Prolonged Leptomeningeal Responses with Brigatinib in Two Heavily Pretreated ALK-Rearranged Non–Small Cell Lung Cancer Patients

Géraud, Arthur; Mezquita, Laura; Bigot, Frédéric; Caramella, Caroline; Planchard, David; Péchoux, C. Le; Besse, Benjamin

doi:10.1016/j.jtho.2018.05.033

Cited by 12 publications

(6 citation statements)

References 6 publications

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“…Recently, Geraud et al reported long LM response with brigatinib in two heavily pretreated patients with ALK-rearranged NSCLC, with progression-free survival times of more than 9 months and 7 months, respectively. 18 In our study, one patient responded to brigatinib for about 16 months and another responded to lorlatinib for about 4 months but relapsed in 1 month. Clinical trials investigating the effect of these drugs on LM are warranted.…”

Section: Discussionsupporting

confidence: 45%

Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC

Zheng

Jiang

et al. 2019

Journal of Thoracic Oncology

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Introduction: Leptomeningeal metastases (LMs) indicated a poor prognosis in NSCLC. LMs were more frequent in driver gene-mutated patients, and cerebrospinal fluid (CSF) cell-free DNA has shown unique genetic profiles of LM in EGFR-mutated LM. However, studies in patients with ALK receptor tyrosine kinase gene (ALK)-rearranged NSCLC with LMs are scarce. Methods: Patients with lung cancer with ALK rearrangement were screened from September 2011 to February 2018 at our institute. CSF and paired plasma were tested by next-generation sequencing. Results: LMs were diagnosed in 30 (10.3%) of 291 patients with ALK-rearranged lung cancer. A total of 11 paired CSF and plasma samples tested by next-generation sequencing were analyzed. Driver genes were detected in 81.8% of the CSF samples (9 of 11) and 45.5% of the plasma samples (5 of 11) (p ¼ 0.183). The maximum allelic fractions were all higher in CSF than in plasma (p ¼ 0.009). ALK and tumor protein p53 gene (TP53) were the two most frequently mutated genes in CSF. Gatekeeper gene ALK G1202R and C1156F mutations were identified in CSF after resistance to alectinib. Multiple copy number variants were mainly found in CSF, including in EGFR, cyclin D1 gene (CCND1), fibroblast growth factor 3 gene (FGF3), and fibroblast growth factor 4 gene (FGF4). Also found were v-myc avian myelocytomatosis viral oncogene homolog gene (MYC) copy number gains and TP53 and cyclin dependent kinase inhibitor 2A gene (CDKN2A) copy number deletions. Brigatinib seemed to be effective in controlling LM. One case showed that CSF could be used to monitor disease development of LM and longitudinally monitor tumor response. Conclusion: Liquid biopsy of CSF is more sensitive than liquid biopsy of plasma to detect targetable alterations, characterizing resistance mechanisms on progression and monitoring tumor response in patients with ALK-rearranged NSCLC with LM. Thus, CSF might be promising as a medium of liquid biopsy in LM.

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Section: Discussionsupporting

confidence: 45%

Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC

Zheng

Jiang

et al. 2019

Journal of Thoracic Oncology

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“…A single arm phase II study of brigatinib alone for patients with symptomatic or asymptomatic brain metastases in ALK -positive NSCLC is still ongoing (NCT04634110) ( 41 ). Furthermore, a case report addressed brigatinib efficacy in leptomeningeal response showing that two patients with ALK -positive NSCLC with leptomeningeal carcinomatosis who progressed during heavy pretreatment with crizotinib and ceritinib subsequently experienced prolonged benefit with brigatinib ( 42 ). Disclosure of these trial results might enlighten future use of brigatinib in treating patients with brain metastases.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis

Xing

Hao²,

Zhang³

et al. 2022

Front. Oncol.

