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Progression patterns, resistant mechanisms and subsequent therapy for ALK-positive NSCLC in the era of second-generation ALK-TKIs.
- Source :
-
Journal of translational medicine [J Transl Med] 2024 Jun 20; Vol. 22 (1), pp. 585. Date of Electronic Publication: 2024 Jun 20. - Publication Year :
- 2024
-
Abstract
- Background: In the era of second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), there was a paucity of data regarding the progression patterns, resistant mechanisms, and subsequent therapeutic approaches for ALK-positive (ALK <superscript>+</superscript> ) non-small cell lung cancer (NSCLC).<br />Methods: Patients with advanced ALK <superscript>+</superscript> NSCLC were retrospectively selected from our center. Cohort 1 consisted of patients who experienced disease progression after receiving first-line alectinib treatment (n = 20), while Cohort 2 included patients who progressed following sequential treatment with crizotinib and second-generation ALK-TKIs (n = 53). Oligo-progression was defined as the occurrence of disease progression in no more than three lesions. Symptomatic progression was determined when patients developed new symptoms or experienced worsening of pre-existing symptoms during radiological progression.<br />Results: The incidence of central nervous system (CNS) progression and symptomatic CNS progression was significantly lower in Cohort 1 compared to patients treated with crizotinib, with rates of 15.0% vs. 56.6% (p = 0.002) and 5.0% vs. 32.1% (p = 0.016), respectively. A total of 60.3% (44/73) patients underwent repeated biopsy and next-generation sequencing subsequent to the second-generation ALK-TKI resistance, with secondary mutation in ALK kinase domain emerging as the predominant mechanism of resistance (56.8%). Local therapy was applied to 50% of oligo-progression cases. Subsequent ALK-TKIs demonstrated significantly prolonged progression-free survival (PFS) (8.6 m vs. 2.7 m, p = 0.021, HR = 0.43, 95%CI: 0.15-0.85) and long-term overall survival (OS) (NA vs. 11.9 m, p = 0.132, HR = 0.50, 95%CI: 0.18-1.25) in patients harboring ALK resistance mutations, compared to those without such mutations. For patients without ALK-resistant mutations following progression on second-generation ALK-TKIs, there was no statistically significant difference in survival outcomes between subsequent chemotherapy or alternative ALK-TKI treatments.<br />Conclusions: First-line alectinib demonstrated superior efficacy in protecting the CNS compared to crizotinib. For patients with ALK-resistant mutations following the resistance to second-generation ALK-TKIs, appropriate sensitive ALK-TKI should be administered; for those without such mutations, the selection of chemotherapy or third-generation ALK-TKI should be based on the patient's overall physical health and personal preferences.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Male
Female
Middle Aged
Aged
Adult
Crizotinib therapeutic use
Crizotinib pharmacology
Retrospective Studies
Mutation genetics
Carcinoma, Non-Small-Cell Lung drug therapy
Carcinoma, Non-Small-Cell Lung pathology
Carcinoma, Non-Small-Cell Lung genetics
Anaplastic Lymphoma Kinase metabolism
Anaplastic Lymphoma Kinase genetics
Anaplastic Lymphoma Kinase antagonists & inhibitors
Protein Kinase Inhibitors therapeutic use
Protein Kinase Inhibitors pharmacology
Lung Neoplasms drug therapy
Lung Neoplasms pathology
Lung Neoplasms genetics
Drug Resistance, Neoplasm genetics
Drug Resistance, Neoplasm drug effects
Disease Progression
Subjects
Details
- Language :
- English
- ISSN :
- 1479-5876
- Volume :
- 22
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 38902768
- Full Text :
- https://doi.org/10.1186/s12967-024-05388-0