty-five months progression-free survival with crizotinib treatment in coexistence of ALK and ROS1 rearrangements in lung adenocarcinoma: an extremely rare case and review of the literature

We wanted to present a case with coexistence of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangements that has been in remission for a long time with crizotinib. A 62-year-old nonsmoker male patient was diagnosed with Non-small cell lung cancer. Progression developed 9 months after the treatment, and coexistence of ALK and ROS1 positivity were detected in driver mutation analysis performed with fluorescent in situ hybridization. Crizotinib 2 × 250 mg was started in November 2016. The treatment of the patient, who has been in remission for approximately 55 months since then, continues. Until recently, the use of next-generation sequencing (NGS) was not common, but the more frequent epidermal growth factor receptor, then ALK, and finally ROS1 mutation were studied in tumor tissues. Sometimes ROS1 was not studied because there was not enough tissue left. We think that this rate will increase a little more with the widespread use of NGS from now on. Showing that ALK a..... READ ARTICLE

Anticancer Drugs DOI:10.1097/CAD.0000000000001224

Authors: Korkmaz M, Eryilmaz MK.

Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), is highly effective in advanced ALK-rearranged non-small-cell lung cancer and represents a standard first-line therapy. New strategies are needed, however, to delay resistance. We conducted a phase I/II study to assess the safety and efficacy of combining alectinib with bevacizumab, a monoclonal antibody against vascular endothelial growth factor.
Patients with advanced ALK-rearranged non-squamous non-small-cell lung cancer were enrolled. The phase I portion employed a dose de-escalation strategy with alectinib and bevacizumab starting at the individual standard doses. The primary objective was to determine the recommended phase II dose (RP2D). In phase II, the primary objective was to evaluate the safety of the combination at the RP2D; the secondary objective was to determine extracranial and intracranial efficacy.
Eleven patients were enrolled between September 2015 and February 2020. Mos..... READ ARTICLE

ESMO Open, Cancer Horizons DOI:10.1016/j.esmoop.2021.100342

Authors: J.J. Lin, A. Muzikansky, E. Kennedy, I. Dagogo-Jack, A.T. Shaw, J.F. Gainor

Prognostic Markers of Survival among Japanese Patients with Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer Receiving First-Line Alectinib.

The prognoses of patients with non-small-cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase (ALK) gene rearrangement have dramatically improved with the use of ALK tyrosine kinase inhibitors. Although immunological and nutritional markers have been investigated to predict outcomes in patients with several cancers, their usefulness in targeted therapies is scarce, and their significance has never been reported in patients receiving first-line treatment with alectinib. Mean-while, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) has been investigated during crizotinib treatment. This multicenter retrospective study evaluated 42 consecutive Japanese patients with ALK-positive NSCLC who received first-line treatment with alectinib. Immunological and nutritional markers were evaluated at baseline and 3 weeks after alectinib introduction, and their significance in predicting progression-free survival (PFS) was explored. PFS duration was significantly associat..... READ ARTICLE

Diagnostics DOI:10.3390/diagnostics11122170

Authors: Takeda T, Yamada T, Tanimura K, Nakano T, Ishida M, Tachibana Y, Shiotsu S, Horiuchi S, Hibino M, Okada A, Chihara Y, Takayama K.

Hexokinases II-mediated glycolysis governs susceptibility to crizotinib in ALK-positive non-small cell lung cancer

Background

Activation of ALK leads to a high level of aerobic glycolysis related to crizotinib insensitivity in anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK+ NSCLC). The strategy and mechanism of glycolysis inhibition in sensitizing ALK+ NSCLC cells to crizotinib requires further investigation.
Methods

The levels of glycolysis in H3122 and H2228 cells were evaluated through detection of glucose consumption and lactate production. MTT assay was used to explore the effects of glycolytic inhibitors on crizotinib sensitivity, and the potential mechanism of action were detected by colony formation, Ki67 incorporation assay, transwell assay, small interfering RNA technology and western blot analysis.
Results

ALK+ NSCLC cells exhibited significantly higher levels of glycolysis compared to ALK− NSCLC cells. Long-term exposure to crizotinib could decrease the sensitivity of ALK+ NSCLC cells to crizotinib via increasing the levels of glycolysis related to hexokinases I..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14184

