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Incidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis.

ABSTRACT: Two anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (-TKIs) have been approved for the treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). Severe hepatotoxicity has been observed in several clinical studies. We aim to assess the incidence and risk of liver toxicity with these drugs by a systematic review and meta-analysis of clinical trials.The databases of PubMed, Web of Science and abstracts presented at oncology conferences' proceedings were searched for relevant studies from January 2000 to January 2017. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated by using either random effects or fixed effect models.A total of 1,908 patients from 10 clinical trials were included. The incidences of all-grade aspartate aminotransferase (AST) and alanine transaminase (ALT) elevation were 25.2% (95% CI 17.7-34.7%), and 26.0% (95% CI 17.8-36.3%), respectively. The incidences of high-grade (grade 3 and 4) AST and ALT elevation were 7.0% (95% CI: 5.4-9.0%), and 9.9% (95%CI: 5.6-16.7%), respectively. Sub-group analysis according to ALK-TKIs showed that the incidence of liver toxicities associated with ceritinib was higher than that of crizotinib and alectinib. In comparison with chemotherapy, ALK-TKIs significantly increased the risk of developing all-grade and high-grade AST elevation (RR, 2.30, 95%CI: 1.87-2.83, p < 0.001; RR 10.14, 95% CI: 3.9-26.39, p < 0.001) and ALT elevation (RR 2.37, 95%CI: 1.97-2.86, p < 0.001; RR 7.34, 95% CI: 3.95-13.63, p < 0.001), respectively.The use of ALK-TKIs significantly increases the risk of developing all-grade and high-grade liver toxicities in lung cancer patients.

SUBMITTER: Liu B

PROVIDER: S-EPMC5823621 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Incidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis.

Liu Bing B Yuan Maoxi M Sun Yi Y Cheng Ziming Z Zhang Zaiyong Z Hou Shizheng S Wang Xiangdong X Liu Jingfeng J

Oncotarget 20171216 10

<h4>Background</h4>Two anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (-TKIs) have been approved for the treatment of patients with ALK-rearranged (ALK-positive) advanced non-small cell lung cancer (NSCLC). Severe hepatotoxicity has been observed in several clinical studies. We aim to assess the incidence and risk of liver toxicity with these drugs by a systematic review and meta-analysis of clinical trials.<h4>Materials and methods</h4>The databases of PubMed, Web of Science and ab ...[more]

PMID: 29507704

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Project description:Lung cancer still represents the leading cause of cancer-related mortality. However, the recent advent of tyrosine kinase inhibitors (TKI), pioneering drugs against targetable mutations, have dramatically improved prognosis of advanced non-small cell lung cancer (NSCLC) patients. Anaplastic lymphoma kinase (ALK) gene rearrangements, identified in 3–7% of NSCLC cases, reflects in the constitutive activation of downstream signalling pathways, stimulating tumour cell proliferation, differentiation and survival. To accurately detect the wide spectrum of ALK rearrangements, the introduction of innovative techniques, like reverse transcriptase polymerase chain reaction (RT-PCR) or next generation sequencing (NGS) now allows for a more precise detection of variants and a more objective reading assessment, compared to the traditional diagnostic approaches. In some occasions, these new tools may dynamically monitor tumor evolution and even guide the choice of the most appropriate ALK inhibitor. In fact, among ALK TKIs available, crizotinib was the first to receive FDA accelerate approval for ALK rearranged NSCLC patients. Notwithstanding its response rate, ranging from 57% to 74%, the majority of patients progress within the first year of drug administration, due to acquired resistance. Both ALK-dependent and independent mechanisms of acquired resistance to TKIs have been identified. If the activation of multiple bypass signaling pathways constitutes the most common ALK-independent mechanism of resistance and one of the most difficult to overcome, ALK-dependent escape strategy mainly consists of mutations in the kinase domain, where the type of mutation largely depends on the TKI administered. Second and third generation TKIs are now available and are demonstrating high systemic and central nervous system (CNS) efficacy in clinical trials. Even though appropriate timing and sequencing of these compounds are still unclear, the large number of ALK inhibitors is now a precious resource aiming to prolong progression-free survival (PFS) and finally overall survival (OS). Here Authors provide an overview of the current approaches in the clinical management of advanced NSCLC patients harboring ALK rearrangement and discuss future perspectives to address current issues, highlighting the perception that ALK-rearranged advanced NSCLC patients benefit from maintained ALK inhibition for as long as possible.

Dataset Information

Incidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis.

Publications

Incidence and risk of hepatic toxicities associated with anaplastic lymphoma kinase inhibitors in the treatment of non-small-cell lung cancer: a systematic review and meta-analysis.

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