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Ref Type Journal Article
PMID (40912045)
Authors Sakaguchi H, Katayama R, Matsumoto M, Nishiyama A, Matsumoto K, Tajima A, Miyagi S, Toyama T, Mizuta H, Furugaki K, Yoshiura S, Takeuchi S
Title Plasma cfDNA analysis of alectinib resistance-related gene alterations in the J-ALEX study.
Journal Vol Issue Date Pages Journal Short Title
ESMO open 10 9 2025 Sep 04 105574 ESMO Open
URL
Abstract Text 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).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.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.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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK rearrange MAP2K1 E203K lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a retrospective analysis of a Phase III trial (J-ALEX), MAP2K1 E203K was identified in the post-progression cell-free DNA of a patient with non-small cell lung cancer with ALK rearrangement who progressed on treatment with Alecensa (alectinib) (PMID: 40912045). 40912045
ALK rearrange BRAF V600E lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a retrospective analysis of a Phase III trial (J-ALEX), BRAF V600E was identified in the post-progression cell-free DNA of a patient with non-small lung cancer with ALK rearrangement who progressed on treatment with Alecensa (alectinib) (PMID: 40912045). 40912045
ALK rearrange NRAS G13S lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a retrospective analysis of a Phase III trial (J-ALEX), Alecensa (alectinib) treatment demonstrated limited activity with a progression-free survival of 4.4 mo in a patient with non-small cell lung cancer harboring ALK rearrangement and NRAS G13S (PMID: 40912045). 40912045
ALK rearrange PIK3CA E545K lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a retrospective analysis of a Phase III trial (J-ALEX), PIK3CA E545K was identified in the post-progression cell-free DNA of 2 patients with non-small cell lung cancer with ALK rearrangement who progressed on treatment with Alecensa (alectinib) (PMID: 40912045). 40912045
ALK rearrange ALK G1202R ALK R1275L lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a retrospective analysis of a Phase III trial (J-ALEX), ALK G1202R and ALK R1275L were identified in the post-progression cell-free DNA of a patient with non-small cell lung cancer with ALK rearrangement who progressed on treatment with Alecensa (alectinib) (PMID: 40912045). 40912045
ALK rearrange ALK L1196M lung non-small cell carcinoma predicted - resistant Alectinib Case Reports/Case Series Actionable In a retrospective analysis of a Phase III trial (J-ALEX), ALK L1196M was identified in the post-progression cell-free DNA of 2 of 67 patients with non-small cell lung cancer with ALK rearrangement who progressed on treatment with Alecensa (alectinib) (PMID: 40912045). 40912045