Brigatinib: Novel ALK Inhibitor for Non–Small-Cell Lung Cancer

2019 ◽  
Vol 53 (6) ◽  
pp. 621-626 ◽  
Author(s):  
Sara A. Spencer ◽  
Angela C. Riley ◽  
Adia Matthew ◽  
Anthony J. Di Pasqua
Keyword(s):  
Lung Cancer ◽  
Adverse Effects ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
English Language ◽  
Small Cell ◽  
Small Cell Lung ◽  
Once Daily ◽  
Anaplastic Lymphoma ◽  
Accelerated Approval

Objective: We review here the pharmacology, pharmacokinetics, efficacy, safety, dosage and administration, potential drug-drug interactions and place in therapy of brigatinib for abnormal anaplastic lymphoma kinase (ALK) specific non–small-cell lung cancer (NSCLC). Data Sources: A literature search using PubMed was conducted using the terms brigatinib and ALK positive NSCLC from January 2013 to November 2018. Study Selection and Data Extraction: All English-language articles evaluating brigatinib were analyzed for this review. Data Synthesis: Brigatinib was granted approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. It is administered at a dose of 90 mg orally once daily for the first 7 days then, if tolerated, increased to a dose of 180 mg orally once daily. Common adverse effects include nausea, fatigue, diarrhea, increased creatine phosphokinase levels, headache, dyspnea, and hypertension. Serious treatment-emergent adverse effects were pulmonary related. Relevance to Patient Care and Clinical Practice: This article discusses the clinical trials that led to the accelerated approval of brigatinib for its ability to overcome crizotinib-resistant mutations and for its increased central nervous system penetration properties. Conclusion: Brigatinib was granted accelerated approval for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. In a subset of NSCLC patients, brigatinib increases survival for approximately 1 year; however, side effects were detected.

scholarly journals Crizotinib versus alectinib for treatment of ALK-positive non-small cell lung cancer: a pooled analysis of the ALEX, ALESIA and J-ALEX clinical trials

2020 ◽  
Author(s):  
Qinghua Zeng ◽  
Xiquan Zhang ◽  
Shan He ◽  
Zhiyong Zhou ◽  
Luping Xia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Adverse Effects ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Pooled Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Alk Positive

Abstract Background: Crizotinib and alectinib were the two most commonly used anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive non-small cell lung cancer (NSCLC). We compared their antitumor efficacies and adverse effects based on a pooled analysis of the ALEX, ALESIA and J-ALEX clinical trials.Methods: Seven databases were searched for eligible articles. The primary endpoints included overall survival (OS), progression-free survival (PFS), central nervous system (CNS)-PFS, drug responses and adverse effects (AEs).Results: Three randomized controlled clinical trials (ALEX, ALESIA and J-ALEX) with a total of 7 articles and 697 patients were included. Compared with crizotinib, alectinib exhibited superior efficacy in PFS (HR [hazard ratio]: 0.35, [0.25-0.49], p < 0.00001), OS (HR: 0.66, [0.47-0.92], p = 0.02), CNS-PFS (HR: 0.17, [0.11-0.24], p < 0.00001), duration of response (HR: 0.31, [0.23-0.42], p < 0.00001), objective response rate (ORR) (Risk ratio [RR]: 0.87, [0.80-0.94], p = 0.0003), partial response (PR) (RR: 0.88, [0.81-0.96], p = 0.004), and grade 3-5 AEs (RR: 1.43, [1.09-1.87], p = 0.009). Additionally, the survival advantages of alectinib compared with crizotinib increased with alectinib’s prolongation of survival time. The disease control rate, complete response and total AEs were comparable between the two groups. A greater increase in constipation, nausea, diarrhea, alanine aminotransferase, vomiting, aspartate aminotransferase, peripheral edema, dysgeusia, and visual impairment as well as a greater decrease in appetite and neutrophil count were associated with the crizotinib groupConclusions: In both antitumor efficacy and safety, alectinib appears to be superior to crizotinib for the treatment of ALK-positive NSCLC.

