Fatal Tumour Lysis Syndrome Induced by Brigatinib in a Lung Adenocarcinoma Patient Treated With Sequential ALK Inhibitors: A Case Report

Tumour lysis syndrome (TLS) represents a group of fatal metabolic derangements resulting from the rapid breakdown of tumour cells. TLS typically occurs soon after the administration of chemotherapy in haematologic malignancies but is rarely observed in solid tumours. Here, we report a case of brigatinib-induced TLS after treatment with sequential anaplastic lymphoma kinase (ALK) inhibitors in a patient with advanced ALK-rearranged lung adenocarcinoma. The patient was treated sequentially with crizotinib, alectinib, and ensartinib. High-throughput molecular profiling after disease progression indicated that brigatinib may overcome ALK resistance mutations, so the patient was administered brigatinib as the fourth-line treatment. After 22 days of therapy, he developed oliguria, fever, and progressive dyspnoea. Clinical manifestations and laboratory findings met the diagnostic criteria for TLS. The significant decrease in the abundance of ALK mutations in plasma indicated a therapeutic res..... READ ARTICLE

Frontiers in Pharmacology DOI:10.3389/fphar.2021.809467

Authors: Wang Yadong, Wang Tiange, Xue Jianchao, Jia Ziqi, Liu Xinyu, Li Bowen, Li Ji, Li Xiaoguang, Wang Weiwei, Bing Zhongxing, Cao Lei, Cao Zhili, Liang Naixin

Case Study, group1Kirk SmithDecember 20, 2021Tumour lysis syndrome (TLS), brigatinib, ALK

The Effect of a High-Fat Meal on the Pharmacokinetics of Brigatinib, an Oral Anaplastic Lymphoma Kinase Inhibitor, in Healthy Volunteers

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK+ non–small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty-four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK-evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high-fat meal) versus fasted conditions, with no effect on area under the concentration-time curve. The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted condit..... READ ARTICLE

Clinical Pharmacology in Drug Development
DOI:10.1002/cpdd.641

Authors: Meera Tugnait,Neeraj Gupta,Michael J. Hanley,Karthik Venkatakrishnan,Daryl Sonnichsen,David Kerstein,David J. Dorer,Narayana Narasimhan

Brigatinib treated ALK positive lung squamous cell carcinoma after failed chemotherapy: A case report

The definitive efficacy of anaplastic lymphoma kinase (ALK) inhibitors in ALK positive lung squamous cell carcinoma (sqCC) patients remain unclear. Here, we report a case in which brigatinib had a therapeutic effect on ALK-positive lung squamous cell carcinoma. The patient in this report was diagnosed with ALK-positive lung squamous cell carcinoma with brain metastases, and received brigatinib after failure of first-line chemotherapy. Response duration was approximately 11 months, with tolerable side effects. In conclusion, a good clinical effect was achieved in a patient with ALK positive lung squamous cell carcinoma who received treatment with an ALK inhibitor. READ ARTICLE

Thoracic Cancer DOI:10.1111/1759-7714.14133

Authors: Shuluan Li, Pei Zhang, Tianyu Wang, Jie Wang, Jianchun Duan,

Case Study, group2Kirk SmithOctober 13, 2021ALK, brigatinib, chemotherapy lung squamous cell carcinoma

STRN-ALK Fusion in a Case of Malignant Peritoneal Mesothelioma: Mixed Response to Crizotinib, Mode of Resistance, and Brigatinib Sequential Therapy

To our knowledge, this is the first description of an STRN-ALK fusion(+) MPM sequentially treated with two different ALK inhibitors. This case underlines the benefit of molecular testing in MPM. Furthermore, it suggests the generalizability of the lessons learned from lung cancer to another entity, which can offer some guidance in the treatment of this rare disease. READ ARTICLE

Journal of Clinical Oncology: Precision Oncology DOI:10.1200/PO.21.00184

Authors: Valeria Gerthofer, Alexander Scheiter, Florian Lüke, Felix Keil, Kirsten Utpatel, Laura-Maria-Giovanna
Pöhmerer, Johannes Seitz, Christoph Niessen, Atanas Ignatov, Wolfgang Dietmaier, Diego F. Calvisi, Matthias Evert, Olaf Ortmann, and Stephan Seitz

