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Plasma cfDNA analysis of alectinib resistance-related gene alterations in the J-ALEX study
H Sakaguchi1, R Katayama2, M Matsumoto3
1Department of Medical Oncology, Kanazawa University Hospital, Kanazawa, Japan.
Background:
Resistance to alectinib, the standard first-line therapy for anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), remains a major clinical challenge. This study aimed to investigate resistance mechanisms using next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA).
Materials And Methods:
Plasma samples from 67 patients in the alectinib group of the J-ALEX study were collected at baseline, on day 57, and at treatment discontinuation. cfDNA was extracted and analyzed using NGS to detect ALK secondary mutations (SMs) and other resistance-related genetic alterations. Progression-free survival (PFS) was compared between patients with and without detectable SMs.
Results:
Alectinib-resistant ALK SMs were detected in 9 of the 67 patients (13%), including resistance mutations, such as L1196M and G1202R. Patients with detected SMs had a significantly shorter PFS [15.2 months; 95% confidence interval (CI) 10.2-25.2 months] compared with those without detectable SMs [34.1 months; 95% CI 20.3-55.0 months; hazard ratio 2.28, 95% CI 1.01-5.16, P = 0.005]. Additional actionable mutations were identified, including MET amplification and KRAS G12D/NRAS G13S. KRAS and NRAS mutations, observed in two patients with a shorter PFS (2.9 and 4.4 months), suggested a potential link to primary resistance.
Conclusions:
Plasma cfDNA analysis using NGS is feasible and offers insights into alectinib resistance mechanisms. Early detection of resistance-associated mutations may guide personalized treatment strategies. Larger prospective studies are needed to validate these findings.
Insights
Detecting anaplastic lymphoma kinase (ALK) mutations in plasma cell-free DNA (cfDNA) can predict resistance to alectinib in non-small cell lung cancer (NSCLC). Early identification of these mutations may personalize treatment for better outcomes.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Alectinib is a standard first-line therapy for anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC).
- Resistance to alectinib poses a significant clinical challenge in managing ALK-rearranged NSCLC.
- Understanding resistance mechanisms is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate alectinib resistance mechanisms in ALK-rearranged NSCLC using next-generation sequencing (NGS) of plasma cell-free DNA (cfDNA).
- To identify specific ALK secondary mutations (SMs) and other genetic alterations associated with resistance.
- To evaluate the correlation between detectable SMs and progression-free survival (PFS).
Main Methods:
- Plasma samples were collected from 67 patients treated with alectinib in the J-ALEX study at multiple time points.
- Next-generation sequencing (NGS) was performed on extracted cfDNA to detect ALK SMs and other resistance-related mutations.
- Progression-free survival (PFS) was compared between patients with and without detectable SMs.
Main Results:
- Alectinib-resistant ALK SMs were identified in 13% of patients, including known resistance mutations like L1196M and G1202R.
- Patients with detectable SMs exhibited significantly shorter PFS (15.2 months) compared to those without (34.1 months).
- Additional actionable mutations such as MET amplification and KRAS/NRAS mutations were identified, with KRAS/NRAS potentially linked to primary resistance.
Conclusions:
- Plasma cfDNA analysis via NGS is a feasible method for identifying alectinib resistance mechanisms in NSCLC.
- Early detection of resistance-associated mutations can inform personalized treatment strategies.
- Further prospective studies are warranted to validate these findings and their clinical utility.
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