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Pharmgenomics Pers Med
2015 Sep 29;8:145-54. doi: 10.2147/PGPM.S71100.
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Personalized treatment options for ALK-positive metastatic non-small-cell lung cancer: potential role for Ceritinib.
El-Osta H
,
Shackelford R
.
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The fusion of echinoderm microtubule-associated protein-like 4 with the anaplastic lymphoma kinase (EML4-ALK) is found in 3%-7% of non-small-cell lung cancer (NSCLC) cases and confers sensitivity to crizotinib, the first United States Food and Drug Administration (FDA)-approved ALK inhibitor drug. Although crizotinib has an excellent initial therapeutic effect, acquired resistance to this drug invariably develops within the first year of treatment. Resistance may involve secondary gatekeeper mutations within the ALK gene interfering with crizotinib-ALK interactions, or compensatory activation of aberrant bypass signaling pathways. New therapeutic strategies to overcome crizotinib resistance are needed. Ceritinib, a second-generation ALK inhibitor, overcomes several crizotinib-resistant ALK mutations and has demonstrated efficacy against tumor growth in several in vitro and in vivo preclinical models of crizotinib resistance. Notably, the dose-escalation Phase I ASCEND-1 trial has shown a marked activity of ceritinib in both crizotinib-naïve and crizotinib-resistant ALK-rearranged lung cancer. The overall response rate was 58% in a subgroup of patients with ALK-rearranged late-stage NSCLC. Drug discontinuation rate due to toxicity was 10%. The standard dose was established at 750 mg daily. This paper outlines the pathogenesis and treatment of ALK-positive lung cancer, focuses on the preclinical and clinical results surrounding the accelerated FDA approval of ceritinib for the treatment of ALK-positive metastatic NSCLC patients who have progressed on/or are crizotinib intolerant, and discusses the potential efforts seeking to maximize ceritinib efficacy and expand its usage to other indications in cancer therapy.
Figure 1. Chemical structure of TAE684 (A) and LDK378 (B).Notes: This figure depicts the structural determinants of Ceritinib potency. The group isopropoxy at the aniline ring confers an improved kinase selectivity of Ceritinib, whereas the reversal of piperidine along with the methyl group para the isopropoxy are thought to minimize the possibility of reactive adducts formation.
Akbay,
Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
2013, Pubmed
Akbay,
Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors.
2013,
Pubmed
Ardizzoni,
Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis.
2007,
Pubmed
Azuma,
Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer.
2014,
Pubmed
Camidge,
Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed.
2011,
Pubmed
Choi,
EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors.
2010,
Pubmed
,
Echinobase
Choi,
Identification of novel isoforms of the EML4-ALK transforming gene in non-small cell lung cancer.
2008,
Pubmed
Cooper,
Ceritinib: a new tyrosine kinase inhibitor for non-small-cell lung cancer.
2015,
Pubmed
Crystal,
Patient-derived models of acquired resistance can identify effective drug combinations for cancer.
2014,
Pubmed
Delbaldo,
Benefits of adding a drug to a single-agent or a 2-agent chemotherapy regimen in advanced non-small-cell lung cancer: a meta-analysis.
2004,
Pubmed
Doebele,
Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer.
2012,
Pubmed
Friboulet,
The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer.
2014,
Pubmed
Galkin,
Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM-ALK.
2007,
Pubmed
Herbst,
Lung cancer.
2008,
Pubmed
Iacono,
Future options for ALK-positive non-small cell lung cancer.
2015,
Pubmed
Iwahara,
Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system.
1997,
Pubmed
Katayama,
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
2012,
Pubmed
Katayama,
Therapeutic targeting of anaplastic lymphoma kinase in lung cancer: a paradigm for precision cancer medicine.
2015,
Pubmed
Katayama,
Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib.
2014,
Pubmed
Khozin,
FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer.
2015,
Pubmed
Kwak,
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
2010,
Pubmed
Loong,
Crizotinib in the management of advanced-stage non-small-cell lung cancer.
2015,
Pubmed
Marsilje,
Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.
2013,
Pubmed
Massarelli,
Ceritinib for the treatment of late-stage (metastatic) non-small cell lung cancer.
2015,
Pubmed
NSCLC Meta-Analyses Collaborative Group,
Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials.
2008,
Pubmed
Ni,
Computationally unraveling how ceritinib overcomes drug-resistance mutations in ALK-rearranged lung cancer.
2015,
Pubmed
Nishio,
Phase I Study of Ceritinib (LDK378) in Japanese Patients with Advanced, Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer or Other Tumors.
2015,
Pubmed
Okamoto,
Echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase-targeted therapy for advanced non-small cell lung cancer: molecular and clinical aspects.
2012,
Pubmed
,
Echinobase
Sang,
Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer.
2013,
Pubmed
Sasaki,
The biology and treatment of EML4-ALK non-small cell lung cancer.
2010,
Pubmed
,
Echinobase
Sequist,
Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer.
2010,
Pubmed
Shackelford,
ALK-rearrangements and testing methods in non-small cell lung cancer: a review.
2014,
Pubmed
Shaw,
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
2013,
Pubmed
Shaw,
Ceritinib in ALK-rearranged non-small-cell lung cancer.
2014,
Pubmed
Shaw,
Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
2009,
Pubmed
Siegel,
Cancer statistics, 2015.
2015,
Pubmed
Socinski,
A multicenter phase II study of ganetespib monotherapy in patients with genotypically defined advanced non-small cell lung cancer.
2013,
Pubmed
Soda,
Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
2007,
Pubmed
,
Echinobase
Soda,
A mouse model for EML4-ALK-positive lung cancer.
2008,
Pubmed
Solomon,
First-line crizotinib versus chemotherapy in ALK-positive lung cancer.
2014,
Pubmed
Takeuchi,
KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer.
2009,
Pubmed
Vanneman,
Combining immunotherapy and targeted therapies in cancer treatment.
2012,
Pubmed