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Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases.

ABSTRACT: Molecular profiling of metastatic nonsquamous non-small cell lung cancer (NSCLC) is required to guide the treatment strategy. Anaplastic lymphoma kinase ( ALK) gene rearrangements are found in approximately 5% of lung adenocarcinomas and are associated with specific clinical features including a high risk of brain metastases. Crizotinib was the first ALK inhibitor developed and it demonstrated improved outcomes in patients with ALK-positive advanced NSCLC in comparison with chemotherapy. However, despite an initial response, all ALK-positive NSCLC patients develop acquired resistance to crizotinib. Because the most frequent mechanism of resistance is the development of a secondary ALK mutation, second (ceritinib, alectinib, brigatinib) and third-generation (lorlatinib) ALK inhibitors were developed. Alectinib is a second-generation ALK inhibitor and was shown to be effective for a broad spectrum of ALK rearrangements and ALK mutations. It was also shown to have high intracranial efficacy. In this article, we review clinical trial evidence of alectinib efficacy as well as publications reporting the experience of alectinib in daily practice, with a focus on brain metastases.

SUBMITTER: Tomasini P

PROVIDER: S-EPMC6385324 | biostudies-literature | 2019 Jan-Dec

REPOSITORIES: biostudies-literature

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Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases.

Tomasini Pascale P Egea Julie J Souquet-Bressand Maxime M Greillier Laurent L Barlesi Fabrice F

Therapeutic advances in respiratory disease 20190101

Molecular profiling of metastatic nonsquamous non-small cell lung cancer (NSCLC) is required to guide the treatment strategy. Anaplastic lymphoma kinase ( ALK) gene rearrangements are found in approximately 5% of lung adenocarcinomas and are associated with specific clinical features including a high risk of brain metastases. Crizotinib was the first ALK inhibitor developed and it demonstrated improved outcomes in patients with ALK-positive advanced NSCLC in comparison with chemotherapy. However ...[more]

PMID: 30786826

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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.

Dataset Information

Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases.

Publications

Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases.

Similar Datasets

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