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Efficacy and safety of ceritinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer: A systematic review and meta-analysis.

ABSTRACT: WHAT IS KNOWN AND OBJECTIVE:Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-resistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC. METHODS:We searched articles published from January 1980 to March 2019 in PubMed, EMBASE, Cochrane Library and Web of Science. The pooled estimate and 95% CI were calculated with DerSimonian-Laird method and the random effect model. RESULTS AND DISCUSSION:From 15 articles, 2,598 patients were included in the meta-analysis. Eleven studies reported the ORR, and the DCR was presented in 10 studies. The ORR and DCR of ceritinib were 0.48 (95% CI, 0.39-0.57) and 0.76 (95% CI, 0.69-0.82), respectively. The PFS and OS were presented in nine and three eligible studies, respectively. The PFS and OS of ceritinib were 7.26 months (95% CI, 5.10-9.43) and 18.73 months (95% CI; 14.59-22.87). These results suggested that ceritinib can effectively treat patients with ALK-rearranged NSCLC. Diarrhoea, nausea and vomiting were the three most common AEs and occurred in 69% (95% CI 51.7-87.1%), 66% (95% CI 47.0-85.8%) and 51% (95% CI 35.9-66.8%) of patients, respectively. Considering serious gastrointestinal AEs, antiemetic and antidiarrhoeal drugs should be considered to improve a patient's tolerance to ceritinib. WHAT IS NEW AND CONCLUSION:Ceritinib is effective in the treatment of patients with ALK-rearranged NSCLC with crizotinib resistance. The DCR was up to 76%, and PFS was extended to 7.6 months. The AEs were acceptable.

SUBMITTER: Tian W

PROVIDER: S-EPMC7384129 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Efficacy and safety of ceritinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer: A systematic review and meta-analysis.

Tian Wei W Zhang Ping P Yuan Yuan Y Deng Xiao-Hui XH Yue Rui R Ge Xiao-Zhu XZ

Journal of clinical pharmacy and therapeutics 20200505 4

<h4>What is known and objective</h4>Ceritinib is a new, oral, potent and selective second-generation anaplastic lymphoma kinase (ALK) inhibitor approved by the Food and Drug Administration of the United States in April 2014. It is active in crizotinib-resistant patients, especially in patients with non-small cell lung cancer (NSCLC) and brain metastasis. The aim of this study was to analyse the effects and side effects of ceritinib in ALK-rearranged NSCLC.<h4>Methods</h4>We searched articles pub ...[more]

PMID: 32369239

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Project description:BackgroundTargeted therapies have led to significant improvement in the management and prognosis of anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). We performed a network meta-analysis of frontline treatment options of ALK-positive NSCLC to provide clinical guidance.MethodsPubMed, Embase, ClinicalTrials.gov, and international conference databases were searched to identify relevant trials from inception to June 30, 2021. Phase III randomized controlled trials (RCTs) comparing treatments for patients with ALK-positive advanced NSCLC in the first-line setting were included in a Bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcomes: progression-free survival (PFS), overall survival (OS), risk of the central nervous system (CNS) progression, adverse events (AEs) of grade (G) 3 or higher (G3 AEs), or serious AEs (SAEs). Hazard ratios (HRs) and CI for primary outcome of PFS and secondary outcome of OS and risk of CNS progression were obtained. A multivariate, consistency model, fixed-effects analysis was used in the network meta-analysis. Data on G3 AEs and SAEs were abstracted and meta-analyzed. Risk of bias (RoB) was assessed using the Cochrane Collaboration's tool.ResultsNine RCTs comprising 2,484 patients were included with seven treatments: alectinib, brigatinib, ceritinib, crizotinib, ensartinib, lorlatinib, and chemotherapy. Compared with chemotherapy, ALK-tyrosine kinase inhibitors (TKIs) significantly prolong PFS and reduced risk of CNS progression except for ceritinib. Lorlatinib appears superior at reducing risk of CNS progression. None of the ALK-TKIs have a significantly prolonged OS as compared with chemotherapy. Lorlatinib increases the risk of G3 AEs as compared with alectinib (odds ratio 4.26 [95% CrI 1.22 to 15.53]), while alectinib caused the fewest G3 AEs.ConclusionsLorlatinib is associated with the highest PFS benefit and lowest risk of CNS progression benefits for patients with advanced ALK-positive NSCLC, compared with other first-line treatments, but with higher toxicity. The implementation of a newer generation of ALK-TKIs in the first-line treatment of ALK-positive NSCLC into current clinical practice is evolving rapidly.

Project description:Non-small-cell lung cancer (NSCLC) harboring the anaplastic lymphoma kinase gene (ALK) rearrangement is sensitive to the ALK inhibitor crizotinib, but resistance invariably develops. Ceritinib (LDK378) is a new ALK inhibitor that has shown greater antitumor potency than crizotinib in preclinical studies.In this phase 1 study, we administered oral ceritinib in doses of 50 to 750 mg once daily to patients with advanced cancers harboring genetic alterations in ALK. In an expansion phase of the study, patients received the maximum tolerated dose. Patients were assessed to determine the safety, pharmacokinetic properties, and antitumor activity of ceritinib. Tumor biopsies were performed before ceritinib treatment to identify resistance mutations in ALK in a group of patients with NSCLC who had had disease progression during treatment with crizotinib.A total of 59 patients were enrolled in the dose-escalation phase. The maximum tolerated dose of ceritinib was 750 mg once daily; dose-limiting toxic events included diarrhea, vomiting, dehydration, elevated aminotransferase levels, and hypophosphatemia. This phase was followed by an expansion phase, in which an additional 71 patients were treated, for a total of 130 patients overall. Among 114 patients with NSCLC who received at least 400 mg of ceritinib per day, the overall response rate was 58% (95% confidence interval [CI], 48 to 67). Among 80 patients who had received crizotinib previously, the response rate was 56% (95% CI, 45 to 67). Responses were observed in patients with various resistance mutations in ALK and in patients without detectable mutations. Among patients with NSCLC who received at least 400 mg of ceritinib per day, the median progression-free survival was 7.0 months (95% CI, 5.6 to 9.5).Ceritinib was highly active in patients with advanced, ALK-rearranged NSCLC, including those who had had disease progression during crizotinib treatment, regardless of the presence of resistance mutations in ALK. (Funded by Novartis Pharmaceuticals and others; ClinicalTrials.gov number, NCT01283516.).

Dataset Information

Efficacy and safety of ceritinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer: A systematic review and meta-analysis.

Publications

Efficacy and safety of ceritinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer: A systematic review and meta-analysis.

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