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

2018 ◽  
Vol 36 (26) ◽  
pp. 2693-2701 ◽  
Author(s):  
D. Ross Camidge ◽  
Dong-Wan Kim ◽  
Marcello Tiseo ◽  
Corey J. Langer ◽  
Myung-Ju Ahn ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Anaplastic Lymphoma Kinase ◽  
Small Cell ◽  
Small Cell Lung ◽  
Once Daily ◽  
Anaplastic Lymphoma ◽  
Alk Positive

Purpose In patients with crizotinib-treated, anaplastic lymphoma kinase gene ( ALK)-rearranged non–small-cell lung cancer (ALK-positive NSCLC), initial disease progression often occurs in the CNS. We evaluated brigatinib, a next-generation ALK inhibitor, in patients with ALK-positive NSCLC with brain metastases. Patients and Methods Patients with ALK-positive NSCLC received brigatinib (90 to 240 mg total daily) in a phase I/II trial (phI/II; ClinicalTrials.gov identifier: NCT01449461) and in the subsequent randomized phase II trial ALTA (ALK in Lung Cancer Trial of AP26113; ClinicalTrials.gov identifier: NCT02094573; patients in arm A received 90 mg once daily; patients in arm B received 180 mg once daily with 7-day lead-in at 90 mg). Primary end points (systemic objective response rates [ORRs]) were previously reported. Independent review committees assessed intracranial efficacy in patients with baseline brain metastases. Results Most patients with ALK-positive NSCLC had baseline brain metastases (50 of 79 [63%], phI/II; 80 of 112 [71%] and 73 of 110 [66%] in ALTA arms A and B, respectively), many of whom had no prior brain radiotherapy (23 of 50 [46%], phI/II; 32 of 80 [40%], ALTA arm A; 30 of 73 [41%], arm B). All patients, except four in phI/II, had received crizotinib. Among patients with measurable (≥ 10 mm) brain metastases, confirmed intracranial ORR was 53% (eight of 15; 95% CI, 27% to 79%) in phI/II, 46% (12 of 26; 95% CI, 27% to 67%) in ALTA arm A, and 67% (12 of 18; 95% CI, 41% to 87%) in arm B. Intracranial ORRs were similar in subsets without prior radiation or progression postradiation. Among patients with any baseline brain metastases, median intracranial progression-free survival (iPFS) was 14.6 months (95% CI, 12.7 to 36.8 months), phI/II; 15.6 months (95% CI, 9.0 to 18.3 months), ALTA arm A; 18.4 months (95% CI, 12.8 months to not reached), ALTA arm B. Conclusion Brigatinib yielded substantial intracranial responses and durable iPFS in ALK-positive, crizotinib-treated NSCLC, with highest iPFS in patients receiving 180 mg once daily (with lead-in).

scholarly journals Crizotinib versus Alectinib for the Treatment of ALK-Positive Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis

Chemotherapy ◽  
2021 ◽  
Author(s):  
Qinghua Zeng ◽  
Xiquan Zhang ◽  
Shan He ◽  
Zhiyong Zhou ◽  
Luping Xia ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Adverse Effects ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Alk Positive

Background: Crizotinib and alectinib are the two most commonly used anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive non-small cell lung cancer (NSCLC). We compared their antitumor efficacies and adverse effects based on a pooled analysis of the ALEX, ALESIA and J-ALEX clinical trials. Methods: Seven databases were searched for eligible articles. The primary endpoints included overall survival (OS), progression-free survival (PFS), central nervous system (CNS)-PFS, drug responses and adverse effects (AEs). Results: Seven articles on three randomized controlled clinical trials (ALEX, ALESIA and J-ALEX) that included 697 patients were included. Compared with crizotinib, alectinib exhibited superior efficacy in PFS (HR [hazard ratio]: 0.35, [0.25-0.49], p < 0.00001), OS (HR: 0.66, [0.47-0.92], p = 0.02), CNS-PFS (HR: 0.17, [0.11-0.24], p < 0.00001), duration of response (HR: 0.31, [0.23-0.42], p < 0.00001), objective response rate (ORR) (risk ratio [RR]: 0.87, [0.80-0.94], p = 0.0003), partial response (PR) (RR: 0.88, [0.81-0.96], p = 0.004), and grade 3-5 AEs (RR: 1.43, [1.09-1.87], p = 0.009). Additionally, compared with crizotinib, alectinib exhibited a survival advantage that increased with its prolongation of survival time. The disease control rate, complete response and total AEs were comparable between the two groups. The crizotinib group reported higher rates of constipation, nausea, diarrhea, vomiting, peripheral edema, dysgeusia, visual impairment and levels of alanine aminotransferase and aspartate aminotransferase as well as greater decreases in appetite and neutrophil count. Conclusions: In both antitumor efficacy and safety, alectinib appears to be superior to crizotinib for the treatment of ALK-positive NSCLC.