Authors: Caiyu Lin, Hengyi Chen, Rui Han, Li Li, Conghua Lu, Shuai Hao, Yubo Wang, Yong He

Pre-Clinical, group2Kirk SmithNovember 2, 20212DG, glycolysis, anaplastic lymphoma kinase (ALK), crizotinib

Successful treatment with lorlatinib in a patient with meningeal carcinomatosis of ALK-positive non-small cell lung cancer resistant to alectinib and brigatinib

Although anaplastic lymphoma kinase (ALK) inhibitors are effective treatment options for ALK-positive non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis, achieving long-term survival in patients with NSCLC with meningeal carcinomatosis resistant to ALK inhibitors is difficult. Lorlatinib, a third-generation ALK inhibitor, was designed for selective CNS penetration, and exerts potent antitumor activity against tumors resistant to first- and/or second-generation ALK inhibitors. However, there is limited information about the activity of lorlatinib in ALK inhibitor-resistant meningeal carcinomatosis. Here, we report a case of ALK-positive lung adenocarcinoma with meningeal carcinomatosis in which lorlatinib was used after resistance to alectinib and brigatinib.We find lorlatinib is an effective treatment option for patient with ALK-positive NSCLC who develop meningeal carcinomatosis resistant to second-generation ALK inhibitors. Therefore, lorlatinib should be considered in such cases, even when patients exhibit serious symptoms associated with meningeal carcinomatosis. READ ARTICLE

Medicine DOI:10.1097/MD.0000000000027385

Authors: Nakashima, Koki MD, Demura, Yoshiki MD, PhD, Kurokawa, Kosuke MD, Takeda, Toshihiro MD, Jikuya, Norihiro MD, Oi, Masahiro MD, Tada, Toshihiko MD, Akai, Masaya MD, PhD, Ishizuka, Tamotsu MD, PhD

Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update

Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment..... READ ARTICLE

Pharmaceutics DOI:10.3390/pharmaceutics13091427

Authors: Annette K. Brenner and Maria W. Gunnes

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.

Outcomes of first, second, and third-generation anaplastic lymphoma kinase (ALK) inhibitors in non-small cell lung cancer brain metastases (NSCLCBM)

Background: Non-small cell lung cancer (NSCLC) is the most common cause of brain metastases. ALK, which codes for tyrosine kinase receptors, is rearranged in 4-7% of NSCLC. First-generation ALK inhibitors have restricted efficacy due to poor blood-brain barrier (BBB) penetration and ALK-resistant tumor mutations. Second-generation ALK inhibitors have shown better BBB penetration, while third-generation ALK inhibitors were efficacious even against ALK-resistant mutations. In this retrospective study, we investigated the overall survival (OS) and progression-free survival (PFS) in NSCLCBM patients treated with first, second, and third-generation ALK inhibitors. Conclusions: Newer generations of targeted therapies in NSCLCBM have improved BBB penetration and effectiveness against resistant mutations. We determined that there was a significant 5-year OS benefit in patients who received second and third-generation ALK inhibitors compared to first-generation ALK inhibitors, and a respective..... READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.2034

Authors: Vineeth Tatineni, Patrick Joseph O'Shea, Yasmeen Rauf, Xuefei Jia, Erin Sennett Murphy, Samuel T. Chao, John H. Suh, David M. Peereboom, Manmeet Singh Ahluwalia

NPM-ALK: A Driver of Lymphoma Pathogenesis and a Therapeutic Target

Initially discovered in anaplastic large cell lymphoma (ALCL), the ALK anaplastic lymphoma kinase is a tyrosine kinase which is affected in lymphomas by oncogenic translocations, mainly NPM-ALK. To date, chemotherapy remains a viable option in ALCL patients with ALK translocations as it leads to remission rates of approximately 80%. However, the remaining patients do not respond to chemotherapy and some patients have drug-resistant relapses. It is therefore crucial to identify new and better treatment options. Nowadays, different classes of ALK tyrosine kinase inhibitors (TKI) are available and used exclusively for EML4-ALK (+) lung cancers. In fact, the significant toxicities of most ALK inhibitors explain the delay in their use in ALCL patients, who are predominantly children. Moreover, some ALCL patients do not respond to Crizotinib, the first generation TKI, or develop an acquired resistance months following an initial response. Combination therapy with ALK inhibitors in ALCL is th..... READ ARTICLE

