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Lung Cancer (Auckl)
2015 Sep 18;6:71-82. doi: 10.2147/LCTT.S63491.
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First-line treatment of advanced ALK-positive non-small-cell lung cancer.
Gandhi S
,
Chen H
,
Zhao Y
,
Dy GK
.
Abstract
Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer deaths, both within the US and worldwide. There have been major treatment advances in NSCLC over the past decade with the discovery of molecular drivers of NSCLC, which has ushered in an era of personalized medicine. There are several actionable genetic aberrations in NSCLC, such as epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). In 3%-7% of NSCLC, a chromosomal inversion event in chromosome 2 leads to fusion of a portion of the ALK gene with the echinoderm microtubule-associated protein-like 4 (EML4) gene. The constitutive activation of the ALK fusion oncogene renders it vulnerable to therapeutic intervention. This review focuses on the first-line treatment of advanced ALK-positive NSCLC using ALK inhibitors. Crizotinib was the first agent proven to be efficacious as first-line treatment for ALK-positive NSCLC. However, acquired resistance inevitably develops. The central nervous system is a sanctuary site that represents a common site for disease progression as well. Hence, more potent, selective next-generation ALK inhibitors that are able to cross the blood-brain barrier have been developed for treatment against crizotinib-resistant ALK-positive NSCLC and are also currently being evaluated for first-line therapy as well. In this review, we provide summary of the clinical experience with these drugs in the treatment of ALK-positive NSCLC.
Figure 1. A chromosomal inversion in chromosome 2 juxtaposes the 5â² end of the EML4 gene with the 3â² end of the ALK gene resulting in the fusion oncogene EML4-ALK.Notes: The resulting chimeric protein, EML4-ALK, contains an N-terminus derived from the EML4 and a C-terminus containing the intracellular tyrosine kinase domain of ALK.Abbreviations: EML4, echinoderm microtubuleâassociated protein-like 4; ALK, anaplastic lymphoma kinase.
Figure 2. EML4-ALK fusions are due to small inversions within chromosome 2p.Notes: These fusions lead to aberrant expression of ALK and constitutive activation of the ALK tyrosine kinase and further downstream signaling pathways. Hence, this results in uncontrolled proliferation and survival of cancer cells.Abbreviations: EML4, echinoderm microtubuleâassociated protein-like 4; ALK, anaplastic lymphoma kinase.
Barlesi,
Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01).
2011, Pubmed
Barlesi,
Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01).
2011,
Pubmed
Bauml,
Determinants of survival in advanced non--small-cell lung cancer in the era of targeted therapies.
2013,
Pubmed
Blackhall,
Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: results from the European Thoracic Oncology Platform Lungscape Project.
2014,
Pubmed
Camidge,
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
2012,
Pubmed
Camidge,
Treating ALK-positive lung cancer--early successes and future challenges.
2012,
Pubmed
Camidge,
Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed.
2011,
Pubmed
Chen,
Inhibition of ALK, PI3K/MEK, and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene.
2010,
Pubmed
Costa,
CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib.
2011,
Pubmed
Costa,
Clinical Experience With Crizotinib in Patients With Advanced ALK-Rearranged Non-Small-Cell Lung Cancer and Brain Metastases.
2015,
Pubmed
Crystal,
Patient-derived models of acquired resistance can identify effective drug combinations for cancer.
2014,
Pubmed
Doebele,
Oncogene status predicts patterns of metastatic spread in treatment-naive nonsmall cell lung cancer.
2012,
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
Gadgeel,
Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study.
2014,
Pubmed
Gainor,
Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib.
2015,
Pubmed
Gainor,
The central nervous system as a sanctuary site in ALK-positive non-small-cell lung cancer.
2013,
Pubmed
Gofton,
Identifying the palliative care needs of patients living with cerebral tumors and metastases: a retrospective analysis.
2012,
Pubmed
Gouji,
Crizotinib can overcome acquired resistance to CH5424802: is amplification of the MET gene a key factor?
2014,
Pubmed
Kaneda,
Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer.
2013,
Pubmed
Katayama,
Two novel ALK mutations mediate acquired resistance to the next-generation ALK inhibitor alectinib.
2014,
Pubmed
Katayama,
Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK.
2011,
Pubmed
,
Echinobase
Katayama,
Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
2012,
Pubmed
Kelleher,
The emerging pathogenic and therapeutic importance of the anaplastic lymphoma kinase gene.
2010,
Pubmed
Kodama,
Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance.
2014,
Pubmed
Kogita,
Activated MET acts as a salvage signal after treatment with alectinib, a selective ALK inhibitor, in ALK-positive non-small cell lung cancer.