Landmark Studies of Targeted Therapies for Advanced Non-Small Cell Lung Cancer: A Guide for Pulmonologists

2020 ◽  
Vol 16 (1) ◽  
pp. 5-10
Author(s):  
Adrien Costantini ◽  
Theodoros Katsikas ◽  
Clementine Bostantzoglou
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Standard Of Care ◽  
Genetic Alterations ◽  
Small Cell ◽  
Extensive Literature ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Mutational Status

Over the past decade, major breakthroughs in the understanding of lung cancer histology and mutational pathways have radically changed diagnosis and management. More specifically, in non-small cell lung cancer (NSCLC), tumour characterisation has shifted from differentiating based solely on histology to characterisation that includes genetic profiling and mutational status of Epidermal Growth Factor (EGFR), Anaplastic Lymphoma Kinase (ALK), c-ros oncogene 1 (ROS1) and BRAF. These genetic alterations can be targeted by specific drugs that result in improved progression-free survival, as well as higher response rates and are currently standard of care for NSCLC patients harbouring these mutations. In this a narrative, non-systematic review we aim to handpick through the extensive literature and critically present the ground-breaking studies that lead to the institution of tailored treatment options as the standard of care for the main targetable genetic alterations.

scholarly journals Circulating tumor cell copy-number heterogeneity in ALK-rearranged non-small-cell lung cancer resistant to ALK inhibitors

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Marianne Oulhen ◽  
Patrycja Pawlikowska ◽  
Tala Tayoun ◽  
Marianna Garonzi ◽  
Genny Buson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Copy Number ◽  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Mesenchymal Transition ◽  
Anaplastic Lymphoma

AbstractGatekeeper mutations are identified in only 50% of the cases at resistance to Anaplastic Lymphoma Kinase (ALK)-tyrosine kinase inhibitors (TKIs). Circulating tumor cells (CTCs) are relevant tools to identify additional resistance mechanisms and can be sequenced at the single-cell level. Here, we provide in-depth investigation of copy number alteration (CNA) heterogeneity in phenotypically characterized CTCs at resistance to ALK-TKIs in ALK-positive non-small cell lung cancer. Single CTC isolation and phenotyping were performed by DEPArray or fluorescence-activated cell sorting following enrichment and immunofluorescence staining (ALK/cytokeratins/CD45/Hoechst). CNA heterogeneity was evaluated in six ALK-rearranged patients harboring ≥ 10 CTCs/20 mL blood at resistance to 1st and 3rd ALK-TKIs and one presented gatekeeper mutations. Out of 82 CTCs isolated by FACS, 30 (37%) were ALK+/cytokeratins-, 46 (56%) ALK-/cytokeratins+ and 4 (5%) ALK+/cytokeratins+. Sequencing of 43 CTCs showed highly altered CNA profiles and high levels of chromosomal instability (CIN). Half of CTCs displayed a ploidy >2n and 32% experienced whole-genome doubling. Hierarchical clustering showed significant intra-patient and wide inter-patient CTC diversity. Classification of 121 oncogenic drivers revealed the predominant activation of cell cycle and DNA repair pathways and of RTK/RAS and PI3K to a lower frequency. CTCs showed wide CNA heterogeneity and elevated CIN at resistance to ALK-TKIs. The emergence of epithelial ALK-negative CTCs may drive resistance through activation of bypass signaling pathways, while ALK-rearranged CTCs showed epithelial-to-mesenchymal transition characteristics potentially contributing to ALK-TKI resistance. Comprehensive analysis of CTCs could be of great help to clinicians for precision medicine and resistance to ALK-targeted therapies.

Complete response after ceritinib treatment in non-small cell lung cancer in an elderly patient

2020 ◽  
Vol 26 (8) ◽  
pp. 2031-2033
Author(s):  
Nilay Sengul Samanci ◽  
Emir Celik ◽  
Burak Akovalı ◽  
Sait Sager ◽  
Fuat Hulusi Demirelli
Keyword(s):  
Lung Cancer ◽  
Elderly Patient ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Complete Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Anaplastic Lymphoma ◽  
Stage 4 ◽  
Alk Positive

Introduction Ceritinib is a selective second-generation ALK inhibitor that is highly sensitive to echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) molecule. Case report In this paper, we report a 68-year-old female that was diagnosed with stage 4 ALK-positive non-small cell lung cancer (NSCLC). Management and outcome: She was treated with crizotinib first-line, cisplatin and gemcitabine as second-line. And for third-line, ceritinib was started. She had complete response over 3.5 years under ceritinib treatment. And she is still receiving ceritinib with no adverse event. Discussion Cases achieving complete response with ceritinib treatment are rare. In this paper, we aimed to emphasize the complete response in stage 4 NSCLC in an elderly patient.

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