ALK on my mind: alectinib takes an early lead in managing intracranial disease in non-small cell lung cancer with ALK rearrangements.
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ABSTRACT:
SUBMITTER: Tran PN
PROVIDER: S-EPMC5401676 | biostudies-literature | 2017 Apr
REPOSITORIES: biostudies-literature
Publications
ALK on my mind: alectinib takes an early lead in managing intracranial disease in non-small cell lung cancer with ALK rearrangements.
Tran Phu N PN Klempner Samuel J SJ
Annals of translational medicine 20170401 7
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Project description:BackgroundAlectinib, a next-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK-TKI), has demonstrated noteworthy efficacy in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, 53.3% of untreated patients receiving first-line treatment with alectinib developed resistance to alectinib. However, despite the widespread use of alectinib, studies on the efficacy and safety of continuing alectinib with other necessary therapies after progression of alectinib and possible population of benefit are still limited.MethodsThis retrospective cohort study included fifteen patients with ALK-positive NSCLC from nine institutions in China who experienced disease progression after first- or second-line treatment and continued to receive alectinib treatment between 2019 and 2022. This study aimed to evaluate the median progression-free survival (mPFS), objective response rate (ORR), median overall survival (mOS), and adverse events (AEs) of continuing alectinib combined with other therapies after the emergence of drug resistance.ResultsAmong fifteen patients eligible for this study, all patients started continuing treatment with alectinib after oligoprogression or central nervous system (CNS) progression. The mPFS for the whole cohort receiving continuing alectinib with other necessary therapies was 8 months [95% confidence interval (CI): 4 to not applicable (NA)], with an ORR of 46.7%. The mOS was not reached. During continuing alectinib treatment, only one patient experienced grade 2 elevation of aspartate aminotransferase (AST) and serum glutamic-oxaloacetic transaminase (SGOT).ConclusionsThe continuation of alectinib treatment combined with other necessary therapies demonstrates favorable response and safety in patients with ALK-positive NSCLC who experienced oligoprogression or CNS progression following alectinib in first- or second-line therapy. Instead of immediately switching to another ALK-TKI, continuing alectinib combined with other necessary therapies may offer greater survival benefits to the patients.
| S-EPMC10891411 | biostudies-literature
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.
| S-EPMC11806492 | biostudies-literature
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.
| S-EPMC8764827 | biostudies-literature
Project description:Transcriptional profiling of NSCLC harboring EML4-ALK comparing parental H2228 cells with alectinib resistant H2228 cells.
2015-09-18 | GSE73167 | GEO
Project description:Transcriptional profiling of NSCLC harboring EML4-ALK comparing parental H2228 cells with alectinib resistant H2228 cells. Two-condition experiment, H2228 vs. H2228/CHR cells. Biological replicates: 1 parental replicates, 3 alectinib-resistant replicates.
2015-09-18 | E-GEOD-73167 | biostudies-arrayexpress
Project description: Not available
| S-EPMC6442948 | biostudies-literature
Project description:PurposeAlectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3-39.0) for alectinib 600 mg twice daily (BID). We investigated exposure-response relationships from final pooled phase II OS and safety data to assess alectinib dose selection.MethodsA semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (Ctrough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between Ctrough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3).ResultsOverall, 92% of patients (n = 207/225) had Ctrough,ss data and were included in the analysis. No statistically significant relationship was found between Ctrough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between Ctrough,ss and AEs.ConclusionAlectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.
| S-EPMC6010493 | biostudies-literature
Project description:PurposeThe performance of alectinib and crizotinib in untreated anaplastic lymphoma kinase (ALK)-positive patients with non-small-cell lung cancer (NSCLC) and symptomatic and synchronic brain metastases is largely unknown. This retrospective study assessed the effectiveness of alectinib and crizotinib, together with intracranial therapies in a cohort of these patients.Patients and methodsThis study included 34 previously untreated ALK-positive NSCLC patients with three or fewer intracranial metastases. Of these patients, 13 received oral alectinib 600 mg twice daily, and 21 received oral crizotinib 250 mg twice daily, until progressive disease, unacceptable toxicity, or death. All intracranial metastases were treated with craniotomy, CyberKnife, or both.ResultsMedian overall progression-free survival (PFS) was 32.8 months (95% CI 24.4-41.2 months) in patients treated with alectinib and 8.0 months (95% CI 7.3-8.7 months) in patients treated with crizotinib. Median PFS of brain lesions was not yet reached with alectinib (95% CI 30.1 months-not estimated) and was 8.5 months (95% CI 7.2-12.3 months) with crizotinib. Median PFS of lung lesions was 38.5 months (95% CI 27.5-49.5 months) with alectinib and 9.2 months (95% CI 7.4-11.0 months) with crizotinib. Median overall survival was not yet reached with alectinib (95% CI 31.0 months-not estimated) and 30.3 months (95% CI 27.3-37.1 months) with crizotinib.ConclusionCompared with crizotinib, alectinib showed superior efficacy and lower toxicity in the treatment of ALK-positive patients with NSCLC and symptomatic and synchronic brain metastases. The inclusion of intracranial therapies such as craniotomy or CyberKnife further improved the brain PFS and overall survival of these patients.
| S-EPMC8722687 | biostudies-literature
Project description: Not available
| S-EPMC6072953 | biostudies-literature
Project description: Not available
| S-EPMC10251428 | biostudies-literature