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Alectinib for treating patients with metastatic ALK-positive NSCLC: systematic review and network metanalysis.

ABSTRACT:

Aim

To compare the efficacy and safety of alectinib with other ALK inhibitors in treating patients with metastatic or locally advanced ALK-positive NSCLC.

Methods

A systematic literature review was conducted up to November 2021. Network meta-analyses were performed using the frequentist method (random effects). GRADE evidence profile was conducted.

Results

13 RCTs were selected. For overall survival, alectinib was found to reduce the risk of death compared with crizotinib. In progression-free survival, alectinib reduced the risk of death or progression compared with crizotinib and ceritinib. Subgroup analysis by brain metastasis at baseline showed the superiority of alectinib over crizotinib and a similar effect compared with second-and third-generation inhibitors. Alectinib showed a good safety profile compared with the other ALK inhibitors.

SUBMITTER: Samaca-Samaca D

PROVIDER: S-EPMC10242442 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Publications

Alectinib for treating patients with metastatic <i>ALK</i>-positive NSCLC: systematic review and network metanalysis.

Samacá-Samacá Daniel D Prieto-Pinto Laura L Peréz Andrés Yepes AY Valderrama Carolina C Hernández Fabián F

Lung cancer management 20230523 2

<h4>Aim</h4>To compare the efficacy and safety of alectinib with other ALK inhibitors in treating patients with metastatic or locally advanced <i>ALK</i>-positive NSCLC.<h4>Methods</h4>A systematic literature review was conducted up to November 2021. Network meta-analyses were performed using the frequentist method (random effects). GRADE evidence profile was conducted.<h4>Results</h4>13 RCTs were selected. For overall survival, alectinib was found to reduce the risk of death compared with crizo ...[more]

PMID: 37287941

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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:BackgroundThe genotypic and histological evolution of non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) has been described as a mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs). However, it was extremely rare in anaplastic lymphoma kinase (ALK) positive NSCLC, and the follow-up care and outcomes of patients with this rare condition were unclear. This case was the first described the effectiveness of combined chemo-immunotherapy in a patient, with a transformed ALK positive NSCLC into SCLC after the administration of an ALK-TKIs.Case descriptionWe described a unique case in which a patient with ALK-positive NSCLC underwent SCLC transformation at a metastatic site and remained ALK positive after TKI treatment. In July 2019, a 77-year-old man was diagnosed with ALK-positive stage IVB NSCLC, received alectinib and responded to alectinib. It was not until more than 7 months later that a cranial MRI showed brain metastases. And whole-brain radiotherapy was administered, and secondary epilepsy and metastatic progression occurred. One year later, computed tomography showed a left submandibular mass with multiple lymph node metastases, a left lower lung mass, and right pleura thickening. A left submandibular biopsy revealed SCLC. Echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion and low tumor mutation burden (2.23 muts/Mb) were identified by next generation sequencing. The patient was administered atezolizumab (1,200 mg, d1) in combination with etoposide (0.13 g, d1-d3) and carboplatin (350 mg, d1). The left neck mass was reduced significantly, showing a partial response. Serum NSE (from 106 to 15 ng/mL), CA19-9 (from 49.4 to 34.6 U/mL) and CEA (from 4.18 to 3.09 ng/mL) returned to normal. Only mild myelosuppression (Grade 1), fatigue (Grade 1), and anorexia (Grade 1) were present. The patient had an overall survival time of 21 months.ConclusionsThis case highlighted the importance of re-biopsies to reveal pathological SCLC transformation after ALK-TKI resistance, and suggested the treatment of atezolizumab in combination with etoposide and carboplatin were potentially helpful for this phenotype.

Project description:Background: ALK inhibitors have shown positive advance in the treatment of ALK+ NSCLC. They have achieved better results in prolonging the progression free survival and improving quality of life in comparison to chemotherapy. We have assembled the evidence related to the efficacy and safety of these agents in the treatment of ALK positive NSCLC. Materials and Methods: A comprehensive search was conducted using electronic databases of PubMed, Medline and Cochrane Library to identify the studies involving comparison of ALK inhibitors to chemotherapy and Next generation ALK inhibitors to crizotinib. PFS was the primary outcome while other outcomes like ORR, adverse events, quality of life and OS were also analyzed and compared. Hazard ratios and odds ratios obtained were analyzed using fixed effect or random effects model in Review Manager Software. Results: A total of 12 studies (n = 3,297) met the criteria for inclusion in this review and meta-analysis. ALK inhibitors including crizotinib, ceritinib and alectinib revealed significantly better PFS (HR 0.42 [0.35, 0.50; p < 0.00001]), ORR (Overall OR 6.59 [4.86, 8.94; p < 0.00001] as compared to chemotherapy in the first line as well as second line treatment settings. Intracranial response rate was better with ALK inhibitors (ceritinib and alectinib) as compared to chemotherapy OR 6.51 [2.86, 14.83; p < 0.00001]. No significant increase in grade 3 or 4 adverse events was observed with crizotinib (OR 1.21 [0.82, 1.77; p = 0.34]) or ceritinib (OR 1.49 [0.86, 2.57; p = 0.17]) when compared to chemotherapy individually. Quality of life indicators assessed were significantly improved with ALK inhibitors. Next generation agents (ceritinib, alectinib and brigatinib) revealed significant improvement in PFS (HR 0.50 [0.43, 0.57; p < 0.00001]), ORR (OR 1.57 [1.21, 2.04; p = 0.0006]) in comparison to crizotinib. Next generation agents (Alectinib and brigatinib) yielded better response intra-cranially than crizotinib in terms of objective response rate (OR 5.87 [3.49, 9.87; p < 0.00001]) and time to CNS progression (HR 0.25 [0.13, 0.46; p < 0.0001]). Alectinib by far resulted in fewer adverse events than chemotherapy or crizotinib. Conclusions: Overall ALK inhibitors are safe and effective treatment option in ALK+ non-small cell lung cancer. Of the ALK inhibitors, Next generation agents in particular alectinib and brigatinib are safer and more effective intra-cranially and can be preferred as first option.