Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase which becomes oncogenic and drives tumor growth in multiple tumor types, including non-small cell lung cancer (NSCLC). We discuss the pathophysiology of ALK in NSCLC, which is driven predominantly by ALK gene rearrangements. We review the various methods of molecular testing for ALK gene rearrangements in NSCLC, and their limitations.
Oral Tyrosine Kinase Inhibitors (TKIs) targeting the ALK pathway have been rapidly developed in the past 10 years. These drugs are well tolerated and offer prolonged disease control. We highlight the most up-to-date clinical data for each of the agents currently available which target the ALK pathway, and discuss adverse events associated with each agent. We discuss mechanisms of resistance to the ALK-targeted TKIs, and options for treatment at disease progression. READ ARTICLE

Encyclopedia of Respiratory Medicine (Second Edition) DOI:10.1016/B978-0-12-801238-3.11701-5

Authors: Maria Coakley, Sanjay Popat

Influence of alectinib and crizotinib on ionizing radiation - in vitro analysis of ALK/ROS1-wildtype lung tissue cells

(1) Background: Just little is known about the interaction of ALK/ROS1-targeting kinase inhibitors with ionizing radiation (IR), particularly regarding side effects. We investigated the toxicity in two different lung cell lines both ALK/ROS1 wildtype (healthy and tumor origin) as representatives for normal lung tissue; (2) Methods: Human lung cell line BEAS-2B and malignant A549 lung cancer cells (ALK/ROS1 wt) were treated with alectinib or crizotinib, 2 Gy irradiation or a combination of KI and IR. Cell toxicity was analyzed by cell death (Annexin, 7AAD), colony forming, migration assay and live-cell imaging (TMRM, DRAQ7, Caspase3/7). Cell cycle (Hoechst) were analyzed by flow cytometry; (3) Results: Crizotinib led to higher cell death rates than alectinib, when cells were treated with 10 µM KI. Alectinib induced a more intense growth inhibition of colonies. Both inhibitors showed additive effects in combination with irradiation. Combination treatment (IR + KI) does not lead to synergistic effect on neither cell death nor colony forming; (4) Conclusions: The influence of simultaneous KI and IR was studied in non-mutated ALK/ROS1 cell lines. Both KIs seems to be well tolerated in combination with thoracic radiotherapy and lacked synergistic reinforcement in cellular toxicity. This supports the feasibility of ALK/ROS1 inhibition in combination with thoracic irradiation in future clinical trials. READ ARTICLE

Neoplasia DOI:10.1016/j.neo.2022.100780

Authors: Tina Jost, Ann-Kristin Schultz, Benjamin Frey, Jennifer Vu, Rainer Fietkau, Luitpold V. Distel, Markus Hecht

Review PaperKirk SmithFebruary 1, 2022Lung cells, Alectinib, Crizotinib, Radiotherapy, Normal tissue, Side effects

Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC

Introduction: Gene fusion variants in ALK-rearranged NSCLC may predict patient outcomes, but previous results have been inconclusive. Fusion isoforms coexisting in the same tumor may affect the efficacy of targeted therapy, but they have not been investigated... Conclusions: Intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Zhengbo Song, Shifeng Lian, Silvia Mak, Maggie Zi-Ying Chow, Chunwei Xu, Wenxian Wang, Hoi Yee Keung, Chenyu Lu, Firaol Tamiru Kebede, Yanqiu Gao, Wah Cheuk, William Chi Shing Cho, Mengsu Yang, Zongli Zheng

Clinical outcome, long-term survival and tolerability of sequential therapy of first-line crizotinib followed by alectinib in advanced ALK+NSCLC: A multicenter retrospective analysis in China

There is limited data on the clinical outcome, long-term survival and tolerability of sequential therapy of first-line crizotinib followed by alectinib in a real-world setting for Chinese patients with advanced ALK+ NSCLC. The medical records of patients who received sequential therapy with first-line crizotinib followed by alectinib (no intermittent systemic therapy was allowed between the two ALK-TKIs) were collected from six centers in China. Combined time treatment to failure (C-TTF) was defined as the period from the start of crizotinib to the complete discontinuation of alectinib due to any cause.
A total of 61 patients were included in our study. Fifty-two patients were switched to alectinib due to disease progression, seven as a result of toxicity, and two due to patient preference. At the time of data cutoff, alectinib treatment was discontinued in 31 patients on account of disease progression while severe adverse events resulted in cessation of alectinib in another two patien..... READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14232

