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Successful intracranial response of lorlatinib after resistance with alectinib and brigatinib in patients with ALK-positive lung adenocarcinoma: Implications of CNS penetration rate of brigatinib.

ABSTRACT: We present the case of a 34-year-old Japanese man with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer and brain metastases. After central nervous system (CNS) disease progression with alecintib and brigatinib, treatment with lorlatinib resulted in a good intracranial response. In this case, we investigated brain penetration ratio of brigatinib using cerebrospinal fluid and paired serum samples, and the ratio was 0.012. Further, we investigated resistance mechanisms via next-generation sequencing (NGS) using lung biopsy at lung cancer diagnosis and brain biopsy sample at progressive disease of brigatinib. No apparent resistance mechanism of known ALK resistance, such as ALK mutations, amplifications, epithelial-mesenchymal transition (EMT) and bypass pathway activation were detected. Taken together, we speculate that the low CNS penetration rate of brigatinib confers CNS progression. Further studies are warranted to reveal the resistance mechanism and propose a treatment strategy for CNS progression in ALK-positive patients.

SUBMITTER: Sato Y

PROVIDER: S-EPMC11320077 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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Successful intracranial response of lorlatinib after resistance with alectinib and brigatinib in patients with ALK-positive lung adenocarcinoma: Implications of CNS penetration rate of brigatinib.

Sato Yuki Y Sato Yoshiharu Y Irie Kei K Nanjo Shigeki S Hara Shigeo S Fujiwara Satoru S Tomii Keisuke K

Thoracic cancer 20240624 23

We present the case of a 34-year-old Japanese man with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer and brain metastases. After central nervous system (CNS) disease progression with alecintib and brigatinib, treatment with lorlatinib resulted in a good intracranial response. In this case, we investigated brain penetration ratio of brigatinib using cerebrospinal fluid and paired serum samples, and the ratio was 0.012. Further, we investigated resistance mechanisms via next ...[more]

PMID: 38924375

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Project description:BackgroundCentral nervous system (CNS) metastases in patients with ALK-positive non-small cell lung cancer (NSCLC) are a cause of substantial morbidity and mortality. Although alectinib had demonstrated promising intracranial efficacy in several clinical trials, data were limited on its CNS activity in real-world settings.MethodsIn this retrospective study, ALK-positive NSCLC patients with brain metastases (BM) or leptomeningeal metastases (LM) from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib. ALK-TKI-naive patients were enrolled in cohort 1, cohort 2 included patients who experienced intracranial progression with or without extracranial progression after treatment with crizotinib, and cohort 3 included patients who developed progression only in CNS following treatment with other second-generation ALK-TKIs. The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1.ResultsSixty-five patients were eligible and included in our study (cohort 1: 20, cohort 2: 32, cohort 3: 13). For the overall population and patients with uncontrolled CNS metastases, similar intracranial response in CNS target lesions was observed: cohort 1: 81.8% and 80%; cohort 2: 76.5% and 86.7%; cohort 3: 42.8% and 33.3%. For patients in these three cohorts, 75% (6/8), 78.6% (11/14), and 83.3% (5/6) were reported to have significant improvement in CNS-related symptoms respectively. The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib (p < 0.001), and there was also a steep fall-over in the number of patients with ECOG ≥2 points before and after the administration of alectinib (p = 0.003). All patients (8/8) diagnosed with LM ± BM experienced substantial alleviation in CNS-related symptoms. In cohort 1 and cohort 2, no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone.ConclusionsOur study substantiated the potent CNS activity of alectinib in real-world settings. Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively, which indicated that alectinib alone might defer the timing of local treatment. However, our results should be treated cautiously owing to limited sample size.

Project description:Background and objectivesThis study aimed to compare the efficacy of the second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) alectinib and brigatinib in the treatment of advanced non-small-cell lung cancer (NSCLC) with ALK rearrangements based on real-world data.Design and methodsWe conducted a multicenter retrospective study using the Clinical Data Warehouse from seven university hospitals affiliated with the Catholic Medical Center. Patients diagnosed with ALK-positive advanced NSCLC and treated with alectinib or brigatinib were included. Key outcomes such as time to discontinuation (TTD), duration of response (DOR), overall survival (OS), and objective response rate (ORR) were analyzed.ResultsA total of 143 patients were included (107 treated with alectinib, 36 with brigatinib). Alectinib was more frequently used as a first-line treatment (71% vs 44.4% for brigatinib, p = 0.008). Prior crizotinib treatment was more frequent in the brigatinib group (52.8% vs 22.4% for alectinib, p < 0.001). The best ORR was similar between the groups (84.1% for alectinib vs 83.3% for brigatinib, p = 0.518). The median TTD was 57.8 months (95% confidence interval (CI): 29.0-86.7) for alectinib and 39.6 months (95% CI: 21.7-57.4) for brigatinib (p = 0.462). No significant differences were observed in intracranial TTD, intracranial DOR, or OS between the groups. Prior crizotinib treatment significantly shortened TTD for second-generation TKIs (p = 0.025), but the overall TKI treatment duration did not show a significant difference between patients who received frontline second-generation ALK TKIs and those who received second-generation ALK TKIs sequentially after crizotinib.ConclusionAlectinib and brigatinib demonstrated comparable efficacy in ALK-positive advanced NSCLC. Undergoing crizotinib followed by a second-generation TKI was not significantly different from initiating a second-generation TKI without prior crizotinib in terms of outcomes.

Dataset Information

Successful intracranial response of lorlatinib after resistance with alectinib and brigatinib in patients with ALK-positive lung adenocarcinoma: Implications of CNS penetration rate of brigatinib.

Publications

Successful intracranial response of lorlatinib after resistance with alectinib and brigatinib in patients with ALK-positive lung adenocarcinoma: Implications of CNS penetration rate of brigatinib.

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