Cancers (Basel) DOI:10.3390/cancers13010144

Authors: Elissa Andraos, Joséphine Dignac, Fabienne Meggetto

Anaplastic lymphoma kinase rearrangement may increase the incidence of venous thromboembolism by increasing tissue factor expression in advanced lung adenocarcinoma

Background Patients with lung cancer are at an increased risk for venous thromboembolism (VTE). Approximately 8–15% of patients with advanced non-small-cell lung cancer (NSCLC) experience a VTE throughout the course of the disease. However, the incidence of VTE in different NSCLC molecular subtypes is rarely reported, although there are significant differences in clinical feature and prognosis. Tissue factor (TF) expressed in many solid tumors could trigger the downstream coagulation cascade and lead to thrombin generation and clot formation. Results: At a median follow up of 2.5 years, 5.85% (n=30/513) patients with advanced lung adenocarcinoma experienced VTE. Compared to patients with EGFR mutation (n=11/218, 5.05%) or both negative (n=13/266, 4.89%), patients with ALK-rearrangement were more likely to develop VTE (n=6/29, 20.69%; P=0.006, P=0.004; respectively). In ALK-rearrangement-positive tissues, 41.67% (n=10/24) had a high TF protein expression; the incidence was significantly..... READ ARTICLE

Annals of Translational Medicine DOI:10.21037/atm-20-6619

Authors: Yang S, Yang L, Wu Y, Zhang C, Wang S, Ma N, Wang L, Wang

Population pharmacokinetic (PK) and exposure-response analyses from the pivotal ALTA-1L study: Model-based analyses supporting the brigatinib dose...

Background: Brigatinib is a next-generation ALK tyrosine kinase inhibitor (TKI) with differential activity by dose (90 mg vs 180 mg [with a 7-day lead-in at 90 mg] qd) in the phase 2 post-crizotinib ALTA trial (NCT02094573). Herein, we describe results from population PK and exposure-response analyses of the efficacy and safety of brigatinib 180 mg qd (with a 7-day lead-in at 90 mg) from data in the first-line phase 3 ALTA-1L study (NCT02737501)... Conclusions: These results support a favorable benefit/risk profile of the proposed 180 mg qd brigatinib dose (with a 7-day lead-in at 90 mg) for the front-line treatment of patients with ALK+ NSCLC. Clinical trial information: NCT02737501. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.e21725

Authors: Neeraj Gupta, Karen L. Reckamp, D. Ross Camidge, Huub Jan Kleijn, Aziz Ouerdani, Francesco Bellanti, John Maringwa, Michael J. Hanley, Shining Wang, Pingkuan Zhang, Karthik Venkatakrishnan

Clinical characteristics and risk factors of drug-induced lung injury by ALK tyrosine kinase inhibitors: A single center retrospective analysis

A total of seven cases were diagnosed with drug induced lung injury (DILI) due to ALK-TKIs; no DILI-related deaths were observed. Chest computed tomography (CT) scan findings identified six patients with the organizing pneumonia (OP) pattern and one with the hypersensitivity pneumonia pattern. The onset of DILI was significantly different in patients age ≥ 64 years and with a creatinine clearance <80 mL/minute. Extra caution for DILI due to ALK-TKIs may be needed when recommending ALK-TKIs for patients over 64 years of age, or with decreased renal function. CT images of the majority of patients with DILI by ALK-TKIs show an OP pattern. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13416

Authors: Ken Koshikawa, Jiro Terada, Mitsuhiro Abe, Shunichiro Iwasawa, Masashi Sakayori, Keiichiro Yoshioka, Yasutaka Hirasawa, Hajime Kasai, Yohei Kawasaki, Kenji Tsushima, Koichiro Tatsumi

Clinical characteristics and risk factors of drug-induced lunginjury by ALK tyrosine kinase inhibitors: A single centerretrospective analysis