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

Comparison of lorlatinib, alectinib and brigatinib in ALK inhibitor–naive/untreated ALK-positive advanced non-small-cell lung cancer: a systematic review and network meta-analysis

Because of lacking of head-to-head comparison among lorlatinib, alectinib and brigatinib for patients with ALK inhibitor–naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced non-small-cell lung cancer (NSCLC), the optimal option for these patients still remains undefined. We searched published reports that described the activity and safety of those novel ALK inhibitors (lorlatinib, alectinib and brigatinib) for ALK inhibitor–naive or untreated (ALK inhibitor-naive and chemotherapy-naive) ALK-positive advanced NSCLC. Five randomized controlled trials were identified, covering 1111 subjects. In the network meta-analysis, lorlatinib seemed to prolong progression free survival than brigatinib (Hazard Ratio: 0.57, P = 0.03) and alectinib (Hazard ratio: 0.65, P = 0.05) for previously untreated patients with ALK-positive advanced NSCLC as assessed by the independent review committee. Meanwhile, lorlatinib significantly improved significant progression free sur..... READ ARTICLE

Journal of Chemotherapy DOI:10.1080/1120009X.2021.1937782

Authors: Lida Wang, Zhixin Sheng, Junying Zhang, Jiwu Song, Lili Teng, Liping Liu, Qianpeng Li, Baohong Wang, Bin Li

Review Paper, group5Kirk SmithJune 17, 2021Lorlatinib, alectinib, brigatinib, crizotinib, advanced NSCLC, meta-analysis

Treatment of brain metastases in ALK-positive Non-Small Cell Lung Cancer

Brain metastases are quite frequent in patients with ALK-translocated non-small cell lung cancer (NSCLC): they are often not amenable to surgical resection and are generally treated with radiotherapy (RT). This however causes severe late toxic side effects that may become invalidating considering the relatively long survival provided by recent medical treatment with target therapies. Several clinical trials have demonstrated that ALK-inhibitors (crizotinib, alectinib, brigatinib) show excellent activity also against brain metastases. It is therefore reasonable, in asymptomatic patients, to start treatment with specific inhibitors: RT will be used at the time of tumor progression or when symptoms appear. This sequence provides the best quality of life for patients. READ ARTICLE

Critical Reviews in Oncology/Hematology DOI: 10.1016/j.critrevonc.2021.103400

Authors: Serena Ceddia and Giovanni Codacci-Pisanelli

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

Review PaperKirk SmithDecember 13, 2020ALK inhibitor, NSCLC, TKI, alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib

Brigatinib Versus Crizotinib in Advanced ALK Inhibitor-Naive ALK-Positive Non-Small Cell Lung Cancer: Second Interim Analysis of the Phase III ALTA-1L Trial

"With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio [HR], 0.49 [95% CI, 0.35 to 0.68]; log-rank P < .0001; median, 24.0 v 11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4 v 9.2 months). No new safety concerns emerged. Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC." READ ARTICLE

Journal of Clinical Oncology DOI: http://doi.org/10.1200/JCO.20.00505

Authors: Camidge DR, Kim HR, Ahn MJ, Yang JCH, Han JY, Hochmair MJ, Lee KH, Delmonte A, García Campelo MR, Kim DW, Griesinger F, Felip E, Califano R, Spira A, Gettinger SN, Tiseo M, Lin HM, Gupta N, Hanley MJ, Ni Q, Zhang P, Popat S.

Clinical TrialsKirk SmithNovember 1, 2020clinical trial, ALTA-1L, TKIs, brigatinib, crizotinib

Optimal Care for Patients with Anaplastic Lymphoma Kinase (ALK)–Positive Non–Small Cell Lung Cancer: A Review on the Role and Utility of ALK Inhibitors

The treatment of advanced non–small-cell lung cancer (NSCLC) has undergone a paradigm shift in the last decade. Molecular characterization of the disease has led to the rapid development of personalized medicine and swift delivery of targeted therapies to patients. The discovery of the anaplastic lymphoma kinase (ALK) gene in patients with NSCLC has resulted in rapid bench–bedside transition of several active drugs, with several others currently in clinical trials. After the first-generation ALK inhibitor crizotinib, next-generation ALK inhibitors have entered clinical applications for ALK-rearranged NSCLC. Ceritinib, alectinib, and brigatinib have all received approval for ALK-positive patients who have failed prior crizotinib, as well as first-line therapy in treatment-naïve patients based on favorable efficacy. Most recently, lorlatinib, a potent, newer-generation ALK inhibitor, has been approved as second- or third-line treatment. These advances have led to better patient outcomes,..... READ ARTICLE