Authors: Zihua Zou, Xuezhi Hao, Cuiying Zhang, Haojing Li, Guilan Dong, Yumei Peng, Kewei Ma, Ye Guo, Li Shan, Yan Zhang, Li Liang, Yangchun Gu, Puyuan Xing, Junling Li

Real-World OutcomesKirk SmithDecember 1, 2021Alectinib, ALK+ NSCLC, Crizotinib

Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial

Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superi..... 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 C.H. 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 and Sanjay Popat

Identification of a High-Level MET Amplification in CTCs and cfTNA of an ALK-Positive NSCLC Patient Developing Evasive Resistance to Crizotinib

We report the case of a 47-year-old female patient with stage IV NSCLC harboring an echinoderm microtubule associated protein like 4 (EML4)-ALK E20;A20 fusion who was initially treated with four cycles of platinum/pemetrexed until progressive disease. Thereafter, she was treated with crizotinib for 9 months until development of evasive resistance. Subsequently, the patient was primarily resistant to alectinib and ceritinib.
We obtained low-pass copy number profiles of single isolated CTCs after the patient had experienced development of evasive resistance to crizotinib and shown primary resistance to alectinib. Furthermore, we generated additional copy number profiles of CTCs upon development of primary resistance to ceritinib. These analyses revealed the presence of an approximately eightfold MNNG HOS Transforming gene (MET) amplification in all evaluable CTCs at both time points. MET amplification (∼sevenfold) could also be detected in the cfTNA at comparable time points.
This study ..... READ ARTICLE

Journal of Thoracic Oncology
DOI:10.1016/j.jtho.2018.08.2025

Authors: Lars-Arne Berger, Melanie Janning, Janna-Lisa Velthaus, Isabel Ben-Batalla, Stefanie Schatz, Markus Falk, Peter Iglauer, Ronald Simon, Ru Cao, Claudio Forcato, Nicolò Manaresi, Kelli Bramlett, Genny Buson, Annkathrin Hanssen, Markus Tiemann, Guido Sauter, Carsten Bokemeyer, Sabine Riethdorf, Martin Reck, Klaus Pantel, Harriet Wikman, and Sonja Loges

Case Study, group2Kirk SmithNovember 29, 2021Crizotinib, Resistance, MET amplification

A Case of Small Cell Lung Carcinoma Harboring an EML4–ALK Fusion with Partial Response to Crizotinib

Clinical Practice Points: •A patient with metastatic small cell lung cancer (SCLC) had an echinoderm microtubule-associated protein-like 4 (EML4)–anaplastic lymphoma kinase (ALK) fusion.
•He had a partial response to crizotinib in the primary lesions.
•ALK tyrosine kinase inhibitors should be considered in SCLC patients with EML4–ALK fusions.
•Gene testing should be performed in young SCLC patients with a limited smoking history. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2021.03.012

Authors: Qian Shen, Farhin Shaheed Kalyani, Jingjing Qu, Zhen Chen, Jing Zhang, Jianying Zhou

Case StudyKirk SmithNovember 1, 2021SCLC, EML4-ALK, Crizotinib, Partial response, Gene testing

Novel treatment of endobronchial inflammatory myofibroblastic tumor in a child

Isolated endobronchial inflammatory myofibroblatic tumors (IMT) are rare, accounting for about 1% of primary endobronchial tumors in children. The mainstay of treatment for this tumor has been surgical resection. Recently, the identification of anaplastic lymphoma kinase (ALK) gene mutations in half of the IMTs and promising results of treatment with ALK inhibitors in other ALK-positive tumors have opened the possibility of alternative approaches. We present a 4-year-old child with an ALK-positive endobronchial IMT, treated with endoscopic resection and neoadjuvant therapy with Crizotinib, without evidence of tumor recurrence 2 years after the initial resection. READ ARTICLE

Pediatric Pulmonology DOI:10.1097/CAD.0000000000001224

Authors: Jessica Reyes-Angel, Louis B. Rapkin, Jeffrey P. Simons and Hiren Muzumdar

Deep RNA Sequencing Revealed Fusion Junctional Heterogeneity May Predict Crizotinib Treatment Efficacy in ALK-Rearranged NSCLC

