Plasma cfDNA analysis of alectinib resistance-related gene alterations in the J-ALEX study

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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.