Cancer Management and Research DOI:10.2147/CMAR.S260274

Authors: Abhay Singh, Hongbin Chen

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

Primary Resistance to Brigatinib in a Patient with Lung Adenocarcinoma Harboring ALK G1202R Mutation and LIPI-NTRK1 Rearrangement

Purpose: Anaplastic lymphoma kinase (ALK) inhibitors have transformed the management of non-small-cell lung cancer (NSCLC) patients with ALK gene rearrangement. This paper reports a new resistance mechanism to a second-generation ALK inhibitor, brigatinib. Case Report: A 43-year-old woman who had no history of smoking was diagnosed with stage IVa (T2bN2M1b) lung adenocarcinoma. After the first-line chemotherapy failed, the patient received crizotinib due to the presence of EML4-ALK fusion by next-generation sequencing (NGS). The patient had disease progression after 8 months on crizotinib, and a second NGS identified the ALK G1202R resistance mutation. Therefore, she was switched to brigatinib. After only 53 days of treatment with brigatinib, the patient developed a new 1.6× 1.2 cm lesion in the mediastinal lymph node. A third NGS testing revealed a new form of NTRK rearrangement (LIPI-NTRK1). The patient died 16 months after diagnosis.Conclusion: This paper provides new insights into ..... READ ARTICLE

OncoTargets and Therapy DOI:10.2147/OTT.S249652

Authors: Xiao Z, Huang X, Xie B, Xie W, Huang M, Lin L.

Case StudyKirk SmithMay 22, 2020LIPI-NTRK1, ALK, primary resistance, brigatinib, NSCLC

"Brigatinib and Alectinib for ALK Rearrangement-Positive Advanced Non-Small Cell Lung Cancer with or without Central Nervous System Metastasis: A Systematic Review and Network Meta-Analysis"

To date, no head-to-head trials have compared the e cacy of brigatinib and alectinib
against anaplastic lymphoma kinase (ALK) rearrangement-positive (ALK-p), ALK-inhibitor-naïve,
advanced non-small cell lung cancer (NSCLC) with central nervous system (CNS) metastasis.
We conducted an indirect treatment comparison (ITC) between brigatinib and alectinib, with crizotinib
as a common comparator, using a Bayesian model with non-informative prior distribution and assessed
the between-study heterogeneity of the studies. The primary e cacy endpoint was progression-free
survival (PFS), and e cacy was ranked using the surface under the cumulative ranking (SUCRA)
curve values. ITC analysis showed that there were no significant di erences in PFS between the
brigatinib and alectinib arms. However, the SUCRA values revealed that alectinib ranked the highest
by e cacy in the overall patient population, whereas brigatinib ranked the highest by e cacy in
the CNS metastasis sub-group. Although there wer..... READ ARTICLE

Cancers DOI:10.3390/cancers12040942

Authors: Koichi Ando, Kaho Akimoto, Hiroki Sato, Ryo Manabe, Yasunari Kishino,
Tetsuya Homma, Sojiro Kusumoto, Toshimitsu Yamaoka , Akihiko Tanaka,
Tohru Ohmori,Hironori Sagara

Intracranial remission with brigatinib rechallenge as fifth-line ALK inhibition therapy in a lung cancer patient

Several anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors have been developed for the treatment of EML4-ALK-rearranged non-small-cell lung cancer, with the newer generation agents brigatinib, alectinib and lorlatinib showing pronounced central nervous system activities. Intracranial efficacy is an important feature for these agents, as metastatic lesions frequently occur in the central nervous system in the ALK-positive setting. Here, we report on an updated case of a patient who received her diagnosis in 2005 and has had disease progression with new lesions on six occasions over the last 8 years. During the first two progressions, only local recurrence was observed. After that, the lungs stayed clear and the patient progressed exclusively in the brain and spinal cord. Initial treatments consisted of chemotherapy and radiotherapy. In 2012, ALK-directed targeted therapy became available, and crizotinib was administered. The treatment was switched to brigatinib 3 years later be..... READ ARTICLE

