Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: Clinical impact of alectinib

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Abstract

A subset of non-small cell lung cancer (NSCLC) tumors (5%) harbors an anaplastic lymphoma kinase (ALK) translocation that drives tumorigenesis. The clinically approved first-line treatment crizotinib specifically inhibits ALK and improves progression-free survival (PFS) in treated and untreated patients by 4 months compared to standard chemotherapy. While some patients relapse after crizotinib treatment due to resistance mutations in ALK, second-generation ALK inhibitors effectively induce tumor response and prolong PFS. Alectinib, a second-generation ALK inhibitor, has recently been approved for ALK-rearranged NSCLC after patients progressed on crizotinib. Alectinib is able to inhibit several crizotinib- and ceritinib-resistant ALK mutations in vitro. Furthermore, alectinib is a more potent tyrosine kinase inhibitor (TKI), with favorable safety profile, and has increased penetration into the central nervous system, inhibiting crizotinib-resistant brain metastases. The discovery of effective personalized therapies to combat ALK-rearranged NSCLC such as alectinib is an example of the importance of genomic profiling of NSCLC and provides an excellent template for future discoveries in managing these tumors.

Original languageEnglish
Pages (from-to)4535-4541
Number of pages7
JournalOncoTargets and Therapy
Volume10
DOIs
Publication statusPublished - 13 Sep 2017

Cite this

@article{0061c7ad771848a6bb9b0c0de08005be,
title = "Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer: Clinical impact of alectinib",
abstract = "A subset of non-small cell lung cancer (NSCLC) tumors (5{\%}) harbors an anaplastic lymphoma kinase (ALK) translocation that drives tumorigenesis. The clinically approved first-line treatment crizotinib specifically inhibits ALK and improves progression-free survival (PFS) in treated and untreated patients by 4 months compared to standard chemotherapy. While some patients relapse after crizotinib treatment due to resistance mutations in ALK, second-generation ALK inhibitors effectively induce tumor response and prolong PFS. Alectinib, a second-generation ALK inhibitor, has recently been approved for ALK-rearranged NSCLC after patients progressed on crizotinib. Alectinib is able to inhibit several crizotinib- and ceritinib-resistant ALK mutations in vitro. Furthermore, alectinib is a more potent tyrosine kinase inhibitor (TKI), with favorable safety profile, and has increased penetration into the central nervous system, inhibiting crizotinib-resistant brain metastases. The discovery of effective personalized therapies to combat ALK-rearranged NSCLC such as alectinib is an example of the importance of genomic profiling of NSCLC and provides an excellent template for future discoveries in managing these tumors.",
keywords = "Acquired resistance, Alectinib, Anaplastic lymphoma kinase, Crizotinib, Non-small cell lung cancer, Tyrosine kinase inhibitors",
author = "Muller, {Ittai B.} and {De Langen}, {Adrianus J.} and Elisa Giovannetti and Peters, {Godefridus J.}",
year = "2017",
month = "9",
day = "13",
doi = "10.2147/OTT.S109493",
language = "English",
volume = "10",
pages = "4535--4541",
journal = "OncoTargets and Therapy",
issn = "1178-6930",
publisher = "Dove Medical Press Ltd.",

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TY - JOUR

T1 - Anaplastic lymphoma kinase inhibition in metastatic non-small cell lung cancer

T2 - Clinical impact of alectinib

AU - Muller, Ittai B.

AU - De Langen, Adrianus J.

AU - Giovannetti, Elisa

AU - Peters, Godefridus J.

PY - 2017/9/13

Y1 - 2017/9/13

N2 - A subset of non-small cell lung cancer (NSCLC) tumors (5%) harbors an anaplastic lymphoma kinase (ALK) translocation that drives tumorigenesis. The clinically approved first-line treatment crizotinib specifically inhibits ALK and improves progression-free survival (PFS) in treated and untreated patients by 4 months compared to standard chemotherapy. While some patients relapse after crizotinib treatment due to resistance mutations in ALK, second-generation ALK inhibitors effectively induce tumor response and prolong PFS. Alectinib, a second-generation ALK inhibitor, has recently been approved for ALK-rearranged NSCLC after patients progressed on crizotinib. Alectinib is able to inhibit several crizotinib- and ceritinib-resistant ALK mutations in vitro. Furthermore, alectinib is a more potent tyrosine kinase inhibitor (TKI), with favorable safety profile, and has increased penetration into the central nervous system, inhibiting crizotinib-resistant brain metastases. The discovery of effective personalized therapies to combat ALK-rearranged NSCLC such as alectinib is an example of the importance of genomic profiling of NSCLC and provides an excellent template for future discoveries in managing these tumors.

AB - A subset of non-small cell lung cancer (NSCLC) tumors (5%) harbors an anaplastic lymphoma kinase (ALK) translocation that drives tumorigenesis. The clinically approved first-line treatment crizotinib specifically inhibits ALK and improves progression-free survival (PFS) in treated and untreated patients by 4 months compared to standard chemotherapy. While some patients relapse after crizotinib treatment due to resistance mutations in ALK, second-generation ALK inhibitors effectively induce tumor response and prolong PFS. Alectinib, a second-generation ALK inhibitor, has recently been approved for ALK-rearranged NSCLC after patients progressed on crizotinib. Alectinib is able to inhibit several crizotinib- and ceritinib-resistant ALK mutations in vitro. Furthermore, alectinib is a more potent tyrosine kinase inhibitor (TKI), with favorable safety profile, and has increased penetration into the central nervous system, inhibiting crizotinib-resistant brain metastases. The discovery of effective personalized therapies to combat ALK-rearranged NSCLC such as alectinib is an example of the importance of genomic profiling of NSCLC and provides an excellent template for future discoveries in managing these tumors.

KW - Acquired resistance

KW - Alectinib

KW - Anaplastic lymphoma kinase

KW - Crizotinib

KW - Non-small cell lung cancer

KW - Tyrosine kinase inhibitors

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U2 - 10.2147/OTT.S109493

DO - 10.2147/OTT.S109493

M3 - Review article

VL - 10

SP - 4535

EP - 4541

JO - OncoTargets and Therapy

JF - OncoTargets and Therapy

SN - 1178-6930

ER -