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Crizotinib in the treatment of non-small-cell lung carcinoma.

ABSTRACT: Recent studies have demonstrated the benefit of EGFR tyrosine kinase inhibitors in the treatment of advanced non-small-cell lung cancer (NSCLC). The role of activation of the anaplastic lymphoma kinase (ALK) pathway and the presence of the fusion gene EML4-ALK are new molecular targets in studies into the pathogenesis and treatment of NSCLC. ALK gene rearrangement is observed in 3-5% of NSCLC patients. Crizotinib is an oral inhibitor of ALK kinase activity, approved for the treatment of NSCLC patients with ALK gene rearrangement. Crizotinib treatment has resulted in a progression-free survival of 7-10 months with 50-60% objective response rate. The present paper gives an overview of literature reports on the role of crizotinib in the treatment of NSCLC patients harbouring a molecular defect in the ALK gene. Molecular diagnosis of ALK-associated aberrations, results of clinical trials of different phases assessing the efficacy and safety profile of crizotinib are also discussed. Attention is given to the likely causes of drug resistance and management strategies in patients with treatment failure.

SUBMITTER: Pluzanski A

PROVIDER: S-EPMC3687470 | biostudies-other | 2012

REPOSITORIES: biostudies-other

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Crizotinib in the treatment of non-small-cell lung carcinoma.

Płużański Adam A Piórek Aleksandra A Krzakowski Maciej M

Contemporary oncology (Poznan, Poland) 20120101 6

Recent studies have demonstrated the benefit of EGFR tyrosine kinase inhibitors in the treatment of advanced non-small-cell lung cancer (NSCLC). The role of activation of the anaplastic lymphoma kinase (ALK) pathway and the presence of the fusion gene EML4-ALK are new molecular targets in studies into the pathogenesis and treatment of NSCLC. ALK gene rearrangement is observed in 3-5% of NSCLC patients. Crizotinib is an oral inhibitor of ALK kinase activity, approved for the treatment of NSCLC pa ...[more]

PMID: 23788933

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Project description:Despite the advances in new targeted therapies in ALK positive population, most patients progress under ALK inhibitors within first 2 years; being the brain the most frequent site of relapse. ALK mutations, in ~30% of patients, are the main known mechanism of resistance. Classically, second-generation ALK inhibitors have been the standard of care in the crizotinib-resistant population; however, each ALK inhibitor has a different spectrum of sensitivity to ALK mutations, complicating the optimal treatment strategy for the resistant population. Brigatinib (AP26113) is a novel highly selective and potent inhibitor of ALK and ROS1 with a high degree of selectivity. In vitro, brigatinib not only inhibited ALK with 12-fold higher potency compared to crizotinib, but also inhibited IGF-1R, FLT3 and EGFR mutants, with some activity against the EGFRT790M resistance mutation. In xenograft models, brigatinib overcomes resistance to ALK inhibitors, including the ALK G1202R mutation, which is resistant to first- and second-generation inhibitors. The efficacy of brigatinib in crizotinib-resistant, ALK-positive patients has been demonstrated in two early studies, which led to its approval in this setting, and it is currently being investigated as the first-line therapy versus crizotinib in tyrosine kinase inhibitor-naïve patients. Brigatinib demonstrates not only promising whole-body activity, but also an impressive improvement of intracranial outcomes in terms of both objective response rate and progression-free survival in the crizotinib-resistant population, with optimal efficacy at 180 mg (following a 90 mg run-in for 7 days) and good tolerance. These data confirm brigatinib as an excellent therapeutic strategy after crizotinib failure, particularly in the setting of central nervous system involvement. In this review, we summarize the two main clinical studies reported to date with brigatinib in ALK-positive advanced NSCLC patients, in particular, in the crizotinib-resistant population. We also address the mechanism of action for development of resistance and the challenging issues of optimal implementation for sequences of administration for ALK inhibitors.

Dataset Information

Crizotinib in the treatment of non-small-cell lung carcinoma.

Publications

Crizotinib in the treatment of non-small-cell lung carcinoma.

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