Gene fusion variants in ALK-rearranged NSCLC may predict patient outcomes, but previous results have been inconclusive. Fusion isoforms coexisting in the same tumor may affect the efficacy of targeted therapy, but they have not been investigated.
Patients with ALK-rearranged NSCLC who received crizotinib treatments were recruited. Precrizotinib tumor tissues were analyzed by the anchored multiplex polymerase chain reaction for targeted RNA sequencing. Kaplan-Meier and Cox regression were used to compare overall and progression-free survivals.
It was concluded that intratumoral EML4-ALK isoforms may predict the efficacy of targeted therapy in ALK-rearranged NSCLC. Temporal changes of intratumoral fusion isoforms may result from differential selection pressures that a drug might have on one isoform over another. Larger studies on fusion heterogeneity using RNA sequencing are warranted. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2021.09.016

Authors: Zhengbo Song, Shifeng Lian, Silvia Mak, Maggie Zi-Ying Chow, Chunwei Xu, Wenxian Wang, Hoi Yee Keung, Chenyu Lu, Firaol Tamiru Kebede, Yanqiu Gao, Wah Cheuk, William Chi Shing Cho, Mengsu Yang, Zongli Zheng

Pathological cytomorphologic features and the percentage of ALK FISH-positive cells predict pulmonary adenocarcinoma prognosis: a prospective cohort study

We conducted a study to explore the relationship between pathological cytomorphologic features and the percentage of anaplastic lymphoma kinase (ALK)-positive cells to better predict pulmonary adenocarcinoma prognosis with crizotinib treatment.
We investigated 60 cases of patients with ALK-positive advanced or metastatic non-small cell lung cancer (NSCLC). Immunohistochemistry was performed to screen for ALK rearrangement. Fluorescence in situ hybridization (FISH) was used to detect the percentage of ALK-positive cells. The primary objectives of the study were the progression-free survival (PFS), the 3-year overall survival, and the 3-year overall survival (OS) rates. The secondary objectives of the study were the disease control rate (DCR) and the overall response rate (ORR).
We concluded that signet ring cell cytomorphologic characteristics of pulmonary adenocarcinoma are associated with the percentage of ALK-positive cells. Signet ring cell cytomorphologic characteristics and the percentage of ALK-positive cells might predict the prognosis of pulmonary adenocarcinoma with crizotinib treatment. READ ARTICLE

World Journal of Surgical Oncology DOI:10.1186/s12957-021-02386-0

Authors: Fenge Jiang, Congcong Wang, Ping Yang, Ping Sun, Jiannan Liu

Drug interaction profile of TKI alectinib allows effective and safe treatment of ALK+ lung cancer in the kidney transplant recipient

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer.Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs h..... READ ARTICLE

International Immunopharmacology DOI:10.1016/j.intimp.2021.108012

Authors: Ondrej Bilek, Milos Holanek, Jan Jurica, Sona Stepankova, Jiri Vasina, Iveta Selingerova, Alexandr Poprach, Simona Borilova, Tomas Kazda, Igor Kiss, Lenka Zdrazilova-Dubska

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

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

Rare coexistence of three novel CDCA7-ALK, FSIP2-ALK, ALK-ERLEC1 fusions in a lung adenocarcinoma patient who responded to Crizotinib

In some occasions, intergenic ALK fusions were identified, whereas one or both breakpoints localized in intergenic regions. However, whether intergenic fusions could retain full coding transcripts and generate chimeric proteins was not clear, causing difficulties in target therapy selection. READ ARTICLE

Lung Cancer DOI: 10.1016/j.lungcan.2020.12.013

Authors: Zhao G, Chen L, Xiao M, Yang S.

Real-World OutcomesKirk SmithFebruary 15, 2021coexistence of three ALK fusions, Crizotinib

Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients

Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms. READ ARTICLE

Journal of Cancer Research and Clinical Oncology DOI:10.1007/s00432-020-03476-4

Authors: Xin, S., Fang, W., Li, J. et al.

The effect of metformin in EML4-ALK+ lung cancer alone and in combination with crizotinib in cell and rodent models

Cell based studies have suggested that the diabetes drug metformin may combine with the anaplastic lymphoma kinase receptor (ALK) inhibitor crizotinib to increase ALK positive lung cancer cell killing and overcome crizotinib resistance. We therefore tested metformin alone and in combination with crizotinib in vivo, by employing a xenograft mouse model of ALK positive lung cancer. We found that 14 days of daily oral metformin (100 mg/kg) alone had a moderate but statistically significant effect on tumour growth suppression, but in combination with crizotinib, produced no greater tumour suppression than crizotinib (25 mg/kg) alone. We also reassessed the effect of metformin on EML4-ALK positive lung cancer (H3122) cell viability. Although metformin alone did have a moderate effect on cell viability (30% suppression) this was only at a clinically irrelevant concentration (5 mM) and there was no additive effect with cytotoxic concentrations of crizotinib. Moreover, metformin did not overco..... READ ARTICLE

