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

Dramatic response to brigatinib in a lung adenocarcinoma patient harboring EML4-ALK fusion and a G1202R de novo gene mutation

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors are the preferred initial treatment for ALK rearranged non-small cell lung cancer (NSCLC). While initial responses to next-generation inhibitors are robust, acquired resistance is expected for nearly all patients. The emergence of the G1202R mutation represents a significant concern for oncologists, as it predicts resistance to almost all ALK inhibitors (ALKi) other than lorlatinib. However, we report the first case of ALK de novo mutation in a patient with advanced NSCLC that responded to brigatinib. READ ARTICLE

European Journal of Cancer DOI:10.1016/j.ejca.2022.02.001

Authors: Yue Pan, Yue Zeng, Yurong Peng, Xiaohan Liu, Yizheng Li, Fang Wu

Case StudyKirk SmithApril 1, 2022Brigatinib, lung adenocarcinoma, EML4-ALK, G1202R, gene mutation

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

Brigatinib in Japanese patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC): First results from the J-ALTA

Background: Brigatinib is a next-generation ALK inhibitor with demonstrated activity against ALK mutations. We report primary analysis results with brigatinib in Japanese patients with ALK-positive NSCLC who have not previously been treated with an ALK TKI in the phase 2 J-ALTA study (NCT03410108). Conclusions: In the J-ALTA TKI-naive cohort, brigatinib demonstrated substantial efficacy and manageable safety in the Japanese patient population. Brigatinib remains one of the treatment options in Japanese patients. Clinical trial information: NCT03410108. READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2021.39.15_suppl.9042

Authors: Masashi Kondo, Shunichi Sugawara, Toshihide Yokoyama, Toru Kumagai, Makoto Nishio, Koichi Goto, Yuichiro Ohe, Takashi Seto, Nobuyuki Yamamoto, Kentarou Kudou, Takayuki Asato, Pingkuan Zhang, Kazuhiko Nakagawa

Brigatinib After Progression From Alectinib or Crizotinib: Paving the Way for Treatment Sequencing of ALK Inhibitors in ALK-Positive NSCLC

Among the 47 Japanese patients who received brigatinib at the standard dose after progression from alectinib with or without history of crizotinib use, objective response rate (ORR) and disease control rate (DCR) were 34% (16 of 47) and 79% (37 of 47), respectively, with a median progression-free survival (PFS) of 7.3 months. READ ARTICLE

Journal of Thoracic Oncology DOI: 10.1016/J.JTHO.2020.11.023

Authors: Lianxi Song, Qinqin Xu, Analyn Lizaso, Yongchang Zhang,

EditorialKirk SmithMarch 1, 2021Alectinib progression, Crizotinib progression, Brigatinib

Treatment of anaplastic lymphoma kinase-positive lung adenocarcinoma with pemetrexed and carboplatin after crizotinib failure and significant liver dysfunction; a case report

Tyrosine kinase inhibitors are the first-line treatment for Anaplastic Lymphoma Kinase-positive lung adenocarcinomas. However, chemotherapy is still an option in patients who are unresponsive or intolerant of tyrosine kinase inhibitors. There is a high likelihood of brain metastasis in patient with lung adenocarcinomas with Anaplastic Lymphoma Kinase rearrangement. Surveillance brain imaging may have a role in clinical follow up. Brigatinib and lorlatinib are two tyrosine kinase inhibitors with excellent intracranial penetrance. READ ARTICLE

Cancer Treatment and Research Communications DOI:10.1016/j.ctarc.2020.100291

Authors: Oranus Mohammadi, Kayla Haines, Mohammad Jahanzeb,

Clinical Benefit From a Combination of Brigatinib and Camrelizumab in Sarcomatoid Transformation of ALK-Rearranged Squamous Cell Lung Cancer Resistant to Crizotinib

A 27-year-old nonsmoking Chinese man was referred to the hospital owing to chest pain in May 2015. He had a diagnosis of stage IV lung squamous cell carcinoma (SCC), (cT2aN3M1b). Computed tomography displayed a 3-cm dense mass in the left superior lung (Fig. 1A, baseline), and immunohistochemistry (IHC) staining of the tumor biopsy reported positive for pulmonary SCC marker p40 (Fig. 1B, baseline). READ ARTICLE

