Management of Resistance to First-Line Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitor Therapy.

Details

Serval ID
serval:BIB_FAAC515CF4F1
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Management of Resistance to First-Line Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitor Therapy.
Journal
Current treatment options in oncology
Author(s)
Peters S., Zimmermann S.
ISSN
1534-6277 (Electronic)
ISSN-L
1534-6277
Publication state
Published
Issued date
28/05/2018
Peer-reviewed
Oui
Volume
19
Number
7
Pages
37
Language
english
Notes
Publication types: Journal Article ; Review
Publication Status: epublish
Abstract
A decade after the discovery of echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (EML4-ALK) rearrangements in non-small cell lung cancer (NSCLC), several inhibitors have gained regulatory approval, and their sequential use has deferred platinum-based chemotherapy to later lines of therapy. Nevertheless, although most ALK-driven tumors dramatically respond to ALK TKIs , all patients ultimately develop drug-resistant disease. Analysis of post-progression biopsy samples has provided invaluable insight into the mechanisms of resistance, now informing on subsequent therapeutic strategies. In particular, the identification of secondary ALK mutations, which are a common mechanism of resistance to both first-generation and to an even larger extent to second-generation ALK TKIs, may shape a personalized optimal treatment strategy beyond the current first-line choice. Alectinib has now become a preferred treatment option in the first line of therapy, and extrapolation of data obtained from post-progression samples after second-line next-generation ALK TKIs suggests that acquired resistance is likely to be mediated in more than half of patients by ALK resistance mutations. Nevertheless, clinical and preclinical evidence suggests that multiple resistance mechanisms may co-exist at different levels in the same TKI-resistant patient. Newer ALK tyrosine kinase inhibitors (TKIs) overcome some resistance mutations through higher exposure and potency, and generally present greater CNS activity, but are unlikely to overcome resistance mediated through separate oncogenic pathway activations, or epithelial to mesenchymal transition (EMT) and small cell lung cancer (SCLC) transformation. Furthermore, while resistance mutations can be detected through commonly available sequencing methods, the identification of other mechanisms of resistance is much less straightforward in the clinic. We hypothesize that the ALK resistance mutation status will likely be crucially important in the choice of second-line therapy after a second-generation TKI. Emerging clinical data also refines the optimal placing of PD-1- and PD-L1-directed immunotherapy in the treatment sequence.
Keywords
ALK, Advanced non-small cell lung cancer, Alectinib, Resistance to crizotinib
Pubmed
Web of science
Create date
13/06/2018 8:09
Last modification date
21/08/2019 6:37
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