Anti-Cancer Drugs
DOI:10.1097/CAD.0000000000000800

Authors: Hochmair, Maximiliana; Weinlinger, Christopha; Prosch, Helmut

Exploratory Analysis of Brigatinib Activity in Patients With Anaplastic Lymphoma Kinase-Positive Non–Small Cell Lung Cancer and Brain Metastases in Two Clinical Trials

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in advanced ALK inhibitor–naive ALK-positive non–small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events). Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.20.00505

Authors: D. Ross Camidge, Dong-Wan Kim, Marcello Tiseo, Corey J. Langer, Myung-Ju Ahn,
Alice T. Shaw, Rudolf M. Huber, Maximilian J. Hochmair, Dae Ho Lee,
Lyudmila A. Bazhenova, Kathryn A. Gold, Sai-Hong Ignatius Ou, Howard L. West,
William Reichmann, Jeff Haney, Tim Clackson, David Kerstein, and Scott N. Gettinger

Clinical TrialsKirk SmithDecember 1, 2018crizotinib, brigatinib, ALTA-1L

Brigatinib versus Crizotinib in ALK-Positive Non–Small-Cell Lung Cancer

A total of 275 patients underwent randomization; 137 were assigned to brigatinib and 138 to crizotinib. At the first interim analysis (99 events), the median follow-up was 11.0 months in the brigatinib group and 9.3 months in the crizotinib group. The rate of progression-free survival was higher with brigatinib than with crizotinib (estimated 12-month progression-free survival, 67% [95% confidence interval , 56 to 75] vs. 43% [95% CI, 32 to 53]; hazard ratio for disease progression or death, 0.49 [95% CI, 0.33 to 0.74]; P<0.001 by the log-rank test). The confirmed objective response rate was 71% (95% CI, 62 to 78) with brigatinib and 60% (95% CI, 51 to 68) with crizotinib; the confirmed rate of intracranial response among patients with measurable lesions was 78% (95% CI, 52 to 94) and 29% (95% CI, 11 to 52), respectively. No new safety concerns were noted. Among patients with ALK-positive NSCLC who had not previously received an ALK inhibitor, progression-free survival was significantly longer among patients who received brigatinib than among those who received crizotinib. (Funded by Ariad Pharmaceuticals; ALTA-1L ClinicalTrials.gov number, NCT02737501.) READ ARTICLE

The New England Journal of Medicine DOI: 10.1056/NEJMoa1810171

Authors: D. Ross Camidge, Hye Ryun Kim, Myung-Ju Ahn, James Chih-Hsin Yang, Ji-Youn Han, Jong-Seok Lee, Maximilian J. Hochmair, Jacky Yu-Chung Li, Gee-Chen Chang, Ki Hyeong Lee, Cesare Gridelli, Angelo Delmonte, Rosario Garcia Campelo, Dong-Wan Kim, Alessandra Bearz, Frank Griesinger, Alessandro Morabito, Enriqueta Felip, Raffaele Califano, Sharmistha Ghosh, Alexander Spira, Scott N. Gettinger, Marcello Tiseo, Neeraj Gupta, Jeff Haney, David Kerstein, Sanjay Popat

Clinical TrialsKirk SmithNovember 1, 2018brigatinib, ALK, crizotinib, non-small cell lung cancer (NSCLC)

Treating ALK-positive non-small cell lung cancer

Targeting genomic alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, have radically changed the treatment of patients with non-small cell lung cancer (NSCLC). In the case of ALK-rearranged gene, subsequent rapid development of effective genotype-directed therapies with ALK tyrosine kinase inhibitors (TKIs) triggered major advances in the personalized molecularly based approach of NSCLC. Crizotinib was the first-in-class ALK TKI with proven superiority over standard platinum-based chemotherapy for the 1st-line therapy of ALK-rearranged NSCLC patients. However, the acquired resistance to crizotinib and its diminished efficacy to the central nervous system (CNS) relapse led to the development of several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib. To date, four ALK TKIs, crizotinib, ceritinib, alectinib and brigatinib have received approval from the Food and Drug Admin..... READ ARTICLE

Annals of Translational Medicine DOI:10.21037/atm.2017.11.34

Authors: Dimitrios C. Ziogas,corresponding author Anna Tsiara, Georgios Tsironis, Maria Lykka, Michalis Liontos, Aristotelis Bamias, and Meletios-Athanasios Dimopoulos