JTO Clinical and Research Reports DOI:10.1016/j.jtocrr.2020.100009

Authors: Wei Jiang, Ruting Guan, Yang W. Shao, Bo Wang, Yina Wang

Brigatinib in Japanese ALK positive NSCLC patients previously treated with ALK tyrosine kinase inhibitors: J-ALTA

Background: Brigatinib is an ALK inhibitor with demonstrated activity against ALK resistance mutations. To evaluate efficacy and safety in Japanese patients with ALK-positive non-small cell lung cancer (NSCLC), a prospective, single-arm, phase 2 study was conducted. We report the efficacy and safety of brigatinib in patients who have progressed on alectinib with or without prior crizotinib and of those who previously received up to two ALK tyrosine kinase inhibitors (TKIs) with or without prior chemotherapy... Conclusions: Brigatinib showed clinically meaningful efficacy in Japanese patients refractory to prior alectinib (first line or post crizotinib), regardless of prior chemotherapy. The safety profile of brigatinib was consistent with prior studies and no new safety findings were identified. Clinical trial information: NCT03410108 READ ARTICLE

Journal of Clinical Oncology DOI:10.1200/JCO.2020.38.15_suppl.9537

Authors: Tatsuya Yoshida, Makoto Nishio, Toru Kumagai, Toyoaki Hida, Ryo Toyozawa, Tadasuke Shimokawaji, Koichi Goto, Kazuhiko Nakagawa, Yuichiro Ohe, Nobuyuki Yamamoto, Kentarou Kudou, Takayuki Asato, Pingkuan Zhang, Takashi Seto

Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance

EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has ..... READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2020.112190

Authors: Ning Sun, Chaowei Ren, Ying Kong, Hui Zhong, Jinju Chen, Yan Li, Jianshui Zhang, Yuedong Zhou, Xing Qiu, Haifan Lin, Xiaoling Song, Xiaobao Yang, Biao Jiang

Pre-ClinicalKirk SmithMay 1, 2020ALK, Brigatinib, Degrader, VHL, PROTAC, NSCLC, ALCL, Resistance

Anaplastic Lymphoma Kinase Mutation–Positive Non–Small Cell Lung Cancer

KEY POINTS:
Non–small cell lung cancer with anaplastic lymphoma kinase (ALK) chromosomal rearrangement is
sensitive to treatment with tyrosine kinase inhibitors (TKIs).
Numerous TKIs have been developed in recent years, including alectinib, which is the current
preferred first-line agent for treatment-naı¨ve patients.
The development of resistance has led to next-generation ALK inhibitors that better penetrate the
central nervous system, which has improved the treatment of brain metastasis. READ ARTICLE

Thoracic Surgery Clinics DOI:10.1016/j.thorsurg.2019.12.001

Authors: Anthony V. Serritella, Christine M. Bestvina

First-Line Therapy Using Brigatinib vs Crizotinib in Patients With Advanced Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: Results From a Phase 3 Trial

Methods: This open-label, multicenter study enrolled patients with advanced ALK+ NSCLC who had ≤ 1 prior systemic therapy; asymptomatic CNS metastases were allowed. Patients were randomized 1 : 1 to brigatinib 180 mg QD with 7-day lead-in at 90 mg or crizotinib 250 mg BID. Primary endpoint: blinded independent review committee (BIRC)-assessed PFS (RECIST v1.1). Secondary efficacy endpoints included BIRC-assessed ORR, intracranial (i) ORR (iORR), and PFS (iPFS). Interim analyses were planned at 50% and 75% of 198 expected PFS events. Results: 275 patients were randomized (brigatinib/crizotinib, n = 137/138); median age: 58/60 y. 26%/27% received prior chemotherapy for advanced disease; 29%/30% had baseline brain metastases. At data cutoff (19 Feb 2018) for the first interim analysis, median follow-up of brigatinib/crizotinib was 11.0/9.25 mo. With 99 PFS events, brigatinib met the prespecified threshold for statistical superiority vs. crizotinib in the primary endpoint, BIRC-assessed P..... READ ARTICLE

Pneumologie DOI:10.1055/s-0039-3403360

Authors: MJ Hochmair , DR Camidge , HR Kim , MJ Ahn , JCH Yang , J Youn Han , KH Lee , A Delmonte , MR Garcia Campelo , DW Kim , F Griesinger , E Felip , R Califano , A Spira , S Gettinger , M Tiseo , Q Ni , P Zhang , S Popat

