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Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer.

ABSTRACT: Anaplastic lymphoma kinase (ALK) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the ALK gene or the ROS1 oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update.A systematic literature search was performed in July 2017. Studies evaluating US FDA approved doses of one of the following ALK inhibitors: Crizotinib, Ceritinib, Alectinib or Brigatinib as monotherapy were included. Data were analyzed using random effects meta-analysis for absolute risks (AR), study heterogeneity, publication bias and differences among treatments.Fifteen trials with a total of 2,005 patients with evaluable toxicity data were included in this report. There was significant heterogeneity amongst different studies. The pooled AR of death and severe adverse events were 0.5% and 34.5%, respectively. Grade 3/4 nausea, vomiting, diarrhea, and constipation were uncommon: 2.6%, 2.5%, 2.7%, 1.2%, respectively.ALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Important differences in toxicity profile were detected amongst the different drugs.

SUBMITTER: Costa RB

PROVIDER: S-EPMC5955140 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Systematic review and meta-analysis of selected toxicities of approved <i>ALK</i> inhibitors in metastatic non-small cell lung cancer.

Costa Rubens Barros RB Costa Ricardo L B RLB Talamantes Sarah M SM Kaplan Jason B JB Bhave Manali A MA Rademaker Alfred A Miller Corinne C Carneiro Benedito A BA Mahalingam Devalingam D Chae Young Kwang YK

Oncotarget 20180424 31

<h4>Introduction</h4>Anaplastic lymphoma kinase (<i>ALK</i>) inhibitors are the mainstay treatment for patients with non-small cell lung carcinoma (NSCLC) harboring a rearrangement of the <i>ALK</i> gene or the <i>ROS1</i> oncogenes. With the recent publication of pivotal trials leading to the approval of these compounds in different indications, their toxicity profile warrants an update.<h4>Materials and methods</h4>A systematic literature search was performed in July 2017. Studies evaluating U ...[more]

PMID: 29774128

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Project description:BACKGROUND:We sought to assess the relative effects of individual anaplastic lymphoma kinase (ALK) inhibitors for the treatment of non-small cell lung cancer (NSCLC). METHODS:We searched MEDLINE, Embase, Cochrane CENTRAL, and grey literature (July 23, 2019) for randomized controlled trials (RCTs) that included participants with ALK- or ROS1-positive NSCLC who received any ALK inhibitor compared with placebo, another ALK inhibitor, or the same ALK inhibitor at a different dose. The primary outcome was treatment-related death. Secondary outcomes were overall survival (OS), progression-free survival (PFS), and serious adverse events. Data were pooled via meta-analysis and network meta-analysis, and risk of bias was assessed. PROSPERO: CRD42017077046. RESULTS:Thirteen RCTs reporting outcomes of interest among participants with ALK-positive NSCLC were identified. Treatment-related deaths were rare, with 10 deaths attributed to crizotinib (risk difference v. chemotherapy: 0.49, 95% credible interval [CrI] -0.16 to 1.46; odds ratio 2.58 (0.76-11.37). All ALK inhibitors improved PSF relative to chemotherapy (hazard ratio [95% CrI]: crizotinib 0.46 [0.39-0.54]; ceritinib 0.52 [0.42-0.64]; alectinib 300 BID 0.16 [0.08-0.33]; alectinib 600 BID 0.23 [0.17-0.30]; brigatinib 0.23 [0.15-0.35]), while alectinib and brigatinib improved PFS over crizotinib and ceritinib (alectinib v. crizotinib 0.34 [0.17-0.70]; alectinib v. ceritinib 0.30 [0.14-0.64]; brigatinib v. crizotinib 0.49 [0.33-0.73]; brigatinib v. ceritinib 0.43 [0.27-0.70]). OS was improved with alectinib compared with chemotherapy (HR 0.57 [95% CrI 0.39-0.83]) and crizotinib (0.68 [0.48-0.96]). Use of crizotinib (odds ratio 2.08 [95% CrI 1.56-2.79]) and alectinib (1.60 [1.00-2.58]) but not ceritinib (1.25 [0.90-1.74), increased the risk of serious adverse events compared with chemotherapy. Results were generally consistent among treatment-experienced or naïve participants. CONCLUSION(S):Treatment-related deaths were infrequent among ALK-positive NSCLC. PFS may be improved by alectinib and brigatinib relative to other ALK inhibitors; however, the assessment of OS is likely confounded by treatment crossover and should be interpreted with caution.

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Systematic review and meta-analysis of selected toxicities of approved ALK inhibitors in metastatic non-small cell lung cancer.

Publications

Systematic review and meta-analysis of selected toxicities of approved <i>ALK</i> inhibitors in metastatic non-small cell lung cancer.

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