2015,
Pubmed
Kumthekar,
Pharmacokinetics and efficacy of pemetrexed in patients with brain or leptomeningeal metastases.
2013,
Pubmed
Kwak,
Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.
2010,
Pubmed
Lee,
Testing for anaplastic lymphoma kinase rearrangement to target crizotinib therapy: oncology, pathology and health economic perspectives.
2013,
Pubmed
Lee,
Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer.
2011,
Pubmed
Lovly,
Insights into ALK-driven cancers revealed through development of novel ALK tyrosine kinase inhibitors.
2011,
Pubmed
Martelli,
EML4-ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues.
2009,
Pubmed
,
Echinobase
Metro,
Novel molecular trends in the management of advanced non-small-cell lung cancer.
2012,
Pubmed
Mino-Kenudson,
A novel, highly sensitive antibody allows for the routine detection of ALK-rearranged lung adenocarcinomas by standard immunohistochemistry.
2010,
Pubmed
Mologni,
NPM/ALK mutants resistant to ASP3026 display variable sensitivity to alternative ALK inhibitors but succumb to the novel compound PF-06463922.
2015,
Pubmed
Neckers,
Hsp90 inhibitors as novel cancer chemotherapeutic agents.
2002,
Pubmed
Ota,
Induction of PD-L1 Expression by the EML4-ALK Oncoprotein and Downstream Signaling Pathways in Non-Small Cell Lung Cancer.
2015,
Pubmed
Ou,
I1171 missense mutation (particularly I1171N) is a common resistance mutation in ALK-positive NSCLC patients who have progressive disease while on alectinib and is sensitive to ceritinib.
2015,
Pubmed
Peled,
Next-generation sequencing identifies and immunohistochemistry confirms a novel crizotinib-sensitive ALK rearrangement in a patient with metastatic non-small-cell lung cancer.
2012,
Pubmed
Reungwetwattana,
Targeted therapies in development for non-small cell lung cancer.
2013,
Pubmed
,
Echinobase
Sakamoto,
CH5424802, a selective ALK inhibitor capable of blocking the resistant gatekeeper mutant.
2011,
Pubmed
Sang,
Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer.
2013,
Pubmed
Sasaki,
A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors.
2011,
Pubmed
Scagliotti,
Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer.
2002,
Pubmed
Sequist,
Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer.
2010,
Pubmed
Seto,
CH5424802 (RO5424802) for patients with ALK-rearranged advanced non-small-cell lung cancer (AF-001JP study): a single-arm, open-label, phase 1-2 study.
2013,
Pubmed
Shaw,
Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.
2009,
Pubmed
Shaw,
Ceritinib in ALK-rearranged non-small-cell lung cancer.
2014,
Pubmed
Shaw,
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
2013,
Pubmed
Shaw,
Targeting anaplastic lymphoma kinase in lung cancer.
2011,
Pubmed
Shaw,
Pemetrexed-based chemotherapy in patients with advanced, ALK-positive non-small cell lung cancer.
2013,
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,
A prospective PCR-based screening for the EML4-ALK oncogene in non-small cell lung cancer.
2012,
Pubmed
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
Steuer,
ALK-positive non-small cell lung cancer: mechanisms of resistance and emerging treatment options.
2014,
Pubmed
,
Echinobase
Takahashi,
Clinicopathologic features of non-small-cell lung cancer with EML4-ALK fusion gene.
2010,
Pubmed
,
Echinobase
Teixidó,
Concordance of IHC, FISH and RT-PCR for EML4-ALK rearrangements.
2014,
Pubmed
,
Echinobase
Wallander,
Comparison of reverse transcription-polymerase chain reaction, immunohistochemistry, and fluorescence in situ hybridization methodologies for detection of echinoderm microtubule-associated proteinlike 4-anaplastic lymphoma kinase fusion-positive non-small cell lung carcinoma: implications for optimal clinical testing.
2012,
Pubmed
,
Echinobase
Weickhardt,
Diagnostic assays for identification of anaplastic lymphoma kinase-positive non-small cell lung cancer.
2013,
Pubmed
Weickhardt,
Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer.
2012,
Pubmed
Wu,
Comparison of IHC, FISH and RT-PCR methods for detection of ALK rearrangements in 312 non-small cell lung cancer patients in Taiwan.
2013,
Pubmed
,
Echinobase
Yamamoto,
ALK molecular phenotype in non-small cell lung cancer: CT radiogenomic characterization.
2014,
Pubmed
Yi,
Detection of anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer and related issues in ALK inhibitor therapy: a literature review.
2012,
Pubmed