Clinical TrialsKirk SmithFebruary 28, 2020ALK, Brigatinib, Crizotinib

Brigatinib: New-generation ALK inhibitor for nonsmall cell lung cancer

Lung cancer, specifically nonsmall cell lung cancer (NSCLC) is the leading cause of death around the world. First-line therapies for metastatic NSCLC such as crizotinib, a tyrosine kinase inhibitor (TKI), have developed resistance due to a rearrangement of the anaplastic lymphoma kinase (ALK) gene. Brigatinib, approved in May 2016, is an ALK inhibitor specifically indicated for ALK-positive metastatic NSCLC in patients who have progressed on or resistant to crizotinib therapy. In several clinical trials, brigatinib has exhibited significant improvement in progression-free survival in patients that have experienced resistance to crizotinib therapy. The optimal dose of brigatinib was found to be 180 mg once daily and demonstrated greater efficacy as compared to its 90 mg once daily dose. Brigatinib was also found to be well tolerated. Although more studies are needed, the current data from these studies indicate brigatinib may be the most favorable therapeutic approach to treat NSCLC ALK..... READ ARTICLE

Current Problems in Cancer
DOI:10.1016/j.currproblcancer.2019.03.005

Authors: Stewart Umbela, Shahinaz Ghacha, Revika Matuknauth, Stacey Gause, Shrijana Joshee, Rahul R. Deshmukh

Review PaperKirk SmithDecember 1, 2019Brigatinib, Crizotinib-resistance, NSCLC, ALK, TKI

$Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial$

Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial

Introduction: We report updated data from a phase 2 randomized study evaluating brigatinib in crizotinib-refractory anaplastic lymphoma kinase–positive NSCLC. Conclusions: Brigatinib (180 mg once daily with lead-in) continues to demonstrate robust PFS, long iPFS and duration of intracranial response, and high intracranial objective response rate in crizotinib-refractory patients. Depth of response may be an important end point to capture in future targeted therapy trials. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.004

Authors: Rudolf M. Huber, MD, Karin H. Hansen, Luis Paz-Ares Rodríguez, Howard L. West, Karen L. Reckamp, Natasha B. Leighl, Marcello Tiseo, Egbert F. Smit, Dong-Wan Kim, Scott N. Gettinger, Maximilian J. Hochmair, Sang-We Kim, Corey J. Langer, Myung-Ju Ahn, Edward S. Kim, David Kerstein, Harry J.M. Groen, D. Ross Camidge

A Compound L1196M/G1202R ALK Mutation in a Patient with ALK-Positive Lung Cancer with Acquired Resistance to Brigatinib Also Confers Primary Resistance to Lorlatinib

We report here the case of a 70-year-old patient with ALK-positive NSCLC treated with crizotinib as part of the ALTA-1L trial.4 The patient relapsed after a partial response. After crizotinib failure, the patient was crossed over to brigatinib, which led to a second partial response lasting 9 months. After progression, the patient was shifted to lorlatinib but the clinical conditions worsened and the patient died. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.06.028

Authors: Geeta G. Sharma, Diego Cortinovis, Francesco Agustoni, Giulia Arosio, Matteo Villa, Nicoletta Cordani, Paolo Bidoli, William H. Bisson, Fabio Pagni, Rocco Piazza, Carlo Gambacorti-Passerini, Luca Mologni

Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non–Small-Cell Lung Cancer During Crizotinib Treatment

"Background: Central nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non–small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment. Conclusion: Although CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2019.06.013

Authors: Yiming Zhao, Bo Zhang, Shuyuan Wang, Rong Qiao, Jianlin Xu, Lele Zhang, Yanwei Zhang, Baohui Han"

Early Onset Pulmonary Toxicity With Lorlatinib in a Patient With Previous Pulmonary Toxicity From Brigatinib

"A 53-year-old female ex-smoker (10 pack-years) presented with progressive dyspnea in February 2014. Her performance status was 1. She was diagnosed with stage IV lung adenocarcinoma with lung, lymph node, and bone involvement. Molecular testing revealed an ALK receptor tyrosine kinase (ALK) translocation with no other concomitant alterations. Our case describes a patient with ALK-rearranged NSCLC who developed pulmonary toxicity on brigatinib that recurred after exposure to lorlatinib at early onset. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.06.013

Authors: Xavier Monzonís, Edurne Arriola"