If anaplastic lymphoma kinase (ALK) gene rearrangement in lungcancer is identified, ALK-tyrosine kinase inhibitors (ALK-TKIs) can be an effec-tive treatment. However, the details of drug-induced lung injury (DILI) causedby ALK-TKI, which can be a serious side effect of ALK-TKIs, remains unclear.This study aimed to investigate the clinical features and the onset risk factors ofDILI by ALK-TKIs in clinical practice.Methods:The clinical features of 56 consecutive patients who receivedcrizotinib, alectinib, and/or ceritinib at our hospital from 2012 to 2018 were ret-rospectively examined. Among these, patients diagnosed with DILI due to ALK-TKIs were evaluated in terms of clinical features and parameters. Each clinicalparameter before the administration of ALK-TKIs was compared between theDILI onset group and the non-onset group.Results:A total of seven cases were diagnosed with DILI due to ALK-TKIs; noDILI-related deaths were observed. Chest computed tomography (CT) scanfind-ings identified six patients with the organizing pneumonia (OP) pat..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.13416

Authors: Ken Koshikawa, Jiro Terada, Mitsuhiro Abe, Shunichiro Iwasawa, Masashi Sakayori, Keiichiro Yoshioka, Yasutaka Hirasawa, Hajime Kasai, Yohei Kawasaki, Kenji Tsushima, Koichiro Tatsumi

Meta-analysis comparing incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with non-small-cell lung cancer

Aim: Using the available literature, this meta-analysis aimed to compare reports of the incidence of grade 3–4 neutropenia with ALK inhibitors and chemotherapy in patients with ALK-positive NSCLC. Conclusion: This meta-analysis of Phase III randomized clinical trials found no significant difference in the incidence of grade 3–4 neutropenia among patients with ALK-positive NSCLC treated with either an ALK inhibitor or chemotherapy, and this was not affected by adjusting for baseline tumor stage. READ ARTICLE

FUTURE ONCOLOGY
DOI:10.2217/fon-2018-0863

Authors: Bernardo Rapoport, Ramin B Arani, Nicola Mathieson, Andriy Krendyukov

Advance of theragnosis biomarkers in lung cancer: from clinical to molecular pathology and biology

One distinct molecular subtype of non-small cell lung cancer (NSCLC) is defined by rearrangement of the anaplastic lymphoma kinase (ALK). The increasing knowledge over the last years has enabled the continuous improvement of ALK inhibitors; however, resistance in these patients remains a major concern. In this review, we summarize recent findings in ALK+-adenocarcinoma of the lung, highlighting the role of TP53 mutations in this specific cancer type and suggest new diagnostic strategies for the future, in order to improve patient’s outcome. READ ARTICLE

Journal of Thoracic Disease
DOI:10.21037/jtd.2018.12.03

Authors: Christina Alidousty, Till Baar, Carina Heydt, Svenja Wagener-Ryczek, Anna Kron, Juergen Wolf, Reinhard Buettner, Anne Maria Schultheis

The role of the ALK receptor in cancer biology

This review summarises the latest research on the receptor tyrosine kinase ALK, and how this information can guide the management of patients with cancer that is ALK-positive. A variety of ALK gene alterations have been described across a range of tumour types, including point mutations, deletions and rearrangements. A wide variety of ALK fusions, in which the kinase domain of ALK and the amino-terminal portion of various protein partners are fused, occur in cancer, with echinoderm microtubule-associated protein-like 4 (EML4)-ALK being the most prevalent in non-small-cell lung cancer (NSCLC). Different ALK fusion proteins can mediate different signalling outputs, depending on properties such as subcellular localisation and protein stability. The ALK fusions found in tumours lack spatial and temporal regulation, which can also affect dimerisation and substrate specificity. Two ALK tyrosine kinase inhibitors (TKIs), crizotinib and ceritinib, are currently approved in Europe for use in ALK-positive NSCLC and several others are in development. These ALK TKIs bind slightly differently within the ATP-binding pocket of the ALK kinase domain and are associated with the emergence of different resistance mutation patterns during therapy. This emphasises the need to tailor the sequence of ALK TKIs according to the ALK signature of each patient. Understanding the role of ALK in tumour biology is key to further optimising therapeutic strategies for ALK-positive disease. READ ARTICLE

Annals of Oncology DOI: 10.1093/annonc/mdw301

Authors: B. Hallberg, R.H. Palmer

Review PaperKirk SmithSeptember 1, 2016EML4-ALK, NSCLC, TKI, cancer biology, anaplastic lymphoma kinase (ALK)