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BackgroundBrigatinib is a central nervous system-active second-generation anaplastic lymphoma kinase (ALK) inhibitor that targets a broad range of ALK rearrangements in patients with non-small cell lung cancer (NSCLC). The current study aimed to analyze the pooled effects and adverse events of brigatinib in patients with ALK-positive NSCLC.MethodsThe pooled estimates and 95% confidence intervals (CI) were calculated with DerSimonian-Laird method and the random effect model.ResultsThe pooled objective response rate (ORR) and disease control rate (DCR) of brigatinib were 64% (95% CI 45%-83%) and 88% (95% CI 80%-96%), respectively. The pooled mPFS was 10.52 months (95% CI 7.66-13.37). In the subgroup analyses by treatment line, the highest mPFS was reached in first-line treatment (24.00 months, 95% CI 18.40-43.20), followed by post-crizotinib second-line treatment (mPFS=16.26 months, 95% CI 12.87-19.65), and second-line with any prior ALK tyrosine kinase inhibitors (mPFS=12.96 months, 95% CI 11.14-14.78). Among patients with any baseline brain metastases, the pooled intracranial ORR (iORR) was estimated as 54% (95% CI 35%-73%) for any treatment line, and 60% (95% CI 39%-81%) for first-line treatment. Intracranial PFS (iPFS) reached 19.26 months (95% CI 14.82-23.70) in patients with any baseline brain metastases. Creatine phosphokinase (CPK) increased (44%, 95% CI 26%-63%), diarrhea (37%, 95% CI 27%-48%), and nausea (28%, 95% CI 17%-39%) of any grade were the most common adverse events.ConclusionBrigatinib is effective in the treatment of patients with ALK-positive NSCLC, particularly showing robust intracranial PFS. Brigatinib used as first-line treatment yielded superior PFS compared with brigatinib used as other treatment lines. These results suggested a benefit of using brigatinib earlier in the patient’s management. All adverse events are manageable, with CPK increased and gastrointestinal reactions found to be the most common types.Systematic Review Registrationhttps://inplasy.com/inplasy-2022-3-0142/, identifier (INPLASY202230141).

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“…105 Switching from crizotinib or ceritinib to alectinib or brigatinib at the time of LMD also resulted in durable LMD responses. 106,107 Recently, a case of improved LMD efficacy in RET-rearranged NSCLC, on changing from pralsetinib to selpercatinib, has also been described. 108 LMD presentations may offer easier CNS molecular profiling than parenchymal CNS metastases.…”

Section: Lmdmentioning

confidence: 99%

Managing Central Nervous System Spread of Lung Cancer: The State of the Art

Tsui

Camidge

Rusthoven

2022

JCO

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Brain metastases (BrM) are common in both non–small-cell lung cancer and small-cell lung cancer. Substantial progress in BrM management has occurred in the past decade related to advances in both radiation and medical oncology. Recent and ongoing radiation trials have focused on increasing the candidacy for focal therapy of BrM with stereotactic radiosurgery; reducing the toxicity and improving patient selection for whole brain radiotherapy; and, in small-cell lung cancer, evaluating brain magnetic resonance imaging surveillance without prophylactic cranial irradiation, hippocampal avoidance in prophylactic cranial irradiation and whole brain radiotherapy, and the role of upfront stereotactic radiosurgery for BrM. In medical oncology, the development of multiple tyrosine kinase inhibitors with encouraging CNS activity and emerging data on the CNS activity of immune checkpoint inhibitors in some patients have opened the door to novel systemic and multidisciplinary treatment strategies for the management of BrM. Future research will focus on more robust characterizations of the CNS activity of targeted therapy and immunotherapies, as well as optimal integration and patient selection for multidisciplinary strategies involving CNS-active drugs, radiation therapy, and CNS surveillance.

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Prolonged Leptomeningeal Responses with Brigatinib in Two Heavily Pretreated ALK-Rearranged Non–Small Cell Lung Cancer Patients

Abstract: Crizotinib gives a 50% objective response rate in brain metastases, but CNS is the first site of progressive disease 3

Cited by 12 publications

References 6 publications

Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC

Clinical Utility of Cerebrospinal Fluid Cell-Free DNA as Liquid Biopsy for Leptomeningeal Metastases in ALK-Rearranged NSCLC

Efficacy and safety of brigatinib in ALK-positive non-small cell lung cancer treatment: A systematic review and meta-analysis

Managing Central Nervous System Spread of Lung Cancer: The State of the Art

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