EditorialKirk SmithNovember 1, 2019Pulmonary Toxicity, Lorlatinib, Brigatinib

Brigatinib in patients with ALK-positive advanced non-small-cell lung cancer pretreated with sequential ALK inhibitors: A multicentric real-world study (BRIGALK study)

Brigatinib is a next-generation ALK inhibitor initially developed in ALK-positive NSCLC pretreated with crizotinib.This retrospective multicentric study analyzed ALK-positive advanced NSCLC patients pretreated with at least one tyrosine-kinase inhibitor, including crizotinib, and enrolled in the brigatinib French early access program. The primary endpoint was investigator-assessed progression-free survival (PFS).Real-world results confirm that the efficacy of brigatinib in a cohort of patients heavily pretreated for ALK-positive advanced NSCLC. READ ARTICLE

Lung Cancer DOI:10.1016/j.lungcan.2019.08.010

Authors: Renaud Descourt, Maurice Perol, Gaëlle Rousseau-Bussac, David Planchard, Bertrand Mennecier, Marie Wislez Alexis Cortot, Florian Guisier, Loïck Galland, Pascal Dô, Roland Schott, Eric Dansin, Jennifer Arrondeau, Jean-Bernard Auliac, Christos Chouaid

Chapter 8 - Approach to Anaplastic Lymphoma Kinase (ALK) Gene Rearranged Non–Small Cell Lung Cancer (NSCLC)

Anaplastic lymphoma kinase (ALK) gene rearrangement occurs in 2%–4% of all non–small cell lung cancer (NSCLC). Treatment with targeted tyrosine kinase inhibitors (TKIs) has shown impressive clinical responses in these patients. Crizotinib was the first agent approved for front-line therapy of ALK-rearranged NSCLC after it demonstrated superior clinical benefit compared with chemotherapy. Eventually, all patients progress on crizotinib therapy, with the central nervous system (CNS) being the most common site. Several next-generation ALK inhibitors were evaluated in crizotinib-treated patients and found to be effective. Currently, ceritinib, alectinib, and brigatinib are all approved for second-line therapy after progression on or intolerance to crizotinib. Clinical efficacy observed with these agents, particularly in the CNS prompted evaluating these agents as front-line therapy. Recently, in two separate phase III trials, alectinib has demonstrated superior clinical efficacy as front-l..... READ ARTICLE

Pulmonary Adenocarcinoma: Approaches to Treatment DOI:10.1016/B978-0-323-55433-6.00008-0

Authors: Shirish Gadgeel Editor: Leora Horn

Kirk SmithAugust 1, 2019Alectinib, ALK, Brigatinib, CNS metastases, Lorlatinib, NSCLC

Intra-cranial efficacy of brigatinib in an ALK-positive non-small cell lung cancer patient presenting leptomeningeal carcinomatosis

Objectives: Brigatinib is a second-generation ALK inhibitor which demonstrated activity over crizotinib-resistance, especially on brain metastasis by increased blood-brain penetration. However, its activity on lepto-meningeal disease is unknown and scarcely reported. Conclusion: Our case provides additional data on brigatinib’s intracranial activity, not only on brain metastasis but also on leptomeningeal disease, after experiencing resistance to both crizotinib and ceretinib, 1st and 2nd generation ALK inhibitors. READ ARTICLE

Lung Cancer
DOI:10.1016/j.lungcan.2019.04.013

Authors: Elisabeth Gaye, Margaux Geier, Paul Bore, Marine Guilloïque, Francois Lucia, Gilles Quéré, Sylvie Gouva, Gilles Robinet, Renaud Descourt

Lorlatinib Salvages CNS Relapse in an ALK-Positive Non–Small-Cell Lung Cancer Patient Previously Treated With Crizotinib and High-Dose Brigatinib

To our knowledge, this is the first detailed case of an anaplastic lymphoma kinase (ALK)-positive patient with central nervous system (CNS) disease who experienced clinical benefit with lorlatinib after disease progression during treatment with high-dose brigatinib.
The efficacy of lorlatinib might reflect activity against an interval change in the biology of ALK-positive CNS disease occurring after initial brigatinib benefit that was not able to be suppressed by brigatinib. READ ARTICLE

Clinical Lung Cancer DOI:10.1016/j.cllc.2018.11.010

Authors: Mandy R. Sakamoto, Justin M. Honce, Deborah L. Lindquist, D. Ross Camidge

Case StudyKirk SmithMarch 1, 2019ALK, Brigatinib, CNS, Lorlatinib