Biochemical Pharmacology DOI:10.1016/j.bcp.2020.114345

Authors: A.R. Bland, N. Shrestha, R.L. Bower, R.J. Rosengren, J.C. Ashton

Pre-ClinicalKirk SmithJanuary 1, 2021Crizotinib, Metformin, EML4-ALK+ lung cancer

Prolonged survival without progression under crizotinib treatment

In recent years, serious changes have been observed in the treatment algorithms of especially lung cancer patients. The start-up phase of treatment planning of metastatic lung adenocarcinoma patients is comprised of driver mutation research. Among the pretreatment options of patients diagnosed with EML4-ALK rearrangement, is crizotinib. The group disgnosed with EML4-ALK rearrangement, composes a little part of metastatic non-small cell lung cancer. In this case presented, I will focus on the start of crizotinib treatment and 53-month follow-up in remission in a patient, who has been operated twice and received cisplatin-based adjuvant chemotherapy twice, and relapsed for the second time as Stage-4. READ ARTICLE

Cancer Treatment and Research Communications DOI: 10.1016/j.ctarc.2020.100259

Author: Gulmez A Dr.

Case StudyKirk SmithDecember 1, 2020Crizotinib, EML4-ALK, Lung cancer

First-Line Lorlatinib or Crizotinib in Advanced ALK-Positive Lung Cancer

The efficacy of lorlatinib, as compared with that of crizotinib, as first-line treatment for advanced ALK-positive NSCLC is unclear.
We conducted a global, randomized, phase 3 trial comparing lorlatinib with crizotinib in 296 patients with advanced ALK-positive NSCLC who had received no previous systemic treatment for metastatic disease.
In an interim analysis of results among patients with previously untreated advanced ALK-positive NSCLC, those who received lorlatinib had significantly longer progression-free survival and a higher frequency of intracranial response than those who received crizotinib. The incidence of grade 3 or 4 adverse events was higher with lorlatinib than with crizotinib because of the frequent occurrence of altered lipid levels. READ ARTICLE

The New England Journal of Medicine
DOI:10.1056/NEJMoa2027187

Authors: Alice T. Shaw, Todd M. Bauer, Filippo de Marinis, Enriqueta Felip, Yasushi Goto, Geoffrey Liu, Julien Mazieres, Dong-Wan Kim, Tony Mok, Anna Polli, Holger Thurm, Anna M. Calella, Gerson Peltz, Benjamin J. Solomon

Clinical TrialsKirk SmithNovember 19, 2020ALK, Lorlatinib, Crizotinib, First-line, Phase 3

Sustained Response to Crizotinib After Resistance to First-Line Alectinib Treatment in Two Patients With ALK-Rearranged NSCLC

... Here, we describe the sustained response to second-line crizotinib in two patients with echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged advanced NSCLC after failure of the first-line alectinib therapy with no secondary ALK mutations... We speculate that the sustained response to crizotinib in our cases was primarily owing to the absence of ALK resistance mutations. However, we cannot completely rule out the activation of other alternative pathways, as tumor rebiopsies were not performed after developing resistance to alectinib. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2020.01.003

Authors: Jing Zheng, Wenjia Sun, Wenhong Chen, Jianying Zhou, Jianya Zhou

Case StudyKirk SmithSeptember 1, 2020Crizotinib, Alectinib, ALK, NSCLC

Development of complex renal cysts: A complication associated with Crizotinib therapy

Crizotinib is a tyrosine kinase inhibitor that has been found to be effective in the treatment of anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer. This targeted cancer therapy agent has been shown to have superior efficacy over standard chemotherapy in this small subset of lung cancer patients. An adverse effect of this drug therapy is the development of complex renal cysts. Here, we present a case of a 68-year-old patient with non-small cell lung cancer on Crizotinib therapy who developed complex bilateral renal cysts. It is important to recognize this drug-related complication in order to avoid mistaking it for disease progression, primary renal malignancy, or renal infection. READ ARTICLE

Clinical Imaging DOI:10.1016/j.clinimag.2020.03.011

Authors: Frank Chen, Neema J. Patel, Jordan D. Legout, Melanie P. Caserta

Case StudyKirk SmithSeptember 1, 2020CT, Crizotinib, Complex renal cyst, Lung cancer