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Ref Type Journal Article
PMID (31358542)
Authors Dagogo-Jack I, Rooney M, Lin JJ, Nagy RJ, Yeap BY, Hubbeling H, Chin E, Ackil J, Farago AF, Hata AN, Lennerz JK, Gainor JF, Lanman RB, Shaw AT
Title Treatment with Next-Generation ALK Inhibitors Fuels Plasma ALK Mutation Diversity.
Journal Vol Issue Date Pages Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research 25 22 2019 Nov 15 6662-6670 Clin Cancer Res
URL
Abstract Text Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary ALK mutations. Here, we investigated utility of plasma genotyping for identifying ALK resistance mutations at relapse on next-generation ALK TKIs.We analyzed 106 plasma specimens from 84 patients with advanced ALK-positive lung cancer treated with second- and third-generation ALK TKIs using a commercially available next-generation sequencing (NGS) platform (Guardant360). Tumor biopsies from TKI-resistant lesions underwent targeted NGS to identify ALK mutations.By genotyping plasma, we detected an ALK mutation in 46 (66%) of 70 patients relapsing on a second-generation ALK TKI. When post-alectinib plasma and tumor specimens were compared, there was no difference in frequency of ALK mutations (67% vs. 63%), but plasma specimens were more likely to harbor ≥2 ALK mutations (24% vs. 2%, P = 0.004). Among 29 patients relapsing on lorlatinib, plasma genotyping detected an ALK mutation in 22 (76%), including 14 (48%) with ≥2 ALK mutations. The most frequent combinations of ALK mutations were G1202R/L1196M and D1203N/1171N. Detection of ≥2 ALK mutations was significantly more common in patients relapsing on lorlatinib compared with second-generation ALK TKIs (48% vs. 23%, P = 0.017). Among 15 patients who received lorlatinib after a second-generation TKI, serial plasma analysis demonstrated that eight (53%) acquired ≥1 new ALK mutations on lorlatinib.ALK resistance mutations increase with each successive generation of ALK TKI and may be underestimated by tumor genotyping. Sequential treatment with increasingly potent ALK TKIs may promote acquisition of ALK resistance mutations leading to treatment-refractory compound ALK mutations.

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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 ALK G1202R lung non-small cell carcinoma predicted - resistant Ceritinib Clinical Study - Cohort Actionable In a retrospective study, ALK G1202R was identified in 33% (23/70) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received second-generation ALK TKI treatment, including Alecensa (alectinib) (n=46), Zykadia (ceritinib) (n=4), Alunbrig (brigatinib) (n=3), Ensartinib (X-396) (n=1), or more than 2 lines of TKIs (n=16) (PMID: 31358542). 31358542
ALK rearrange ALK I1171X lung non-small cell carcinoma predicted - resistant Brigatinib Clinical Study - Cohort Actionable In a retrospective study, ALK I1171X was identified in 24% (17/70) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received second-generation ALK TKI treatment, including Alecensa (alectinib) (n=46), Zykadia (ceritinib) (n=4), Alunbrig (brigatinib) (n=3), Ensartinib (X-396) (n=1), or more than 2 lines of TKIs (n=16) (PMID: 31358542). 31358542
ALK rearrange ALK V1180L lung non-small cell carcinoma predicted - resistant Alectinib Clinical Study - Cohort Actionable In a retrospective study, ALK V1180L was identified in 11% (5/46) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received Alecensa (alectinib) treatment (PMID: 31358542). 31358542
ALK rearrange ALK G1202R lung non-small cell carcinoma predicted - resistant Brigatinib Clinical Study - Cohort Actionable In a retrospective study, ALK G1202R was identified in 33% (23/70) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received second-generation ALK TKI treatment, including Alecensa (alectinib) (n=46), Zykadia (ceritinib) (n=4), Alunbrig (brigatinib) (n=3), Ensartinib (X-396) (n=1), or more than 2 lines of TKIs (n=16) (PMID: 31358542). 31358542
ALK rearrange ALK F1174L lung non-small cell carcinoma predicted - resistant Lorlatinib Clinical Study - Cohort Actionable In a retrospective study, ALK F1174C/L was identified in 14% (4/29) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received Lorbrena (lorlatinib) treatment (PMID: 31358542). 31358542
ALK rearrange ALK L1196M lung non-small cell carcinoma predicted - resistant Alectinib Clinical Study - Cohort Actionable In a retrospective study, ALK L1196M was identified in 22% (10/46) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received Alecensa (alectinib) treatment (PMID: 31358542). 31358542
ALK rearrange ALK I1171X lung non-small cell carcinoma predicted - resistant Alectinib Clinical Study - Cohort Actionable In a retrospective study, ALK I1171X was identified in 26% (12/46) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received Alecensa (alectinib) treatment (PMID: 31358542). 31358542
ALK rearrange ALK D1203N lung non-small cell carcinoma predicted - resistant Lorlatinib Clinical Study - Cohort Actionable In a retrospective study, ALK D1203N was identified in 24% (7/29) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received Lorbrena (lorlatinib) treatment (PMID: 31358542). 31358542
ALK rearrange ALK L1196M lung non-small cell carcinoma predicted - resistant Ensartinib Clinical Study - Cohort Actionable In a retrospective study, ALK L1196M was identified in 17% (12/70) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received second-generation ALK TKI treatment, including Alecensa (alectinib) (n=46), Zykadia (ceritinib) (n=4), Alunbrig (brigatinib) (n=3), Ensartinib (X-396) (n=1), or more than 2 lines of TKIs (n=16) (PMID: 31358542). 31358542
ALK rearrange ALK G1202R lung non-small cell carcinoma predicted - resistant Alectinib Clinical Study - Cohort Actionable In a retrospective study, ALK G1202R was identified in 37% (17/46) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received Alecensa (alectinib) treatment (PMID: 31358542). 31358542
ALK rearrange ALK L1196M lung non-small cell carcinoma predicted - resistant Brigatinib Clinical Study - Cohort Actionable In a retrospective study, ALK L1196M was identified in 17% (12/70) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received second-generation ALK TKI treatment, including Alecensa (alectinib) (n=46), Zykadia (ceritinib) (n=4), Alunbrig (brigatinib) (n=3), Ensartinib (X-396) (n=1), or more than 2 lines of TKIs (n=16) (PMID: 31358542). 31358542
ALK rearrange ALK I1171X lung non-small cell carcinoma predicted - resistant Ensartinib Clinical Study - Cohort Actionable In a retrospective study, ALK I1171X was identified in 24% (17/70) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received second-generation ALK TKI treatment, including Alecensa (alectinib) (n=46), Zykadia (ceritinib) (n=4), Alunbrig (brigatinib) (n=3), Ensartinib (X-396) (n=1), or more than 2 lines of TKIs (n=16) (PMID: 31358542). 31358542
ALK rearrange ALK G1202R lung non-small cell carcinoma predicted - resistant Ensartinib Clinical Study - Cohort Actionable In a retrospective study, ALK G1202R was identified in 33% (23/70) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received second-generation ALK TKI treatment, including Alecensa (alectinib) (n=46), Zykadia (ceritinib) (n=4), Alunbrig (brigatinib) (n=3), Ensartinib (X-396) (n=1), or more than 2 lines of TKIs (n=16) (PMID: 31358542). 31358542
ALK rearrange ALK F1174C lung non-small cell carcinoma predicted - resistant Lorlatinib Clinical Study - Cohort Actionable In a retrospective study, ALK F1174C/L was identified in 14% (4/29) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received Lorbrena (lorlatinib) treatment (PMID: 31358542). 31358542
ALK rearrange ALK L1196M lung non-small cell carcinoma predicted - resistant Ceritinib Clinical Study - Cohort Actionable In a retrospective study, ALK L1196M was identified in 17% (12/70) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received second-generation ALK TKI treatment, including Alecensa (alectinib) (n=46), Zykadia (ceritinib) (n=4), Alunbrig (brigatinib) (n=3), Ensartinib (X-396) (n=1), or more than 2 lines of TKIs (n=16) (PMID: 31358542). 31358542
EML4 - ALK ALK C1156Y ALK L1196M ALK G1202R lung non-small cell carcinoma predicted - resistant Lorlatinib Case Reports/Case Series Actionable In a clinical case study, a non-small cell lung cancer patient with EML4-ALK, ALK G1202R, ALK L1196M, and ALK V1180L prior to Lorbrena (lorlatinib) treatment demonstrated loss of the V1180L variant and acquisition of ALK C1156Y following progression on Lorbrena (lorlatinib) (PMID: 31358542). 31358542
ALK rearrange ALK I1171X lung non-small cell carcinoma predicted - resistant Ceritinib Clinical Study - Cohort Actionable In a retrospective study, ALK I1171X was identified in 24% (17/70) of plasma samples at disease progression in ALK-positive non-small cell lung cancer patients who received second-generation ALK TKI treatment, including Alecensa (alectinib) (n=46), Zykadia (ceritinib) (n=4), Alunbrig (brigatinib) (n=3), Ensartinib (X-396) (n=1), or more than 2 lines of TKIs (n=16) (PMID: 31358542). 31358542